new research on cholesterol and heart disease

New Cholesterol Guidelines Could Drastically Reduce Statin Use for Millions

Adopting new PREVENT equations could lead to a significant reduction in statin recommendations, impacting 40% of currently eligible U.S. adults, and highlights the importance of precise risk assessment and patient communication in cholesterol management.

If national guidelines were updated to include a new risk equation, approximately 40% fewer individuals may qualify for cholesterol-lowering statins to prevent heart disease, suggests a study involving researchers from the University of Pittsburgh , Beth Israel Deaconess Medical Center , and University of Michigan . The research, published in JAMA Internal Medicine , explores the implications of broadly implementing the PREVENT equations, introduced by the American Heart Association in November 2023. These equations are intended to refine the tools doctors use to estimate a patient’s 10-year risk of a heart attack or stroke.

At a population level, the number of adults recommended for statins could decrease from 45.4 million to 28.3 million. At the same time, the study showed that most people who would be recommended to take statins are not currently taking them.

“This is an opportunity to refocus our efforts and invest resources in the populations of patients at the highest risk,” said lead author Dr. Timothy Anderson, M.D., M.A.S., a primary care physician at UPMC and health services researcher and assistant professor of medicine at Pitt.

Methodology of the Study

For their analysis, the team used nationally representative data from 3,785 adults, ages 40 to 75, who participated in the National Health and Nutrition Examination Survey from January 2017 to March 2020. The researchers estimated the 10-year risk of atherosclerotic cardiovascular disease (ASCVD) using the Predicting Risk of cardiovascular disease EVENTs (PREVENT) equations and compared the results to risk estimated using the previous tool, known as Pooled Cohort Equations (PCE). The PREVENT equations were developed by the American Heart Association to more accurately represent risk across the current U.S. population, as the PCE equations were based on patient data that were decades old and lacked diversity.

PREVENT also reflects more recent insights into the biology of ASCVD. Current statin use as well as metabolic and kidney diseases are incorporated into the new calculation, while race has been removed from it, reflecting a growing awareness that race is a social construct.

Using PREVENT, the team found that among the study’s entire cohort, the 10-year risk of developing ASCVD was 4%, half as high as the risk calculated by the PCE (8%). The difference was even larger for Black adults (5.1% versus 10.9%) and for adults between the ages of 70 and 75 (10.2% versus 22.8%).

An estimated 4.1 million patients who are currently taking statins would no longer be recommended to take them based on PREVENT. For these patients and their physicians, clear and careful communication is key, said Anderson. “We don’t want people to think they were treated incorrectly in the past. They were treated with the best data we had when the PCE was introduced back in 2013. The data have changed.”

At the same time, it’s important to note that everyone’s risk will inevitably change over time, as well, he added. “For a patient who we now know is at lower risk than we previously thought, if we recommend they stop taking statins, they still could be back to a higher risk five years down the road, for the simple reason that everybody’s risk goes up as we get older.”

Reference: “Atherosclerotic Cardiovascular Disease Risk Estimates Using the Predicting Risk of Cardiovascular Disease Events Equations” by Timothy S. Anderson, Linnea M. Wilson and Jeremy B. Sussman, 10 June 2024, JAMA Internal Medicine . DOI: 10.1001/jamainternmed.2024.1302

Other authors on the study were Linnea Wilson, M.P.H., of Beth Israel Deaconess Medical Center, and Jeremy B. Sussman, M.D., M.P.H., of University of Michigan, Ann Arbor.

This research was supported by the National Institute on Aging (#K76AG074878).

Related Posts

Higher olive oil consumption linked with lower risk of dying from heart disease or cancer, walking is good, but moderate-vigorous exercise boosts fitness 3x more, new study provides reassuring data on myocarditis heart condition after mrna covid vaccination, new research finds eating lots of avocados has public health benefits for issues like obesity, the latest research on coffee and your risk for heart rhythm problems – good news, low-dose aspirin use for heart disease may reduce likelihood of covid-19 infection, popular energy drinks’ harmful effects on heart revealed in new research, vape flavorings are cardiotoxic and can damage the heart, covid-19’s impact on the heart – an in-depth look.

“…, while race has been removed from it, reflecting a growing awareness that race is a social construct.”

Statistics don’t support that naive, woke view. The social ideology behind such decisions may end up costing the lives of minorities who have a predisposition for certain diseases. Whether a particular race has predispositions for certain diseases is well established. What is less well understood is why the predispositions exist. However, be that as it may, pretending that race doesn’t correlate can be deadly because those susceptible may be less alert for symptoms. “The road to Hell is paved with good intentions.”

Everything about this study is useless. Read the article carefully and you will see all of the contradictions. When woke ideologies enter into medical research the results are corrupted .The fact is that statins are useless and dangerous. If you want to take a pill every day to lower cholesterol then take one of many natural supplements that have proven to work as well or better. Garlic and bergamot lowered my cholesterol significantly. The pharmaceutical companies have sponsored bogus studies to lie to the public about the facts. More corporate greed at the expense of our health.

Statins have been around for decades and the side effects, if any, are minimal. It is a proven fact that they are safe. I tend to trust my cardiologist more than conspiracy theories from social media. This article does not change anything for any sane person. Listen to your cardiologist.

If I’m 40 years old, I care about my 40 year risk, not my 10 year risk. Unless you are over 70, 10 year risk is extremely short sighted. My dad has always had marginally high LDL (between 100 and 130). Doctors never prescribed him statins because his 10 year risk was low. Now at age 74 he needs open heart surgery to clear plaques in the artery going to his heart. Meanwhile my mom had LDL above 250 in her 40s and was prescribed statins for decades keeping her LDL around 70-80 and her heart is perfectly fine.

If race is just a social construct, why is it hereditary?

Save my name, email, and website in this browser for the next time I comment.

Type above and press Enter to search. Press Esc to cancel.

An official website of the United States government

Here’s how you know

Official websites use .gov A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS A lock ( A locked padlock ) or https:// means you’ve safely connected to the .gov website. Share sensitive information only on official, secure websites.

• Heart-Healthy Living
• High Blood Pressure
• Sickle Cell Disease
• Sleep Apnea
• Information & Resources on COVID-19
• The Heart Truth®
• Learn More Breathe Better®
• Blood Diseases & Disorders Education Program
• Publications and Resources
• Clinical Trials
• Blood Disorders and Blood Safety
• Sleep Science and Sleep Disorders
• Lung Diseases
• Health Disparities and Inequities
• Heart and Vascular Diseases
• Precision Medicine Activities
• Obesity, Nutrition, and Physical Activity
• Population and Epidemiology Studies
• Women’s Health
• Research Topics
• All Science A-Z
• Grants and Training Home
• Policies and Guidelines
• Funding Opportunities and Contacts
• Training and Career Development
• Email Alerts
• NHLBI in the Press
• Research Features
• Ask a Scientist
• Past Events
• Upcoming Events
• Mission and Strategic Vision
• Divisions, Offices and Centers
• Advisory Committees
• Budget and Legislative Information
• Jobs and Working at the NHLBI
• Contact and FAQs
• NIH Sleep Research Plan
• News and Events
• < Back To All News

Study challenges “good” cholesterol’s role in universally predicting heart disease risk

Lower levels of HDL cholesterol were associated with increased risks for heart attacks in white but not Black adults, and higher levels were not protective for either group

A National Institutes of Health-supported study found that high-density lipoprotein (HDL) cholesterol, often called the “good cholesterol,” may not be as effective as scientists once believed in uniformly predicting cardiovascular disease risk among adults of different racial and ethnic backgrounds. The research, which published in the Journal of the American College of Cardiology , found that while low levels of HDL cholesterol predicted an increased risk of heart attacks or related deaths for white adults – a long-accepted association – the same was not true for Black adults. Additionally, higher HDL cholesterol levels were not associated with reduced cardiovascular disease risk for either group.

“The goal was to understand this long-established link that labels HDL as the beneficial cholesterol, and if that’s true for all ethnicities,” said Nathalie Pamir, Ph.D., a senior author of the study and an associate professor of medicine within the Knight Cardiovascular Institute at Oregon Health & Science University, Portland. “It’s been well accepted that low HDL cholesterol levels are detrimental, regardless of race. Our research tested those assumptions.”

To do that, Pamir and her colleagues reviewed data from 23,901 United States adults who participated in the Reasons for Geographic and Racial Differences in Stroke Study (REGARDS). Previous studies that shaped perceptions about “good” cholesterol levels and heart health were conducted in the 1970s through research with a majority of white adult study participants. For the current study, researchers were able to look at how cholesterol levels from Black and white middle-aged adults without heart disease who lived throughout the country overlapped with future cardiovascular events. Study participants enrolled in REGARDS between 2003-2007 and researchers analyzed information collected throughout a 10- to 11-year period. Black and white study participants shared similar characteristics, such as age, cholesterol levels, and underlying risk factors for heart disease, including having diabetes, high blood pressure, or smoking. During this time, 664 Black adults and 951 white adults experienced a heart attack or heart attack-related death. Adults with increased levels of LDL cholesterol and triglycerides had modestly increased risks for cardiovascular disease, which aligned with findings from previous research.

However, the study was the first to find that lower HDL cholesterol levels only predicted increased cardiovascular disease risk for white adults. It also expands on findings from other studies showing that high HDL cholesterol levels are not always associated with reduced cardiovascular events. The REGARDS analysis was the largest U.S. study to show that this was true for both Black and white adults, suggesting that higher than optimal amounts of “good” cholesterol may not provide cardiovascular benefits for either group.

“What I hope this type of research establishes is the need to revisit the risk-predicting algorithm for cardiovascular disease,” Pamir said. “It could mean that in the future we don’t get a pat on the back by our doctors for having higher HDL cholesterol levels.”

Pamir explained that as researchers study HDL cholesterol’s role in supporting heart health, they are exploring different theories. One is quality over quantity. That is, instead of having more HDL, the quality of HDL’s function – in picking up and transporting excess cholesterol from the body – may be more important for supporting cardiovascular health . They are also taking a microscopic look at properties of HDL cholesterol, including analyzing hundreds of proteins associated with transporting cholesterol and how varying associations, based on one protein or groups of proteins, may improve cardiovascular health predictions.

“HDL cholesterol has long been an enigmatic risk factor for cardiovascular disease,” explained Sean Coady, a deputy branch chief of epidemiology within the National Heart, Lung, and Blood Institute (NHLBI)’s Division of Cardiovascular Sciences. “The findings suggest that a deeper dive into the epidemiology of lipid metabolism is warranted, especially in terms of how race may modify or mediate these relationships.” The authors conclude that in addition to supporting ongoing and future research with diverse populations to explore these connections, the findings suggest that cardiovascular disease risk calculators using HDL cholesterol could lead to inaccurate predictions for Black adults.

“When it comes to risk factors for heart disease, they cannot be limited to one race or ethnicity,” said Pamir. “They need to apply to everyone.”

The REGARDS study is co-funded by the National Institute of Neurological Disorders and Stroke and the National Institute of Aging and received additional support from NHLBI. To learn more about cholesterol and heart health, visit https://www.nhlbi.nih.gov/health/blood-cholesterol . To learn about heart-healthy living, visit https://www.nhlbi.nih.gov/health/heart-healthy-living . Study: Zakai NA, Minnier J, Safford MM, et al. Race-dependent association of high-density lipoprotein cholesterol levels with incident coronary artery disease. J Am Coll Cardiol . 2022; doi: 10.1016/j.jacc.2022.09.027.

About the National Heart, Lung, and Blood Institute (NHLBI):  NHLBI is the global leader in conducting and supporting research in heart, lung, and blood diseases and sleep disorders that advances scientific knowledge, improves public health, and saves lives. For more information, visit  www.nhlbi.nih.gov .

About the National Institutes of Health (NIH):  NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit  www.nih.gov .

More Information

Related health topics, health education, related news.

Masks Strongly Recommended but Not Required in Maryland, Starting Immediately

Due to the downward trend in respiratory viruses in Maryland, masking is no longer required but remains strongly recommended in Johns Hopkins Medicine clinical locations in Maryland. Read more .

• Vaccines  
• Masking Guidelines
• Visitor Guidelines  

Study Suggests ‘Remnant Cholesterol’ As Stand-alone Risk for Heart Attack and Stroke

.@HopkinsMedicine researchers suggest “remnant #cholesterol” could become sole predictor of #HeartAttack, #Stroke risk beyond #LDL, AKA “bad cholesterol.” @rquispe183 @hopkinsheart #EuropeanHeartJournal ›

An analysis of data gathered from more than 17,000 adults by Johns Hopkins Medicine researchers supports the belief that so-called “remnant cholesterol” (RC) provides an accurate stand-alone metric — just as doctors currently use measures of low-density lipoprotein (LDL) — for predicting risk of clogged arteries, heart attacks and strokes. In fact, the researchers say, an RC measure may detect the potential for disease when LDL levels do not.

Remnant cholesterol represents the amount of cholesterol in remnant lipoproteins, a form of very low-density lipoproteins (VLDL) from which sugary fatty acids — called triglycerides — have been removed. Along with traditional measurements of blood LDL cholesterol (frequently called “bad cholesterol”) levels, the cholesterol within remnant lipoproteins has been studied as an additional means of assessing a person’s risk for developing cardiovascular disease and stroke.

Remnant cholesterol levels are basically calculated as the total cholesterol amount minus the LDL and high-density lipoprotein cholesterol (HDL, the so-called “good cholesterol”) counts.

In their study, first published July 19, 2021, in the European Heart Journal , the researchers suggest that for people with relatively low levels of LDL cholesterol, a measured RC level greater than 24 micrograms per deciliter (24 millionths of a gram in a little more than a quart) of blood have a 40–50% higher risk for major heart disease or stroke.

“For decades, the thought was that people with low LDL cholesterol levels and relatively high levels of HDL cholesterol [the so-called “good cholesterol”] were at low risk for major heart disease,” says study lead author Renato Quispe, M.D., M.H.S. , a cardiovascular disease clinical and research fellow at the Johns Hopkins University School of Medicine. “But over time, studies kept suggesting that remnant cholesterol was a predictor of heart disease, independent of LDL cholesterol levels.”

To better assess the purported link between remnant cholesterol and disease risk, the Johns Hopkins Medicine team pooled information on 17,532 adults, obtained from three U.S. research databases. The data were from men and women between the ages of 30 and 68, who had no history of atherosclerotic cardiovascular disease (buildup of fatty plaque inside arteries) when they were originally studied. Data included cholesterol levels and other important cardiovascular risk factors, as well as which people developed major heart disease or stroke after recruitment to one of the databases.

The new study found that almost one of five individuals with levels of RC at or greater than 24 micrograms per deciliter experienced major heart disease or stroke within the following 18 years. Interestingly, say the researchers, this proportion was similar to those who had relatively low LDL cholesterol.

After accounting for non-cholesterol-related heart disease risk factors — such as tobacco use, high blood pressure, diabetes, advanced age and race (Blacks are at higher risk) — the researchers found a steady link between higher than normal RC and major heart disease.

Another important finding, the researchers claim, is that individuals with higher levels of RC also had more obesity and diabetes, and almost everyone had high triglyceride levels.

“We’re not saying LDL cholesterol is a poor measure of cardiovascular disease risk,” Quispe notes. “Instead, our analysis suggests that LDL should remain an important assessment tool; however, clinicians also should look at remnant cholesterol because it indicates a significant amount of risk on its own.”

Quispe emphasizes that calculating remnant cholesterol can be done easily with data available from a standard lipid panel — a test commonly given to patients by their doctors.

The U.S. Centers for Disease Control and Prevention estimates that 38 percent of the American adult population has high levels of total cholesterol, and one in four shows high levels of triglycerides. One-third of all deaths in this country are attributed to heart disease, stroke and other cardiovascular disease.

Quispe says future studies are likely to increase attention to remnant cholesterol measures and encourage clinical trials of drugs and lifestyle changes designed to reduce the risk of the diseases for which they provide warning.

Quispe is available for interviews.

In two studies, experimental drugs for cholesterol show ‘revolutionary’ promise

New, experimental drugs designed to drive down dangerous levels of cholesterol were shown to be safe and effective in two groundbreaking bodies of research presented Sunday at an annual meeting of the American Heart Association.

Both medications target people born with a genetic predisposition to high cholesterol. While drugs like statins , as well as diet and exercise, can help these individuals manage cholesterol, they cannot change the underlying genetic cause.

The two new approaches work in different ways, but with a singular mission: go after genes responsible for raising cholesterol to change the trajectory of a person’s risk for heart attack and stroke .

Neither treatment had ever been tested in humans before. And both will need years of additional research before they'd be considered for approval by the Food and Drug Administration. Still, experts are impressed with the results.

"There is no way to categorize this other than revolutionary," said Dr. Hugh Cassiere, director for critical care services at South Shore University Hospital, Northwell Cardiovascular Institute in New York. Cassiere was not involved with either study.

A tiny change to a gene

One of the treatments, from Boston-based Verve Therapeutics, uses a gene-editing approach called base editing. It involves an IV infusion of a drug that targets the PCSK9 gene, which is instrumental in the production of LDL, often called "bad" cholesterol .

When the drug zeroes in on PCSK9, it makes a tiny change to the gene. The effect is akin to a permanent eraser, removing its ability to raise cholesterol, said Dr. Sekar Kathiresan, Verve's co-founder and chief executive officer.

In theory, the one-time treatment should last a lifetime. Patients so far have only been followed for six months.

Verve's preliminary study, which was presented on Sunday, was meant to test the safety of the drug. Ten patients participated. Most received doses that didn't make a measurable difference in their LDL levels, but were found to be safe.

Three patients, however, were given higher doses — and their LDL cholesterol levels were reduced by more than half. Additional studies will be needed to ensure the treatment remains safe, without unexpected side effects, and effective.

Verve's research was limited to people with a genetic condition called heterozygous familial hypercholesterolemia , in which cholesterol levels are sky-high from birth. Many people affected suffer heart attacks at young ages, in their 30s or 40s.

Kathiresan, a cardiologist who previously worked at Massachusetts General Hospital and was a professor of medicine at Harvard Medical School, has long focused his research on understanding why some people have heart attacks at young ages, and why others do not. He has a strong family history of high cholesterol. In 2012, his brother died from a heart attack at age 40.

That's when Kathiresan decided "to try to develop a therapy that could avert tragedies like what's happened in my family."

It is unclear whether the approach will make a measurable impact on heart attack and stroke risk — that remains to be seen in future studies.

Experts were still optimistic about the technology.

"While larger and longer-term studies are required to assess both effectiveness, durability and safety, this should be the dawn of an era of therapeutic gene targeting for cardiovascular disease," said Dr. Sahil Parikh, director of endovascular services at Columbia University Irving Medical Center in New York. Parikh was not involved with Verve's research.

Shooting the messenger

Findings on a second novel therapy were also presented on Sunday.

The results, though early, offer a promising glimpse of what could be the first treatment for a particularly dangerous type of cholesterol called lipoprotein(a).

People with high levels of Lp(a) are at extremely high risk of having fats and cholesterol build up in their arteries.

That's because Lp(a) gloms onto LDL cholesterol, making those LDL particles even stickier and more likely to cause plaque.

It's like adding super glue to duct tape. And it's purely genetic, meaning that people are born with this elevated risk. Diet and exercise have no impact on Lp(a) levels.

"It is essentially untreatable," said study author Dr. Steven Nissen, chief academic officer of the Heart, Vascular & Thoracic Institute at Cleveland Clinic. "The only way to target such a genetic risk factor is to find a way to interfere with the product of the gene."

Nissen and colleagues used a novel approach to correcting how that gene acts.

They used a drug called lepodisiran, which targets mRNA. If that sounds familiar, it should: Most Covid vaccines use mRNA to prompt the body to make an antibody against SARS-CoV-2.

In this case, the mRNA in question tells the body to produce Lp(a). The drug stops this from happening, essentially shooting the messenger.

Nissen's study was meant to test the safety of lepodisiran. It was small, including just 48 adults in the U.S. and Singapore. All had very high levels of Lp(a). Overall, the drug was found to be safe, with no major side effects, Nissen said.

But it also dramatically lowered their Lp(a) levels. A single shot of lepodisiran drove down Lp(a) by more than 94% for nearly one year, the study found.

The results of the study, which was sponsored by drugmaker Eli Lilly, were published Sunday in the Journal of the American Medical Association .

"This really offers a lot of hope for patients with elevated lipoprotein(a)," Nissen said. "We're working as fast as we can because there are patients dying every day because of this disorder. We've not been able to treat it, and we need to change that."

As many as 64 million Americans have elevated Lp(a) levels, most commonly people of African and South Asian descent.

Additional research is critical. An important question moving forward is whether lowering Lp(a) actually cuts heart risks.

"We've had to wait until this generation of therapeutics where we can directly and specifically target Lp(a) and do it safely to see whether that will also result in fewer heart attacks and strokes," said Dr. Donald Lloyd-Jones, professor and chair of the department of preventive medicine Northwestern Feinberg School of Medicine in Chicago. Lloyd-Jones, also a past president of the American Heart Association, was not involved with the lepodisiran study.

Nissen predicts that the treatment could someday be used as an "annual vaccine-like treatment for this previously untreatable disorder."

While many heart problems may be avoided with lifestyle changes such as exercise and healthy diets, Lloyd-Jones said, the medical community needs therapies to help people whose genes put them at greater risk for heart attacks and stroke.

"We'll always need some medication for people who are at very high risk," he said.

Follow  NBC HEALTH  on  Twitter  &  Facebook .

Erika Edwards is a health and medical news writer and reporter for NBC News and "TODAY."

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

• View all journals
• Explore content
• About the journal
• Publish with us
• Sign up for alerts
• Review Article
• Open access
• Published: 02 August 2022

Regulation of cholesterol homeostasis in health and diseases: from mechanisms to targeted therapeutics

• Yajun Duan 1 , 2 ,
• Ke Gong 2 ,
• Suowen Xu 1 ,
• Feng Zhang 2 ,
• Xianshe Meng 2 &
• Jihong Han 2 , 3  

Signal Transduction and Targeted Therapy volume  7 , Article number:  265 ( 2022 ) Cite this article

23k Accesses

106 Citations

7 Altmetric

Metrics details

• Cardiovascular diseases
• Molecular medicine

Disturbed cholesterol homeostasis plays critical roles in the development of multiple diseases, such as cardiovascular diseases (CVD), neurodegenerative diseases and cancers, particularly the CVD in which the accumulation of lipids (mainly the cholesteryl esters) within macrophage/foam cells underneath the endothelial layer drives the formation of atherosclerotic lesions eventually. More and more studies have shown that lowering cholesterol level, especially low-density lipoprotein cholesterol level, protects cardiovascular system and prevents cardiovascular events effectively. Maintaining cholesterol homeostasis is determined by cholesterol biosynthesis, uptake, efflux, transport, storage, utilization, and/or excretion. All the processes should be precisely controlled by the multiple regulatory pathways. Based on the regulation of cholesterol homeostasis, many interventions have been developed to lower cholesterol by inhibiting cholesterol biosynthesis and uptake or enhancing cholesterol utilization and excretion. Herein, we summarize the historical review and research events, the current understandings of the molecular pathways playing key roles in regulating cholesterol homeostasis, and the cholesterol-lowering interventions in clinics or in preclinical studies as well as new cholesterol-lowering targets and their clinical advances. More importantly, we review and discuss the benefits of those interventions for the treatment of multiple diseases including atherosclerotic cardiovascular diseases, obesity, diabetes, nonalcoholic fatty liver disease, cancer, neurodegenerative diseases, osteoporosis and virus infection.

Similar content being viewed by others

Mechanisms and regulation of cholesterol homeostasis

Dysregulation of cholesterol metabolism in cancer progression

Functional significance of cholesterol metabolism in cancer: from threat to treatment

Introduction.

Cholesterol is a waxy and fat-like substance with pivotal pathophysiological relevance in humans. More than two centuries ago, Michel Eugène Chevreul, a French chemist, found that cholesterol is one of the components in human gallstones. 1 Following this event, many scientists input a lot efforts to elucidate cholesterol structure. In 1927, Heinrich Otto Wieland from Germany won the Nobel Prize in Chemistry for his work on clarifying the structure of cholesterol and bile acids. A year later, Adolf Windaus also from Germany was awarded the Nobel Prize in Chemistry for his work on sterols and the related vitamins, such as vitamin D which is derived from cholesterol. 2 However, it was until 1932, the correct cholesterol structure was finally formulated. 1

Cholesterol can be synthesized in our body and the biosynthesis of this complex molecule starts from acetyl coenzyme A (acetyl-CoA) with involvement of nearly 30 enzymatic reactions. Among these reactions, the step for reduction of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) to mevalonate catalyzed by HMG-CoA reductase (HMGCR) is rate-limiting, indicating regulation of HMGCR expression/activity is critical for cholesterol biosynthesis. In 1964, Konrad Emil Bloch and Feodor Lynen won the Nobel Prize in the Medicine and Physiology for discovering the major intermediate reactions in the pathway for cholesterol biosynthesis. 3

The cholesterol biosynthesis is an intensely regulated process biologically. 4 The first demonstration of feedback inhibitory loop by the end product in biosynthetic pathways is that cholesterol inhibits its own synthesis intracellularly. In 1933, Rudolph Schoenheimer demonstrated that animals can also synthesize cholesterol, more importantly, he observed that the cholesterol synthesis in animal body was inhibited by cholesterol supplied in the diet. This finding laid the groundwork for discovering sterol regulatory element binding protein (SREBP) pathway. 5 SREBP binds to the sterol regulatory element (SRE) in the proximal region of the promoter of HMGCR . The binding of SREBP triggers transcription of HMGCR to speed up cholesterol biosynthesis. 6 SREBP is also able to bind to the SRE in the promoter of low-density lipoprotein receptor ( LDLR ), the molecule responsible for the LDL cholesterol (LDL-C) clearance in the liver. 6 As a transcription factor, SREBP needs to be chaperoned by SREBP cleavage activating protein (SCAP) from endoplasmic reticulum (ER) to Golgi, where SREBP is cleaved into mature and functional form by sphingosine-1-phosphate (S1P) and S2P proteases. Cholesterol can interact with unmatured SREBP on the ER. 6 , 7 Thus, when the cellular cholesterol level is reduced, the mature SREBP is increased and consequently to activate HMGCR expression. Reciprocally, increased cellular cholesterol level inhibits HMGCR expression. 8

Mounting evidence has established the intricate link between cholesterol levels and atherosclerotic cardiovascular disease (ASCVD). In fact, atherosclerosis is a disease with a long research history. The role of cholesterol in atherosclerosis was initially reported in 1910. 9 Adolf Windaus found that cholesterol content in atherosclerotic plaques of human diseased aorta was 25 times higher than that of normal aortas. 8 Three years later, the first experimental recapitulation of atherosclerosis was completed by Nikolaj Anitschkow. He fed rabbits pure cholesterol contained in diet, and observed severe atherosclerosis in aortas of the animals. 10 In history, Robert Wissler and coworkers set up the first mouse model for atherosclerosis in 1960s. 11 Now, the mice with genetic manipulation, such as ApoE or LDLR deficient mice, is the most frequently-used animal model for investigation on atherosclerosis based on the time and cost issues.

Accumulation of cholesterol in atherosclerotic plaques may lead to formation of cholesterol crystals, a hallmark of advanced atherosclerotic plaques. 12 , 13 , 14 Cholesterol crystals can stimulate the generation of NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome to promote inflammation and accelerate atherogenesis. 15 , 16 It also induces arterial inflammation and involves in destabilizing atherosclerotic plaques. 17 Currently, the critical role of inflammation in mediating all stages of atherosclerosis has been well defined, and targeting inflammatory pathways may provide a new notion for atherosclerosis prevention and/or treatment. 18 , 19

Cholesterol is a hydrophobic molecule which travels through the bloodstream on proteins called “lipoproteins”. Ultracentrifuge was used to separate lipoproteins in plasma by John Gofman. He also demonstrated that heart attacks were associated with increased blood cholesterol levels, especially LDL-C. In contrast, when blood high-density lipoprotein (HDL) levels rise, the heart attack frequency was reduced. 20 , 21 , 22 Moreover, the beneficial effects of HDL cholesterol (HDL-C) and the negative effects of LDL-C on heart diseases were further confirmed by the Framingham Heart Study, one of the most important epidemiological studies in cardiovascular arena. 23

It was first time that Carl Müller discovered the genetic link between cholesterol and heart attacks. He demonstrated that families with high plasma cholesterol levels and early-onset heart disease are autosomal dominant traits. 24 This kind of disease is called familial hypercholesterolemia (FH). Avedis Khachadurian described two different clinical forms of FH in inbred families. Homozygous patients showed severe hypercholesterolemia at birth (the plasma cholesterol level in this kind of patients is about 800 mg/dl), and they can have heart attack as early as 5 years old, while the heterozygous patients showed cholesterol levels of 300–400 mg/dl and early-onset heart attack usually between 35-60 years old. 25 In 1970s, Joseph Goldstein and Michael Brown discovered the essence of LDLR functional defect in FH, which led them to be awarded the Nobel Prize in 1985. 26 The cellular uptake of LDL requires LDLR and most LDL-C is cleared from circulation by LDLR expressed in the liver. In the absence of LDLR, LDL-C reaches high level in the circulation, eventually deposits in the artery to drive the formation of atherosclerotic plaques. 27 The seminal work by Goldstein and Brown strongly supports the importance of lipid hypothesis in onset of cardiovascular diseases (CVD). In addition to HMGCR, SREBP also regulates LDLR expression in response to cellular cholesterol levels to fine-tune the cholesterol level in cell membranes constant. 6 , 7 , 8

Based on the evidence from epidemiological studies and randomized clinical trials, a cholesterol hypothesis was suggested which indicates the high circulating cholesterol level as a major risk factor for ASCVD while cholesterol-lowering strategies can reduce ASCVD risk. 28 In 1976, Akira Endo discovered the first HMGCR inhibitor, thus inaugurating a category of cholesterol-lowering drugs called statins, which is a therapeutic milestone for CVD treatment. 29 Statins deprive hepatocytes of endogenous synthesis as a source of cholesterol, which can alleviate the feedback inhibition of LDLR, and thus the increased LDLR expression will further reduce plasma LDL-C levels. 30 In 1987, lovastatin (Mevacor) developed by Merck was approved as the first statin for human use to lower plasma LDL-C. Currently, statins are used as the first-line therapy to reduce LDL-C and prevent ASCVD. 31

However, the doubled dose of a statin only leads to about 6% increase in LDL-C lowering efficacy, which may cause statin resistance/intolerance. 32 Thus, there is a need to develop novel lipid-lowering approaches beyond statins. In 2002, ezetimibe was introduced as an intestinal cholesterol absorption inhibitor to decrease total cholesterol (TC) and LDL-C levels. In 2003, Nabil Seidah and co-workers discovered proprotein convertase subtilisin/kexin type 9 (PCSK9). 33 PCSK9 is synthesized in the liver and then secreted into plasma. The circulating PCSK9 can bind hepatic LDLR and disrupt the recycle in which LDLR returns to the cell surface after internalization and release of the bound LDL-C. 34 , 35 The decrease of cell surface LDLR results in impaired LDL-C clearance and elevated LDL-C level. In 2015, alirocumab and evolocumab, the fully human anti-PCSK9 antibodies, were approved by US FDA to treat patients with hypercholesterolemia. 36 Likewise, a long-acting synthetic siRNA targeting PCSK9 mRNA called inclisiran was developed by Novartis and used to treat hypercholesterolemia. In 2020, inclisiran was approved by EU. 37 ATP citrate lyase (ACLY) is a cytoplasmic enzyme catalyzing acetyl-CoA generation, with which cholesterol biosynthesis begins. 38 Thus, inhibition of ACLY can also reduce cholesterol synthesis. Indeed, among ACLY inhibitors, bempedoic acid was approved by US FDA in 2020 for hypercholesterolemia treatment. 39 Notably, bempedoic acid only acts locally in the liver, thereby avoiding the muscle-related toxicities associated with statin use. 40

Taken together, when reviewing the milestones of cholesterol research, we realize that the findings in regulation of cholesterol homeostasis determined the progress on the development of therapeutic strategies, and the feedback from clinical observations may further advance the investigation on cholesterol homeostasis, thereby promoting clinical progress. “HMGCR-statin-LDLR-rule of 6%-PCSK9” should be a typical example. To lower cholesterol synthesis in the liver, statins were initially developed to inhibit HMGCR. Later on, Brown and Goldstein proved that statins increased LDLR on hepatocyte surfaces to soak up excess blood LDL-C, thereby reducing heart attack. Associated with wide use of statins in clinics, the “rule of 6%” was observed, which was mysterious until the discovery of PCSK9. SREBP-2 activates LDLR and PCSK9 expression simultaneously and activated PCSK9 binds to LDLR toward lysosomal degradation, which clearly antagonizes the efficacy of statin-induced LDL-C clearance. Therefore, PCSK9 has become a valuable therapeutic target for cholesterol-lowering therapy and PCSK9 inhibitors have been developed rapidly.

Nowadays, the cholesterol homeostasis is involved in development of various diseases and determined by processes of biosynthesis, uptake, efflux, transport, storage, utilization, and/or excretion. Therefore, in this article, we will summarize the key regulations in cholesterol homeostasis and cholesterol-lowering interventions. Furthermore, we will discuss the benefits of the pharmaceutical interventions targeting cholesterol homeostasis on the multiple related diseases, such as ASCVD, obesity, diabetes and more.

The references used in this review were acquired using the PubMed search engine with a time range from January 1930 to April 2022 by four researchers (Y. D., K. G., F. Z. and X. M.) independently. A list of relevant literature that met the inclusion criteria was manually searched. The following search strategy was applied by using the keywords of “cholesterol history”, “cholesterol development”, “cholesterol metabolism”, “cholesterol homeostasis”, “cholesterol synthesis”, “cholesterol transport”, “ASCVD cholesterol”, “ASCVD cholesterol ester”, “ASCVD foam cells”, “ASCVD statins”, “ASCVD ezetimibe”, “ASCVD PCSK9 inhibitor”, “ASCVD bempedoic acid”, “ASCVD bile acid sequestrants”, “ASCVD lomitapide”, “ASCVD evinacumab”, “ASCVD fibrates”, “ASCVD lipoprotein apheresis”, “ASCVD APOC3”, “ASCVD lipoprotein (a)”, “ASCVD LXRs”, “ASCVD LOX-1”, “ASCVD SR-BI”, “ASCVD LCAT”, “ASCVD MiR-33”, “ASCVD MiR-122”, “ASCVD prekallikrein”, “cholesterol homeostasis NAFLD”, “cholesterol homeostasis obesity”, “cholesterol homeostasis diabetes”, “cholesterol homeostasis Alzheimer’s disease”, “cholesterol homeostasis Parkinson’s disease”, “cholesterol homeostasis Huntington’s disease”, “cholesterol homeostasis cancer”, “cholesterol homeostasis osteoporosis”, or “cholesterol virus infection”. No additional restrictions were placed on the type of research model (in vivo / in vitro), article type (e.g., research article, review, editorial, letter, etc.), or publication language. References cited in articles associated with the literature search were also analyzed for additional information. The studies were excluded from the content retrieved if they are irrelevant or of limited relevance to the main topic.

Regulatory mechanisms of cholesterol homeostasis

Disturbed cholesterol homeostasis is not only the pathological basis of cardiovascular and cerebrovascular diseases, but also participates in the progression of other kinds of diseases including neurodegenerative diseases and cancers. Maintaining cholesterol homeostasis plays a crucial role physiologically. Normally, the cholesterol homeostasis can be well maintained by a dynamic balance among the intake, biosynthesis, transport, cellular uptake and efflux, and/or esterification. Thus, we will review the state-of-the-art research on the molecular mechanisms that regulate cholesterol homeostasis, and provide future research directions.

Sources of cholesterol: intake or biosynthesis

Dietary cholesterol.

Two main sources of cholesterol are present in our body, one is through dietary intake, known as exogenous cholesterol or dietary cholesterol; and another one is through the de novo biosynthesis, known as endogenous cholesterol. 41 A variety of daily foods, such as eggs, animal offal and seafood, contain cholesterol, of which eggs are the main source of dietary cholesterol. 42 The solubility of cholesterol in an aqueous environment is extremely low, so before absorption, it must be dissolved into bile salt micelles, which can be transported to the brush edge of intestinal cells. Then the net cholesterol is absorbed, the process is regulated by Niemann-Pick C1 (NPC1) like 1 (NPC1L1) protein. Inhibition of NPC1L1 by ezetimibe can reduce cholesterol absorption, thereby improving coronary artery disease. 43 After a series of processes, the absorbed cholesterol is esterified and then secreted into circulation as chylomicrons and eventually being taken up by the liver. 44 , 45 In addition, phytosterols/phytostanols can be added into the foods to replace cholesterol in micelles, leading to less cholesterol is absorbed by enterocytes and enters the liver. 46

To maintain hepatic cholesterol pool, the liver enhances LDL-C uptake from plasma by increasing LDLR expression and decreases cholesterol efflux, thereby reducing plasma TC and LDL-C levels. 47 NPC1L1 promoter also contains a SRE, the sterol-sensing structural domain, therefore, NPC1L1 expression is repressed by a high-cholesterol contained diet and increased by cholesterol-depleted food. 48 In addition, endogenous cholesterol synthesis is negatively regulated by the exogenous cholesterol. Hepatic cholesterol biosynthesis accounts for approximately three-quarters of the total endogenous cholesterol production at the low cholesterol intake situation. However, hepatic cholesterol biosynthesis is completely inhibited when 800–1000 mg exogenous cholesterol is ingested in experiments with baboons and humans. 49 , 50

Biosynthesis of cholesterol

Cholesterol can be synthesized by all nucleated cells, with most by hepatocytes, indicating the liver is the main site for cholesterol biosynthesis in vivo. 51 Acetyl-CoA is used as the starting material for cholesterol biosynthesis via the mevalonate pathway including nearly 30 enzymatic steps (Fig. 1 ). The biosynthesis of cholesterol can be divided into four stages: (I) Synthesis of mevalonate (MVA); (II) Production of isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP); (III) Synthesis of squalene; (IV) Squalene cyclizes to form lanosterol and subsequently to synthesize cholesterol. The process is regulated by a negative feedback mechanism with the downstream products. 52 , 53 The SREBP pathway and the HMGCR degradation pathway serve as two major negative feedback regulatory mechanisms to regulate cholesterol de novo synthesis. 54

The pathway for cholesterol biosynthesis. In cholesterol biosynthesis, all the carbon atoms are derived from acetyl-CoA. The biosynthesis of cholesterol can be divided into four stages. (I) Synthesis of mevalonate (MVA). Two molecules of acetyl-CoA are reversely catalyzed by thiolase to form acetoacetyl-CoA. Acetoacetyl-CoA and acetyl-CoA are catalyzed to form 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) by HMG-CoA synthase (HMGCS). Finally, the HMG-CoA is catalyzed by HMG-CoA reductase (HMGCR) to convert to MVA, a step that requires two molecules of NADPH and H + and determines the rate of cholesterol biosynthesis. (II) Production of isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP). MVA is sequentially phosphorylated twice by mevalonate kinase and phosphomevalonate kinase to produce 5-pyrophosphate mevalonate, which is further decarboxylated by 5-pyrophosphatemevalonate decarboxylase to produce isopentenyl pyrophosphate (IPP). IPP is converted to dimethylallyl pyrophosphate (DMAPP) catalyzed by isopentanoyl pyrophosphate isomerase, and DMAPP is used together with IPP as the starting materials for the third step of cholesterol synthesis. (III) Synthesis of squalene. IPP and DMAPP are condensed by farnesyl transferase to form geranyl pyrophosphate (GPP), followed by a second condensation reaction between GPP and IPP to form farnesyl pyrophosphate (FPP), and finally two molecules of FPP are condensed by squalene synthase to form squalene. (IV) Squalene cyclizes to form lanosterol and subsequently to synthesize cholesterol. Squalene forms a closed loop catalyzed by squalene monooxygenase and 2,3-oxidosqualene lanosterol cyclase to form lanosterol. Lanosterol is converted into cholesterol in more than twenty steps totally

SREBPs, the transcription factors anchored to the ER, include three isoforms, SREBP1a, SREBP1c and SREBP2. The N-terminal sequences of SREBPs belong to the basic-helix-loop-helix-leucine zipper (bHLH-Zip) protein superfamily. 6 , 55 When cellular cholesterol is depleted, the N-terminus of SREBPs can be cleaved into the form of mature and functional SREBP, which can translocate with chaperone by SCAP to the nucleus where the mature SREBP identifies and binds to the SRE in the target gene promoter, followed by activation of these genes transcription.

Further studies revealed that SREBPs interact with SCAP to form a complex in a stoichiometric ratio of 4:4. 56 When ER membrane cholesterol is depleted, SCAP binds to COPII vesicles that allows the SCAP-SREBP complex to move from ER to Golgi for cleavage. When ER membrane cholesterol exceeds 5% of total ER lipids at molar basis, cholesterol and oxysterols, such as 25-hydroxycholesterol, trigger the interaction between SCAP sterol-sensing domain (SSD) and insulin-induced gene (INSIG), thereby blocking the binding of SCAP to COPII vesicles and keeping the SCAP-SREBP complex in the ER 57 , 58 (Fig. 2 ). At present, the structure of SCAP in cholesterol-free and cholesterol-bound states, as well as the structure of SCAP-INSIG or SCAP-COPII complex need to be verified by further ultrastructural study. In the recent studies, the conformation of SCAP-INSIG has been resolved by the cryo-electron microscopy technology. 59 , 60 These findings may benefit to the screening of the small molecules affecting the conformation change of SCAP to inhibit cholesterol synthesis.f

SREBP2 pathway in regulation of cholesterol biosynthesis. The process of cholesterol biosynthesis is strictly regulated by negative feedback, of which the sterol regulatory element binding protein (SREBP) pathway and the HMG-CoA reductase (HMGCR) degradation pathway are the two main mechanisms of negative feedback regulation. a SREBP2 forms a complex with SREBP cleavage activating protein (SCAP) at the ER. When sterol depletion occurs to cells, SCAP binds to COPII vesicles, allowing the SCAP-SREBP complex to translocate from the ER to the Golgi for cleavage. SREBP2 is sequentially cleaved by S1P and S2P in the Golgi, and the N-terminal of SREBP2 is subsequently transported to the nucleus, where the N-terminal of SREBP2 recognizes and binds to the SRE sequence on the target gene promoter to activate the target gene transcription. In addition, HMGCR is also prevented from binding to INSIGs and gp78 (ubiquitin ligase) during cholesterol depletion, thereby stabilizing HMGCR to activate cholesterol biosynthesis. b When the cell sterol is replete, it triggers the interaction of SCAP with INSIGs, resulting in blocking the binding of SCAP to COPII and keeping the SCAP-SREBP2 complex in the ER. At the same time, HMGCR also binds to INSIGs and gp78, which catalyzes the ubiquitination of HMGCR. The ubiquitinated HMGCR is eventually degraded in the proteasome via ER-related degradation (ERAD). Ub ubiquitin

In the process of cholesterol biosynthesis, HMGCR is subjected to strict feedback regulation 54 (Fig. 2 ). As a target gene of SREBP2, HMGCR is regulated by SREBP2 at the transcriptional level. In addition to this long-term transcriptional regulation, HMGCR is also subject to short-term epigenetic modulation. Ubiquitination and phosphorylation of HMGCR are two common post-translational modifications. 61

HMGCR is located in the ER and divided into an N-terminal transmembrane region and a C-terminal cytoplasmic region based on its function and structure. The amino acid sequence of the transmembrane region is highly conserved and the membrane structural domain can respond to increases of sterols and mediate its own degradation. 62 In 2005, Song et al. found that gp78, also known as autocrine motility factor receptor (AMFR), functions as a ubiquitin ligase to mediate HMGCR degradation. In cells with high cholesterol levels, INSIG binds to both HMGCR and gp78, which allows gp78 to catalyze the ubiquitination of the lysine residues at position 89 and 248 of HMGCR. 63 The ubiquitin fusion degradation 1 (Ufd1) protein contains ubiquitin binding sites, which serves as an accelerator of degradation by binding to gp78 to accelerate HMGCR degradation. 64 Meanwhile, gp78 is also involved in the ubiquitination and proteasomal degradation of INSIGs, and promotes SREBP maturation and lipid synthesis. Surprisingly, in hepatic gp78-deficient mice, both cholesterol and fatty acid synthesis were reduced despite enhanced HMGCR enzymatic activity, which resulted from reduced SREBP maturation to suppress downstream gene expression. 65 , 66 The recent studies have found that increased postprandial insulin and glucose concentrations enhance the effect of mechanistic target of rapamycin complex 1 (mTORC1) on phosphorylation of ubiquitin specific peptidase 20 (USP20). Once phosphorylated, USP20 can be recruited to HMGCR complex to antagonize HMGCR degradation. Thus, deleting or inhibiting USP20 significantly reduces diet-induced weight gain, serum and liver lipid levels, improves insulin sensitivity and increases energy expenditure. 67 Taken together, these studies suggest that ubiquitin ligase gp78 and USP20 could be the new targets for treatment of diseases with cholesterol metabolic disorders.

In addition to ubiquitination, HMGCR is also regulated by phosphorylation. Clarke and Hardie found that Ser-872 within the catalytic fragment of rat HMGCR can be phosphorylated by AMP-activated protein kinase (AMPK), which inactivates HMGCR and reduces the flux of the formaldehyde valerate pathway. 68 Meanwhile, Sato et al. found that AMPK-activated phosphorylation of Ser-872 did not affect sterol-mediated feedback regulation of HMGCR, but functioned when cellular ATP levels were depleted, thereby reducing the rate of cholesterol synthesis and preserving cellular energy stores. 69 In contrast, dephosphorylation of HMGCR activates itself and increases cholesterol synthesis. Studies have shown that miR-34a, a microRNA increased in nonalcoholic fatty liver disease (NAFLD), dephosphorylates HMGCR via inactivating AMPK, leading to dysregulation of cholesterol metabolism and increased risk of cardiovascular disease. 70 Subclinical hypothyroidism leads to elevated serum thyroid stimulating hormone (TSH) and elevated serum cholesterol levels. Zhang et al. found that TSH can reduce HMGCR phosphorylation to increase its activity in the liver via AMPK also, revealing a mechanism for hypercholesterolemia in subclinical hypothyroidism. 71

Uptake and transport of cholesterol

Dietary cholesterol absorbed by enterocytes or hepatic de novo synthesized cholesterol can form the protein-lipid complexes with lipoproteins and then release into circulation, followed by transportation to cells for utilization. In humans, about a quarter of excess cholesterol is excreted directly through enterocytes into feces, and the rest enters the liver via reverse cholesterol transport (RCT) and to be excreted with bile. Only a small percentage is re-circulated back into the free cholesterol (FC) pool 72 , 73 , 74 (Fig. 3 ). A variety of proteins are involved in cholesterol uptake and transport. Thus, targeting these key proteins to regulate cholesterol levels is also a potential strategy for treatment of hypercholesterolemia and CVD. 75

Regulation of cholesterol transport. Daily food and the hepatic endogenous synthesis are the two main sources of human cholesterol, of which dietary free cholesterol (FC) uptake is mediated by Niemann-Pick C1 Like 1 (NPC1L1) protein in enterocytes. The endocytosis of cholesterol by NPC1L1 responds to the change of cellular cholesterol concentration. FC taken up by NPC1L1 in enterocytes is esterified to cholesteryl ester (CE) by acyl-CoA:cholesterol acyltransferase 2 (ACAT2), which is loaded into ApoB-48 with triglycerides (TG) mediated by microsomal triglyceride transfer protein (MTP), to form chylomicron (CM). After TG in CM is hydrolyzed and utilized, most of the remaining cholesterol will be absorbed through low-density lipoprotein receptor (LDLR) in the liver. In contrast, some unesterified cholesterol is pumped back to the intestinal lumen by ATP-binding cassette (ABC) transport proteins G5 and G8 (ABCG5/ABCG8) or synthesized into pre-β-HDL by ABCA1 and released into circulation. Cholesterol synthesized endogenously in the liver is converted into VLDL with TG, ApoB-100, and most of VLDL is then converted into LDL, which is the main carrier for transporting endogenous cholesterol. LDL is taken up by scavenger receptors in macrophages, where expression of CD36, scavenger receptor A1 (SR-A1), and LDL receptor 1 (LOX1) is increased in atherosclerosis, further promoting cholesterol accumulation. LDL is endocytosed into macrophages and hydrolyzed by lipase (LAL) to produce FC. Excess FC is esterified by ACAT1 and stored as lipid droplets, and the excess accumulation of CE in macrophages can contribute to formation of foam cells. To mediate cholesterol efflux, macrophages hydrolyze CE into FC by the neutral cholesteryl ester hydrolase (NEH). Macrophage-mediated cholesterol efflux includes simple diffusion, SR-BI-facilitated diffusion, and ABCA1/ABCG1-mediated efflux. Among them, simple diffusion dominates cholesterol efflux in normal macrophages, regulated by cholesterol concentrations. In cholesterol overloaded macrophages, ABCA1 and ABCG1 are critical for cholesterol efflux. ABCA1 is able to bind to ApoA-I to mediate the production of pre-β-HDL, lecithin cholesterol acyltransferase (LCAT) further matures pre-β-HDL particles into HDL3, while ABCG1 and SR-BI mediate cholesterol flow directly to HDL3. HDL3 is further esterified by LCAT to produce HDL2, in which CE is eventually taken up by SR-BI in the liver and converted to FC. In addition, CE in HDL2 particles can be exchanged by cholesteryl ester transfer protein (CETP) to LDL particles, which are subsequently taken up by LDLR. Excess cholesterol in the liver is excreted into the bile mediated by ABCG5/ABCG8 and eventually enters the intestinal lumen for excretion in feces. Some other cholesterol in the blood can be excreted directly into the intestinal lumen via transintestinal cholesterol excretion (TICE) pathway in enterocytes

Cholesterol uptake and efflux in enterocytes

Dietary cholesterol is one of the main sources of cholesterol access in humans, and its uptake is mediated by NPC1L1 protein in enterocytes. 45 NPC1L1 contains 13 transmembrane helices, five of which form the SSD that mediates NPC1L1 movement between the plasma membrane and the endocytic recycling compartment in response to intracellular cholesterol concentrations. 76 , 77 In addition, the N-terminal structural domain of NCP1L1 has a sterol-binding pocket which interacts with cholesterol to change NPC1L1 conformation and allows cholesterol to enter cells. 78 In earlier years, Song et al. found that the VNXXF (X for any amino acid) sequence at the C-terminus of NPC1L1 is involved in clathrin/adaptin 2-dependent endocytosis to mediate cholesterol uptake. 79 , 80 However, NPC1L1-mediated cholesterol uptake is not mainly dependent on endocytosis. 81

In 2020, the NPC1L1 structure was fully elucidated by the cryo-electron microscopy, making it easier to understand the mechanism of NPC1L1-mediated cholesterol uptake. 82 After binding to the sterol-binding pocket, cholesterol triggers NPC1L1 conformation changes to form a delivery tunnel for cholesterol uptake by cells. 82 Recently, Hu et al. found that SSD in NPC1L1 can respond to cholesterol concentrations by binding different amounts of cholesterol. 83 In addition, the effective cholesterol uptake by NPC1L1 depends on its dimerization. 84 Based on the crucial role of NPC1L1 in cholesterol uptake, ezetimibe has been developed and used clinically as an inhibitor of hypercholesterolemia, and other NPC1L1 inhibitors are being developed. 85 , 86 Cellular cholesterol uptake by NPC1L1 is then esterified by acyl-CoA: cholesterol acyltransferase (ACAT) 2 in the ER and loaded with triglycerides (TG) into ApoB-48 to form chylomicrons. The mature chylomicrons are eventually transported into circulation, where TG is hydrolyzed for use in peripheral tissues and the majority of cholesterol is absorbed by the liver. In contrast, FC can be pumped back into intestinal lumen via ATP-binding cassette (ABC) transport protein G5 and G8 (ABCG5/8), or processed by synthesis of HDL-C and release into circulation directly via ABCA1. 87

Cholesterol uptake, esterification and efflux in macrophages

Macrophage cholesterol homeostasis plays an essential role in the development of atherosclerosis. 88 Excessive uptake of cholesterol, excessive intracellular cholesterol esterification and impaired cholesterol efflux can drive differentiation of macrophages into foam cells and formation of atherosclerotic plaques in the vessel wall. 89 Macrophage cholesterol uptake is mainly mediated through multiple scavenger receptors, the molecules lack of SRE, rather than LDLR. 90 Thus, without feedback control mechanisms, macrophage scavenger receptors may uptake cholesterol unlimitedly in patients with hypercholesterolemia. Macrophages scavenger receptors include scavenger receptor A1 (SR-A1), SR-BI, lectin-like oxidized LDL receptor 1 (LOX-1), CD36 and so on. Among them, SR-A1 and CD36 mediate most of the endocytosed LDL (75–90%). 91 , 92 , 93 Meanwhile, compared with LDL, these scavenger receptors have higher affinity for modified LDL, particularly the oxidatively modified LDL (oxLDL). 94 In atherosclerosis, expression of SR-A1, LOX-1, and CD36 in macrophages are increased. The activated scavenger receptors can elevate the levels of pro-inflammatory cytokines, oxLDL, lysophosphatidylcholine, advanced glycosyl end products (AGEs), and vasopressors in macrophages, further promoting cholesterol accumulation and foam cell formation. 89

After endocytosis, lipoproteins will be hydrolyzed in lysosomes by action of lysosomal acid lipase (LAL, also named as cholesterol ester hydrolase or lipase A) to generate FC. The excess FC is then esterified in the ER by ACAT1, which can attenuate FC cytotoxicity. The cholesteryl ester (CE) can be stored as lipid droplets (LD) in the cytoplasm. 95 However, if ACAT1 esterifies too much FC to CE, the excessive lipid accumulation can also result in conversion of macrophages into foam cells. Therefore, ACAT1 is also considered as a possible effective target in reduction of foam cells. Consistently, deletion or inhibition of ACAT1 in macrophages has an inhibitory effect on atherosclerosis in mouse models. 96 , 97 , 98 , 99 However, the ACAT1 inhibitors failed to produce desired athero-protective effects in clinic, which may be due to excessive accumulation of FC in cells and generation of lipotoxicity, resulting in profound cell death. 100 , 101 , 102 Macrophages are not able to degrade sterols, thus, CE needs to be hydrolyzed into FC for efflux. Neutral cholesteryl ester hydrolase (NEH) hydrolyzes CE to release FC. 103 There are three main NEHs, of which carboxylesterase 1 (CES1) and neutral cholesteryl ester hydrolase 1 (NCEH1) are mainly expressed in human macrophages for CE hydrolysis. 104 , 105

When cholesterol is abnormally accumulated in macrophages, the cells acquire a defense mechanism to combat the deleterious effects caused by excessive cholesterol uptake by promoting cholesterol efflux via the mechanisms involving simple diffusion, SR-BI-facilitated diffusion, and ABCA1 and/or ABCG1-mediated efflux. 95 , 106 Among them, the simple diffusion is a passive process regulated by cellular cholesterol concentrations and dominates the cholesterol efflux in normal cells, whereas in cholesterol-overloaded cells, ABCA1 and ABCG1 are critical for cholesterol efflux. 107 The cholesterol efflux mediated by ABCA1 is the most efficient way for macrophages to remove intracellular cholesterol. ABCA1 can bind to ApoA-I and drive cholesterol flow to ApoA-I to form nascent pre-β-HDL particles. Expression of ABCA1 strongly influences the level of plasma HDL-C. 108 , 109 In 2017, the elucidation of the crystal structure of ABCA1 established that ABCA1 forms hydrophobic tunnels to transport lipids, but the mechanism for cholesterol delivery from ABCA1 to ApoA-I still remains incompletely clarified. 110 In contrast to ABCA1, ABCG1 is not directly bound to the empty ApoA-I, instead, it mediates the cholesterol flow to pre-βHDL particles formed by ABCA1-mediated cholesterol efflux. 111 , 112 Meanwhile, expression of ABCA1 and ABCG1 are strictly controlled by liver X receptors (LXRs). The increased cellular cholesterol levels promote production of hydroxysteroids, the endogenous LXR agonizts, thereby increasing ABCA1 and ABCG1 expression. 113 Compared to ABCA1 and ABCG1, SR-BI was initially recognized as the receptor for HDL-mediated CE uptake and only a minor contributor in cholesterol efflux. 114

Liver cholesterol transport and RCT

The liver is the main site of cholesterol metabolism. It is also the most essential organ for effective RCT. In general, cholesterol is transported to the liver from peripheral cells (especially macrophages) by HDL particles, which is considered to be the first step in RCT. Thus, HDL particles play a key role for lipid homeostasis as lipid receptors in lymphatic fluid and plasma. 115 HDL is a smaller lipoprotein with a core of ApoA-I loaded with CE and TG, and an outer layer of phospholipids (PL) which allows the solubilization of FC to complete the transport. 116 According to the particle size, HDL can be divided into two subclasses, one is HDL2, which is rich in lipids with larger volume, and the another one is HDL3, which is rich in proteins with smaller volume. 117 , 118 Lipid-poor ApoA-I synthesized in hepatocytes or enterocytes accepts FC transported by ABCA1 from peripheral cells to form pre-β HDL particles. 119 , 120 Afterwards, lecithin cholesterol acyltransferase (LCAT) and phospholipid transfer protein (PLTP) further mature pre-β-HDL particles to produce HDL3, and HDL3 acts as an acceptor for FC discharged by ABCG1 and/or SR-BI to produce HDL2 finally. 121 , 122 , 123 Among them, LCAT mediates the cleavage of fatty acids at the sn -2 position of phospholipids and transesterification to the 3-β-hydroxyl group on the A ring to form CE. 124 , 125 PLTP mediates the transfer of PL from ApoB-containing lipoproteins to HDL to facilitate FC influx. 126 The liver selectively absorbs lipids from HDL via SR-BI and transfers CE to bile for intestinal excretion to complete the entire RCT process. 114

Based on the key role of HDL in RCT, it is widely believed that HDL-C is a “good” cholesterol to the extent that it inhibits the progression of atherosclerosis. The results of several clinical studies found that interventions to increase plasma HDL-C concentrations by inhibiting cholesteryl ester transfer protein (CETP) or using niacin did not reduce the development of atherosclerosis. 127 , 128 , 129 The esterification of cholesterol by LCAT is critical for the inhibition of atherosclerosis by RCT, whereas the rate of clearance of FC in HDL is much higher than that of LCAT esterification, due to the fact that FC can enter the liver directly through cell membrane without LCAT esterification, which may also explain the controversial protective effects of interventions targeting LCAT against atherosclerosis. 130 , 131 Meanwhile, several large studies also found a U-shaped curve between HDL-C concentrations and all-cause mortality in ASCVD patients, with both too low and too high levels of HDL-C leading to an increased risk of ASCVD. 132 , 133 In addition, the HDL collected from patients with CVD or chronic kidney disease lose the capacity of RCT by promoting LOX-1 mediated vascular dysfunction. Patients suffering from ASCVD with high HDL-C tend to lack PL in HDL, which leads FC to flow back to macrophages to facilitate foam cell formation. 131 Therefore, maintaining the normal function of HDL rather than simply increase of HDL-C concentrations is the more important aspect of RCT therapy.

In addition to uptake of HDL-C via SR-BI, the liver also uptakes LDL-C via LDLR to directly remove atherosclerotic lipoproteins from the plasma. In the hepatic ER, ApoB-100 is the main apolipoprotein to synthesize very low-density lipoprotein (VLDL) to transport endogenous TG and cholesterol. When TG contained in VLDL is hydrolyzed by LAL, the remaining particles are converted to LDL. 134 LDL is the primary carrier of endogenous cholesterol for transport, and two-thirds of TC in plasma binds to LDL to form LDL-C, which is absorbed and converted through hepatic LDLR. In humans, CE in mature HDL particles is also exchanged to LDL or VLDL particles by CETP, then the CE in these particles is absorbed by LDLR. 135 In mammals, LDLR is highly expressed in the liver to mediate more than 70% of LDL-C clearance. 136 LDLR deficiency is the most common cause of FH, in which patients present with markedly elevated LDL-C level and early ASCVD onset. 137 , 138 LDLR transcription is mainly regulated by SREBP2 and can respond to changes of intracellular cholesterol. 90 PCSK9 reduces LDLR expression in the post-translational manner. It binds to LDLR to induce LDLR entry into cells for lysosomal degradation and inhibits the ability of LDL uptake in the liver. 34 Similarly, the inducible degrader of LDLR (IDOL) can also promote LDLR degradation through polyubiquitination and lysosomal degradation pathways. 139 A recent cognitively subversive study found that HDL can bind to PCSK9 to increase PCSK9 activity and accelerate PCSK9-mediated LDLR degradation. This study further elucidates the interaction between circulating lipoproteins and PCSK9, and provides new therapeutic ideas for targeting PCSK9. Furthermore, coagulation factor prekallikrein (PK) was recently reported to regulate plasma cholesterol levels via binding to LDLR to induce its lysosomal degradation. Deficiency of PK stabilizes LDLR protein expression, promotes hepatic LDL-C clearance and inhibits atherosclerosis in mice. 140 All the evidence above suggest that LDLR still represents a promising therapeutic target for ASCVD treatment.

Cholesterol utilization and excretion

Utilization of cholesterol.

As an important component in biological membranes, cholesterol accounts for more than 20% of lipids in membranes. 141 , 142 Cholesterol is a largely hydrophobic molecule, and only the 3β-hydroxyl portion is a polar group, thus, cholesterol is amphiphilic and can be oriented in the phospholipid bilayer perpendicular to the membrane surface. 143 , 144 , 145 In domains or pools of biological and model membranes, cholesterol is usually non-randomly distributed, in which many structural domains are thought to be important for maintaining membrane structure and function. 146 , 147 , 148 Besides participating in the composition of biological membranes, cholesterol is the essential precursor for synthesis of oxysterols. Formation of oxysterols is the step converting cholesterol into more polar compounds, which can facilitate elimination of cholesterol. Meanwhile, oxysterols have different important physiological roles. Some oxysterols can activate LXR to regulate cholesterol efflux from macrophages, and some of them can bind to INSIG to regulate SREBP2 maturation, therefore, these oxysterols play an important role to maintain cholesterol homeostasis. 149 , 150 Oxidoreductases, hydrolases and transferases are the three main enzymes involved in the metabolism of oxysterols. Among the oxidoreductases, the enzymes catalyzing formation of oxysterols, cytochrome P450 (CYP) has been relatively well studied. The earlier identified two enzymes, cholesterol 7α-hydroxylase (CYP7A1) and cholesterol 27-hydroxylase (CYP27A1), participate in bile acid synthesis by producing 7α-hydroxycholesterol (7α-OHC) and 27-OHC, respectively. In addition, formation of OHC by CYP7A1 is the rate-limiting step for bile acid production. 151 , 152 Cholesterol 25-hydroxylase (CH25H), another key oxidoreductase, does not belong to the CYP450 superfamily. 153 CH25H catalyzes the production of 25-OCH, which is capable of acting as an agonist of estrogen receptor α. 154 In addition to the aforementioned enzymes, there are many other enzymes that catalyze synthesis of specific oxysterols, indicating the mechanisms for oxysterol production/metabolism still need further investigation. Moreover, cholesterol is the precursor for generation of all steroid hormones. Various steroid-producing tissues (adrenal glands, testes, ovaries) and brain cells produce steroid hormones. The inner mitochondrial membrane contains CYP450, a key enzyme to convert cholesterol to pregnenolone. Subsequently, pregnenolone leaves the mitochondria and is further catalyzed by the corresponding enzyme in the ER as a substrate for steroid hormone synthesis. 155

Excretion of cholesterol

The elimination of cholesterol from the liver to remove excess cholesterol is considered as the final step in RCT. Both ABCG5/8-mediated hepatobiliary secretion and transintestinal cholesterol excretion (TICE) pathways mediate this process. 156

During the hepatobiliary cholesterol secretion, ABCG5 and ABCG8 form a heterodimer to mediate cholesterol excretion into the bile and intestinal lumen. 157 , 158 At the same time, bile salt is the main acceptor for ABCG5/8-mediated hepatic cholesterol efflux. 159 , 160 Bile acids secreted from hepatocytes will combine with glycine or taurine to form bile salts. CYP7A1 is the key enzyme for bile acid synthesis, converting cholesterol (usually from LDL particles) to 7α-OCH through a multienzyme process. 151 Subsequently, CYP450 enzymes including CYP8B1, CYP27A1 and CYP7B1 located on the ER of hepatocytes are involved in many of the subsequent reactions. 161 , 162 , 163 Lee et al. determined the structure of ABCG5/8 heterodimer by extracting the crystals of phospholipid bilayer ABCG5 and ABCG8. The structure shows that the transmembrane structural domain of this heterodimer is coupled to the nucleotide binding site through different interaction networks between the active and inactive ATPases, indicating the catalytic asymmetry of ABCG5 and ABCG8 protein. 164 Similar to ABCA1 and ABCG1, ABCG5 and ABCG8 are also transcriptionally regulated by LXR. When hepatic cholesterol is overloaded, increased oxysterols activate LXR and enhance expression of ABCG5/8. 165 , 166

Another non-biliary TICE pathway of cholesterol excretion refers to cholesterol secretion directly to the proximal small intestine from the blood via enterocytes. 167 In both rodents and humans, TICE mediates about 30% of the total fecal cholesterol excretion and plays a significant role in cholesterol efflux. 166 , 168 , 169 When the synthesis of bile acids/salts is abnormal in the body, TICE takes on more to maintain normal cholesterol efflux. 170 Stöger et al. found that interleukin 10 (IL-10) receptor 1 (IL-10R1)-deficient LDLR −/− mice showed an increase in TICE-mediated cholesterol efflux and inhibited atherosclerosis, suggesting that TICE may have potential anti-atherosclerotic effects. 171 Since enhanced hepatobiliary cholesterol secretion has the side effect of causing gallstones, promoting TICE may be a new idea to combat atherosclerosis. 172 However, the molecular mechanism of TICE has not been fully clarified, and various factors of cholesterol metabolism can affect TICE to some extent, which is a direction worthy of the future attention. 173 , 174 , 175

Epigenetic modulation of cholesterol metabolism

In addition to the classical models of cholesterol metabolism regulation described above, the recent evidence has revealed multiple epigenetic regulatory mechanisms involved in uptake, synthesis and efflux of cholesterol, such as histone acetylation, DNA methylation and ubiquitylation.

Bromodomain and extra-terminal domain (BET) proteins are epigenetic readers that are recruited to chromatin in the presence of acetylated histones, thereby regulating gene expression. Inhibition of BET effectively reduces intracellular cholesterol levels by significant regulating genes involved in cholesterol biosynthesis, uptake and intracellular trafficking, indicating that most of the genes involved in regulation of cholesterol homeostasis can be regulated by epigenetic mechanisms. 176

Intestinal NPC1L1 is differentially expressed in the gastrointestinal tract, with much higher levels in small intestine than colon, which is associated with high levels of methylation upstream of NPC1L1 gene start site in the colon, suggesting a possible reduction in cholesterol uptake and prevention of atherosclerosis by alteration of DNA methylation. 177 Whereas data on the epigenetic regulation of ABCG5/8 in the intestine are very limited. A few studies in mouse liver suggest that the common promoters of ABCG5/8 are acetylated and unmethylated. Histone methyltransferase SET domain 2 (SETD2) catalyzes trimethylation on H3K36 (H3K36me3), and recent studies have revealed that STED2 is involved in regulating hepatic ABCA1 expression and cholesterol efflux homeostasis. 178

Brahma related gene 1 (BRG1, a chromatin remodeling protein) interacts with SREBP2 and recruits histone 3 lysine 9 (H3K9) methyltransferase (KDM3A) at the promoter of SREBP2 target genes to regulate the transcription of genes involved in cholesterol synthesis. 179 Euchromatic histone-lysine N-methyltransferase 2 (EHMT2) is a histone methyltransferase that catalyzes H3K9 of SREBP2 monomethylation and dimethylation (H3K9me1 and H3K9me2, respectively). Inhibition of EHMT2 is able to directly induce SREBP2 expression by reducing H3K9me1 and H3K9me2 at the promoter. 180 At the same time, the complex of histone acetylase cAMP response element binding protein 1 (CREB) binding protein (CBP)/P300 bromodomain acetylates the conserved lysine residues of SREBP protein, thereby preventing the ubiquitination and degradation of SREBP, prolonging its residence time in the nucleus and promoting its transcriptional activity. In contrast, sirtuin 1 (SIRT1) can antagonize the action of CBP/P300 by deacetylating SREBP. 181 Thus, the transcriptional activity of SREBP is regulated by multiple epigenetic mechanisms, keeping it in a complex dynamic equilibrium.

Various genes associated with cholesterol elimination, such as CYP7A1, CYP46A1 and CH25H, have been shown to be differentially regulated epigenetically. CYP7A1 can be regulated by indirect negative feedback from small heterodimeric chaperone (SHP) proteins. Several studies have identified the presence of BRG1-mediated chromatin remodeling and SIRT1-mediated histone deacetylation at the SHP promoter, which further regulates CYP7A1 expression. 182 , 183 CYP46A1 is regulated by the acetylation status of histones. in vitro, treatment of hepatocytes with deacetylase inhibitor, trichostatin A, significantly upregulates CYP46A1 mRNA levels. 184 The signal transducers and activators of transcription 1 (STAT1) pathway regulates CH25H expression, which also requires the involvement of histone acetylation. 185 , 186

The epigenetic regulation of cholesterol homeostasis is a promising research area, with multiple genes being differentially regulated. Research in this area could provide the basis for transcriptional therapies for related diseases, drug development and the clinical application of dietary epigenetic modulators. However, there are still many questions and gaps in this field that need to be solved.

Cholesterol-related diseases and interventions

Cholesterol and ascvd, role of cholesterol in the development of ascvd.

Deregulated cholesterol metabolism leads to the development of multiple human diseases, among which atherosclerosis is the major one. Atherosclerosis is the process of accumulation of lipids and fibrous substances in arterial intima, and results in ASCVD as the main cause of death worldwide. 187 The main reason of atherosclerotic plaque formation is the excessive accumulation of cholesterol-rich lipoproteins in the arterial intima (Fig. 4 ). 187 , 188

Inhibition of atherosclerosis by cholesterol-lowering interventions. Bempedoic acid and statins reduce acetyl-CoA and HMG-CoA production by inhibiting ACLY and HMGCR, respectively, thereby lowering cholesterol synthesis. Ezetimibe inhibits intestinal uptake of cholesterol by inhibiting NPC1L1. PCSK9 inhibitors reduce LDLR degradation by inhibiting PCSK9 expression/function. Bile acid sequestrants bind to BA in the small intestine, thus preventing BA from being reabsorbed into the liver. Lomitapide reduces the assembly of ApoB-containing lipoproteins in intestine and liver. Evinacumab restores LPL activity by inhibiting ANGPTL3. Fibrates reduce TG levels. All of the above interventions can reduce plasm LDL-C levels, which is the base for the development of atherosclerosis. The arterial wall consists of three layers: adventitia, media, and intima. The outermost layer, adventitia, is mainly composed of connective tissues. The middle layer, media, consists of smooth muscle cells. The innermost layer, intima, is bounded by endothelial cells (ECs) on the inner side of the lumen and internal elastic membrane on the outer side. Atherosclerotic plaques form in the intima. In the early stage of atherosclerosis, LDL particles enter the intima through EC layer and undergo oxidation and other modifications to form oxLDL, which makes it pro-inflammatory and immunogenic. ECs secrete adhesion molecules and chemokines after activation, and monocytes circulating in the blood bind to adhesion molecules and enter the intima under the promotion of chemokines. After entering the intima, the infiltrated monocytes then differentiate into macrophages and express scavenger receptors to bind and internalize oxLDL to form foam cells. A subset of smooth muscle cells from the media can also differentiate into a macrophage-like phenotype, which in turn phagocytoses oxLDL to form foam cells. As the lesion progresses, dead foam cells and SMCs aggregate with free lipoprotein and cholesterol crystals in the intima to form a necrotic core. SMCs migrate to endothelium and forms fibrous cap during the evolution of atherosclerotic plaque. As cholesterol crystals grow, they eventually penetrate the intima, causing plaque instability and further rupture of the plaques. Acetyl CoA acetyl coenzyme A, ACLY ATP citrate lyase, ANGPTL3 angiopoietin-like protein 3, BA bile acid, CE cholesteryl ester, CM chylomicron, EC endothelial cell, FA fatty acid, FC free cholesterol, HMGCR 3-hydroxy-3-methylglutaryl coenzyme A reductase, HMG-CoA 3-hydroxy-3-methylglutaryl coenzyme A, LDL low-density lipoprotein, LDLR LDL receptor, LPL lipoprotein lipase, MTP microsomal triglyceride transfer protein, NPC1L1 Niemann-Pick C1 like 1, oxLDL oxidatively modified low-density lipoprotein, PCSK9 proprotein convertase subtilisin/kexin type 9, SMC smooth muscle cell, TG triglyceride, VLDL very low-density lipoprotein

Accumulation and retention of ApoB-containing lipoproteins in the arterial intima are thought to induce atherosclerosis. 189 Recent evidence has suggested that SR-BI in endothelium is an important scavenger receptor that promotes LDL transcytosis/accumulation and atherosclerosis. 190 Retained LDL particles activate an initial immune response in the endothelium, thus, triggering chronic inflammation by releasing monocyte chemotactic protein-1 (MCP-1) and some other inflammatory factors. 191 Endothelial chemokines and cytokines including MCP-1, intercellular adhesion molecule 1 (ICAM1), vascular cell adhesion molecule 1 (VCAM1), E-selectin, macrophage colony stimulating factor (M-CSF), IL-18 and tumor necrosis factor α (TNF-α), further promote monocyte migration to endothelium. 192 , 193 Monocytes can differentiate into macrophages after migration to the underneath of endothelium, where macrophages bind and internalize modified LDL or lipoprotein residues in the intima to form foam cells. 194

Foam cell formation is the major hallmark of early lesions in atherosclerosis. 89 Macrophages differentiated from circulating monocytes are the main source of foam cells. 195 , 196 A small number of foam cells can be derived from endothelial cells (ECs) and/or vascular smooth muscle cells (VSMCs). ECs may differentiate into VSMC-like cells while VSMCs will further differentiate into macrophage-like cells, which become foam cells after lipid overload. 197

LDL must undergo oxidative modification before it can be rapidly taken up by macrophages and accumulated in lysosomes. 198 LOX-1 is one of the scavenger receptors and highly expressed in ECs, which binds oxLDL and transfers it to the intima infiltrated by macrophages. Next, macrophages bind oxLDL through scavenger receptors including SR-A1, CD36, and LOX-1. 89

The formation of CE is an important part in the transition of macrophages to foam cells. Disruption of the balance between esterification and de-esterification results in accumulation of CEs in macrophages, leading to foam cells formation. 17 As an important part of lipoprotein metabolism, RCT can prevent foam cell formation. Imbalanced conversion between CE and FC and dysregulation of HDL function lead to formation of cholesterol crystals. 199 As cholesterol crystals grow and accumulate in the extracellular space of the plaque necrosis core, it eventually reaches and penetrates the arterial intima. 200 This will lead to increased plaque instability, which in turn causes plaque rupture and further thrombus formation. 17

Cholesterol-lowering intervention therapy

LDL-C is involved in the occurrence and development of atherosclerosis, indicating LDL-C is the main risk factor for ASCVD. More and more studies show that lower LDL-C levels are better for cardiovascular system. 201 , 202 In the following sections, we will discuss the drugs that possess cholesterol-lowering capacities (Table 1 ).

Statins are competitive HMGCR inhibitors, which can effectively reduce the level of plasma cholesterol, especially LDL-C levels. Statins represent the mainstream therapy for CVD. 203 , 204 , 205 , 206 Historical studies have confirmed that statins are able to reduce the incidence of CVD by 23% which leads to statins as the first choice for the treatment of hypercholesterolemia. 207 Mevastatin is the first statin discovered in the world, and it was isolated from fungal species Penicillium citrinum . 208 But till the 1990s, the landmark Scandinavian Simvastatin Survival study (4S) showed convincing results that support the use of statins to reduce cholesterol and CVD. 209 By 2020, at least nine different statins have been developed, among which seven have been approved in USA and one has been withdrawn from the market. 203 Statins inhibit HMGCR activity by competitively binding to the enzymatic site of HMGCR, resulting in decreased cholesterol synthesis and reduced plasma cholesterol levels. 210 Low plasma cholesterol levels in turn increase hepatic LDLR expression via the SREBP2-dependent pathway. The increased LDLR expression in hepatocytes speeds up the uptake and clearance of LDL-C from plasma, another important mechanism of statins improving cholesterol metabolism systematically. 211 However, some studies have shown that statin can also induce PCSK9 expression since PCSK9 also contains SRE in its promoter. The increased PCSK9 expression substantially attenuates the expected efficacy of statins on cholesterol lowering. 212 , 213

Without the influence of PCSK9, the extent of LDL-C reduced by statins should be dose-dependent and may vary among different statins. According to the effect of lowering LDL-C, different types and doses of statin therapy are divided into three intensities: low, moderate and high. Low-intensity is defined as a daily dose of statin that can reduce LDL-C < 30%; moderate-intensity is indicated as reducing LDL-C to 30–50%; and high-intensity is to reduce LDL-C ≥ 50%. 214 A meta-analysis showed a 10% reduction in all-cause mortality for per 1 mmol/l (equivalent 39 mg/dl) reduction in LDL-C, mainly due to a reduction in deaths from CVD. 207 Further meta-analysis showed that statins can reduce all-cause mortality and the risk of cardiovascular events, regardless of age and sex. 215 , 216 Even in patients with low cardiovascular risk, statins could reduce all-cause mortality and cardiovascular events. 217

In addition to reduction of LDL-C, statins have been demonstrated to have many other beneficial effects, known as the pleiotropic effects of statins. 218 , 219 Statins have been reported to elevate HDL-C, which also varies with dose among different statins. 220 However, when LDL-C is below a certain level, statin-elevated HDL-C has little effect on disease regression. 221 The anti-inflammatory and antioxidant effects of statins may also make contributions to prevention and/or reduction of ASCVD, at least confirmed by in vitro and animal studies. However, the clinical significance of these positive effects on ASCVD may need more exploration. 222 , 223

Although the efficacy of statins in lowering LDL-C and treating ASCVD is unquestionable, there are still many controversies regarding the application of statins. 224 Myopathy is one of the most common clinical adverse reactions caused by statins. 225 The most severe form of statin-associated muscle symptoms (SAMS), rhabdomyolysis, is characterized by severe muscle pain, muscle necrosis, and myoglobinuria, which can lead to kidney failure or death. 226 However, the nocebo effect may outweigh the side effects caused by the statins themselves. 227 Thus, in all international guidelines, the availability of statins for the secondary prevention of ASCVD is consistent in patients without statins intolerance or adverse reactions, and the benefits of statins treatment are supported by a large amount of data. 228 When it comes to primary prevention, the international guidelines for the treatment of isolated adult patients with elevated LDL-C (defined as ≥190 mg/dL) have not yet reached consensus. At the same time, the application of statins in patients with chronic kidney disease, diabetes, the elderly over 75 years old, and patients with heart failure also demonstrated mixed results. 229 , 230 , 231 , 232 For those patients with intolerance to the recommended-intensity statins due to the adverse effects or those who do not achieve LDL-C reducing goals, the non-statin lipid-lowering drugs added to the maximally tolerated statins can be recommended. 233 , 234

Ezetimibe is an intestinal cholesterol absorption inhibitor, which can block intestinal uptake of cholesterol by interacting with NPC1L1 without effect on absorption of TG and fat-soluble vitamins. 235 , 236 In addition to lowering plasma cholesterol levels, similar to statins, ezetimibe also up-regulates LDLR expression in the liver, thereby enhancing LDL-C clearance. 237 Experiments have also shown that ezetimibe may reduce inflammation in atherosclerotic plaques by increasing LDL-C breakdown and promoting fecal excretion of LDL-derived cholesterol. 238 , 239

Ezetimibe is a good option for patients with contraindications, statin intolerance and/or insufficient LDL-C reduction. 235 Clinical studies and meta-analyses show that ezetimibe monotherapy significantly reduces LDL-C and TC levels. It also slightly increases HDL-C levels in patients with hypercholesterolemia. 237 , 240 LDL-C lowering treatment with ezetimibe reduces the risk of cardiovascular events in patients aged ≥75 years with elevated LDL-C. 241 In a rabbit model of plaque erosion, ezetimibe lowered serum oxysterols, thereby reducing atherothrombotic complications following superficial plaque erosion. 242

In order to achieve better therapeutic effects, ezetimibe is often used in combination with a statin. In 2018, Ezetimibe was the most prescribed non-statin lipid-lowering therapy. In patients treated with statins, the addition of ezetimibe reduced LDL-C by an additional 23.8%, and fixed-dose combination (FDC) therapy reduced LDL-C by an additional 28.4% compared with statin therapy alone. However, treatment outcomes vary widely among individuals that only a small percentage of patients achieved recommended LDL-C levels (FDC, 31.5%; separate pills, 21.0%). 243 In addition, bempedoic acid plus ezetimibe FDC together with maximally tolerated statin therapy also significantly lowered LDL-C and had a favorable safety profile. 244 It has been reported that co-administration of ezetimibe with a bile acid sequestrant can reduce LDL-C by an additional 10–20%. 245 The combination of ezetimibe and PCSK9 inhibitor may have an additional effect in cholesterol lowering. 246

Notably, age, gender, or race do not affect the pharmacokinetics of ezetimibe, and no dose adjustment was required in patients who had mild hepatic impairment or mild to severe renal impairment. 235 Furthermore, ezetimibe also shows favorable drug interaction characteristics and has little effect on plasma levels of statins. In addition, the bioavailability of ezetimibe is not significantly affected by concurrent statin administration. 247

PCSK9 inhibitors

The discovery of PCSK9 provides a new idea for controlling plasma LDL-C levels. PCSK9 inhibitors can increase LDLR expression by attenuating PCSK9 expression/function, leading to the lowering plasma LDL-C. 248 In addition, it has been reported that inflammatory state could promote PCSK9 expression and increased PCSK9 would up-regulate LOX-1 expression, thus promoting oxLDL uptake and accelerating the progression of atherosclerosis. 249 , 250 At present, there are three approved PCSK9 inhibitors, among which alirocumab and evolocumab are the full human monoclonal antibodies, and the third one, inclisiran, is a double-stranded siRNA. 251 , 252

In meta-analysis, evolocumab and alirocumab could significantly reduce cardiovascular events, but had no significant effect on cardiovascular mortality. 253 , 254 , 255 , 256 Evolocumab and alirocumab, either alone or in combination with statins or other lipid-lowering drugs, can reduce LDL-C levels by an average of 60%. 235 When evolocumab and alirocumab were used in combination with the high-intensity statins, there was an additional 46–73% reduction in LDL-C compared to placebo, and an additional 30% reduction compared to ezetimibe. 235 Inclisiran is a novel PCSK9 inhibitor, which was approved for treatment of ASCVD by US FDA in 2021. 252 In the two phase 3 trials of inclisiran in the patients with elevated LDL-C, subcutaneous injection of inclisiran once every 6 months resulted in a 50% reduction in LDL-C levels. 257 Adverse events at the injection site of inclisiran were more frequent than placebo, but the reaction was usually mild. 257 Recently, a study showed that inclisiran inhibited foam cell formation by inhibiting oxLDL uptake by RAW264.7 macrophages, which was associated with activation of peroxisome proliferator-activated receptor γ pathway. This observation may provide new insights into the cholesterol-lowering mechanism of inclisiran. 258

Itching at the injection site and flu-like symptoms are the most common side effects of PCSK9 inhibitors. 259 PCSK9 inhibitors are effective. However, given the high cost and limited data on the long-term safety, they may be only cost-effective in patients with high risk of ASCVD, while not be available in some areas with no enough medical resources. 235 Therefore, lower-cost alternative drugs need to be developed.

Bempedoic acid (ETC-1002)

Bempedoic acid, an inhibitor of ACLY, is the first FDA-approved non-statin oral cholesterol-lowering drug in nearly 20 years. 40 , 260 In fact, bempedoic acid is a prodrug and needs to be converted into bempedoic acid-CoA thioester, the active form of ACLY inhibitor, by very long-chain acyl-CoA synthetase-1 (ACSVL1). 261 Interestingly, expression of ACSVL1 is tissue-dependent with little in the muscle and high in the liver. Therefore, inhibition of ACLY activity by bempedoic acid administration simply occurs to the liver, thereby avoiding the muscle-related side effects. 262 ACLY inhibition can also upregulate LDLR expression, which can make additional contributions to the reduction of plasma LDL-C levels. 263 Studies have shown that in high-fat and high-cholesterol diet-fed mice, in addition to inhibition of cholesterol synthesis and activation of LDLR expression, bempedoic acid also reduces inflammation by directly inhibiting ACLY and activating AMPKβ1 activity, thereby potently preventing atherosclerosis. 262 , 264

The CLEAR trials showed that adding bempedoic acid to current cholesterol-lowering therapy can further reduce LDL-C levels in patients with high risk for CVD. 244 , 263 , 265 When combined with statins, ezetimibe lowered LDL-C by an additional 25%, while bempedoic acid add-on therapy lowered LDL-C by an additional 16%. 266 , 267 This finding contrasted with the findings of the monotherapy arms in phase 3 trial, in which LDL-C was reduced by ~30% by bempedoic acid and ~21% by ezetimibe alone. 268

The application of bempedoic acid may cause an increase in serum uric acid and increase the risk of tendon rupture, so patients with gout or a history of tendon disease should avoid using bempedoic acid. 269 In view of some drug interactions found in clinical trials, the administration of drugs containing bempedoic acid is not recommended when using simvastatin at a dose >20 mg or pravastatin at a dose >40 mg. 268

For patients at high risk of ASCVD, bempedoic acid alone or in combination with ezetimibe can be considered as an additional treatment of statins. 270 Given the high cost of PCSK9 inhibitors, the use of bempedoic acid would be a higher priority than PCSK9 inhibitors, but lower than ezetimibe based on the limited data on the overall efficacy. Nonetheless, the combination of bempedoic acid or ezetimibe with statins is suggested for the patients who require greater LDL-C lowering than either drug alone. At present, the lipid-lowering ability of bempedoic acid is clear, but whether it can reduce the risk of ASCVD remains unknown, which needs further study.

Bile acid sequestrants

Bile acid sequestrants (BAS) are macromolecular polymers which can bind to bile acids in the small intestine, thus, BAS can prevent bile acids from being reabsorbed back into the liver. 271 Due to bile depletion in the liver, more bile acids than usually required are synthesized from liver cholesterol, which increases the demand for cholesterol in the liver, leading to increased LDLR expression and clearance rate of circulating LDL-C. 272 Three types of BAS have been approved for clinical use: cholestyramine, colestipol and colesevelam hydrochloride. The past clinical trials demonstrated that BAS was effective in lowering LDL-C and reduction of the risk of cardiovascular events in hypercholesterolemic patients. 272 , 273 , 274 , 275

Even low-dose BAS could also cause gastrointestinal adverse reactions, which limits its application. It has been reported that use of BAS can reduce the absorption of intestinal fat-soluble vitamins and sometimes increase the level of circulating TG in some patients. 235 In addition, BAS interacts with several commonly used drugs, so it must be used with caution in combination therapy. Among them, colesevelam is well tolerated and has less interaction with other drugs, thus, it can be used concurrently with drugs for other kinds of disease treatment. 276

Lomitapide is an oral microsomal TG transfer protein (MTP) inhibitor, which can reduce the assembly of lipoproteins containing ApoB in intestine and liver, so the reduction of LDL-C levels by MTP inhibitors is independent of LDLR. 277 Lomitapide has been proved to reduce LDL-C in homozygous FH (HoFH) patients by nearly 50% in combination with other lipid-lowering drugs. 278

In a real-world European study, lomitapide has been proved to be a very effective adjuvant drug to reduce LDL-C in HoFH patients for the longest follow-up period so far. 279 As lomitapide blocks MTP, it leads to impaired intestinal fat transport, making gastrointestinal symptoms as the most common adverse event in patients. 280 In terms of safety, lomitapide-related hepatic steatosis may not indirectly increase the risk of liver fibrosis, and the data suggest that lomitapide may reduce cardiovascular events in HoFH patients. 279

Evinacumab is a human monoclonal IgG4 antibody neutralizing angiopoietin-like protein 3 (ANGPTL3). ANGPTL3 is a protein secreted by the liver, which inhibits activity of lipoprotein lipase and endothelial lipase, the two lipases involved in the regulation of lipid hydrolysis in serum. 281 Inhibition of ANGPTL3 by evinacumab restores activity of the two lipases, thus reducing serum cholesterol and TG levels. 282

In 2021, evinacumab was approved in USA as an adjunctive cholesterol-lowering treatment for FH in adults and children 12 years of age or older. The previous clinical trials showed that evinacumab reduced TC and LDL-C by 45–55% in HoFH patients already receiving maximum tolerated doses of lipid-lowering drugs. 282 An animal study showed that alirocumab, evinacumab, and atorvastatin triple therapy significantly reduced hyperlipidemia and atherosclerosis. 283 , 284 Currently, no randomized clinical trials demonstrate that evinacumab can reduce cardiovascular events, so the further research is needed.

Frequent adverse events of evinacumab include mild local injection reaction, flu-like illness, headache, urinary tract infection and limb pain. 285 In addition, no clinically apparent liver injury or serious hepatic adverse events attributable to treatment were reported.

Fibrates are PPARα agonizts, which can increase HDL-C levels and decrease TG levels in plasma by regulating molecules related to lipid metabolism. 286 The clinical effects of fibrate class on blood lipids are different, but are estimated to reduce TG levels by 50% and LDL-C levels by ≤20%, and increase HDL-C levels by ≤20%. These effects are closely related to baseline lipid levels. 287 Meta-analysis showed that fibrates-treated patients with high TG and low HDL-C had a decrease of major cardiovascular events without reduced CVD or total mortality. 288 , 289 Recently, a novel fibrate, pemafibrate, was reported to significantly reduce TG-rich lipoproteins, such as chylomicrons and VLDL. 290 In addition, fibrates are well tolerated with common adverse effects of myopathy, elevated liver enzymes, and cholelithiasis. 291 Overall, the CVD benefit of fibrates requires further confirmation.

Lipoprotein apheresis

Lipoprotein apheresis (LA) is a non-drug lipoprotein-lowering therapy commonly used in patients with HoFH, heterozygous FH and other forms of hypercholesterolemia or CVD. 292 Although highly effective, LA is time-consuming and expensive, and has long been the last resort for treating uncontrolled dyslipidemia. 293

New targets for cholesterol-lowering therapy

In addition to the classical targets for drug mentioned above, some new targets for cholesterol lowering are also being investigated, which we will elaborate below (Table 2 ).

Apolipoprotein C3 (APOC3) is an apolipoprotein encoded by the gene APOC3 and mainly found in VLDL and chylomicron. 294 , 295 APOC3 can stimulate liver to synthesize and secrete VLDL. 296 It also reduces liver clearance of TG-rich lipoproteins by regulating LDLR/LDLR-related protein 1 (LRP1) pathway. 297 Epidemiological studies show that plasma APOC3 levels can be used to predict CVD risk and mortality. 298 , 299 , 300 , 301 It has been reported that carriers of rare heterozygous deletion mutations in APOC3 have lower TG, enhanced HDL-C, little change in LDL-C and lower cardiovascular risk. 302 , 303

Volanesorsen is a second-generation of antisense oligonucleotide (ASO) targeting APOC3 mRNA in hepatocytes to decrease APOC3 expression, thereby significantly reducing plasma TG levels. 304 APO-CIII-L Rx is a next-generation of N-acetylgalactosamine-conjugated ASO targeting APOC3. In a double-blind, placebo-controlled, dose-escalation phase 1/2a study, multiple injections of 30 mg/week APO-CIII-L Rx reduced APOC3, TG, VLDL, TC, LDL-C by ~80%, 70%, 70%, 15%, and 15%, respectively, and increased HDL-C by about 70%. 305

Based on these studies, it is suggested that inhibition of APOC3 also has cholesterol lowering potential, although the mechanism remains unclear.

Lipoprotein (a) [Lp(a)]

Lp(a) is a special form of LDL particle encoded by LPA , to which part of Apo(a) is covalently bound to ApoB. Lp(a) contains 35–46% CE and 6–9% cholesterol. 306 , 307 The concentration of Lp(a) is mainly determined by genes and varies greatly among individuals. 308 In the past, multiple studies have demonstrated that Lp(a) is another risk factor for ASCVD. 309 , 310 , 311 , 312

The in vitro and animal studies suggest that Lp(a) is important in the progression of atherosclerosis by influencing formation of foam cells, VSMC proliferation, and plaque inflammation and instability. 313 , 314 But in individuals with high Lp(a) levels, the content of atherogenic cholesterol carried by LDL is generally much higher than carried by Lp(a). 315 However, vascular dynamics studies have shown that Lp(a) accumulates preferentially in the vascular wall, which may indicate that the cholesterol carried by Lp(a) has more atherogenic potential than LDL-C. 316

So far, there is no approved pharmacological approaches to reduce Lp(a) to the level which can benefit ASCVD. 317 However, niacin, mipomersen and PCSK9 inhibitors show a certain effect on lowering Lp(a), although these effects may not translate into substantial clinical benefits. 318 , 319 , 320 The recently concluded phase 2 trial of pelacarsen demonstrated significant Lp(a) lowering capacity. Pelacarsen is a hepatocyte-directed ASO targeting liver LPA mRNA, and can significantly reduce Lp(a) production. 321 In addition, another siRNA drug, olpasiran, also shows a strong Lp(a)-lowering effect. 322 Taken together, existing evidence suggests that Lp(a) is a potential target to treat ASCVD, and drugs targeting it are under intense development.

The oxysterol-activated receptors, LXRα and LXRβ, are members of the nuclear transcription receptor family. LXRs play important roles in RCT through multiple mechanisms. In different mouse models, in vivo activation of LXRs increases the rate of RCT by increasing ABCG1 and ABCA1 expression in macrophages. 323 , 324 , 325 In addition, activation of LXRs also has a significant anti-inflammatory effect. 326 Therefore, targeting LXRs is a potential anti-atherosclerotic strategy. T0901317 and GW3965 are synthetic agonizts of LXRs that could significantly reduce plaque formation in atherosclerotic mice. 327 , 328 However, activation of LXRs also up-regulates liver SREBP1c, leading to hepatic steatosis and hypertriglyceridemia, which limits clinical application of LXR agonizts. 329 For this reason, some specific targeted agonizts have been developed. GW6340 is a gut-specific LXR agonist which promotes macrophage RCT but has no effect on TG levels in plasma. 330 Furthermore, IMB-808 significantly activates cholesterol efflux from RAW264.7 and THP-1-derived macrophages while has little effect on expression of lipogenic genes in HepG2 cells. 331

In order to avoid the side effects of LXRs agonizts, some methods of drug combination or targeted therapy have also been developed. We demonstrated that T0901317 in combination with a MEK1/2 inhibitor, U0126, inhibited atherosclerosis and blocked T0901317-induced hypertriglyceridemia. 332 We also reported that the combined treatment of metformin and T0901317 not only blocked T0901317-induced hypertriglyceridemia, but also enhanced the atherosclerosis-inhibiting effect of T0901317 by selectively activating LXRβ but not LXRα. 333 In view of the good targeting of nanomaterials, the side effects of liver can be avoided by using nano-carriers to deliver LXR agonizts. Last year, we reported a nanofibrous hydrogel, encapsulated T0901317 by the small peptide D-Nap-GFFY, selectively targeted macrophages but not hepatocytes. Thus, the hydrogel-encapsulated T0901317 inhibited the development of atherosclerosis without increasing TG levels. 334 Although LXR agonizts have been shown the potential to slow atherosclerosis progression in animal models, they are still a long way from clinical use.

CETP inhibitors can reduce LDL-C and increase HDL-C levels by inhibiting the transfer of cholesterol esters from HDL to LDL particles. 188 It has been reported that CETP activity is significantly elevated in patients with metabolic disorders and a high cardiovascular risk, indicating CETP can be a potential indicator of cardiovascular risk. 335 In vivo experiments show that elimination of CETP activity inhibits cholesterol diet-induced atherosclerosis in rabbits. 336 These results provide a basis for the potential of CETP inhibitors to improve blood lipids and reduce ASCVD risk.

CETP inhibitors to date include torcetrapib, dalcetrapib, evacetrapib, anacetrapib and obicetrapib. Since CETP is not existing in mice, most translational studies of CETP inhibitors are performed in ApoE3*CETP Leiden mice. Unfortunately, the first CETP inhibitor, torcetrapib, has been observed to increase the incidence of cardiovascular events and overall mortality, although it increased HDL-C while decreased LDL-C. 337 When used in treatment of patients with acute coronary syndrome, dalcetrapib had no effect on reduction of the recurrent cardiovascular events, therefore, use of dalcetrapib was discontinued early. 338 Similarly, evacetrapib adversely affected the cardiovascular outcomes in patients who had high risk of vascular disease. 339 On the other hand, anacetrapib significantly improved lipids and reduced the incidence of major coronary events in patients with a good tolerance. 340 However, anacetrapib was also discontinued due to its long half-life. A 12-week monotherapy trial of obicetrapib, the latest CETP inhibitor, showed a 45.3% reduction in LDL-C compared to placebo. 341 Current studies are evaluating obicetrapib in patients who are intolerant of statins in a phase 3 study.

LOX-1 is a scavenger receptor for oxLDL and plays an important role in oxLDL uptake by cells. 342 In atherosclerotic plaques and surrounding tissues, LOX-1 is highly expressed. It promotes uptake of oxLDL by ECs, VSMCs, monocytes and macrophages, resulting in foam cell formation. 342 At the same time, some studies have shown that LOX-1 deletion significantly reduces oxidative stress, nitric oxide degradation and inflammatory responses, reducing the progression of atherosclerosis. 343 , 344 Therefore, it is suggested that LOX-1 promotes the atherosclerosis progression. Contradictorily, liver overexpression of LOX-1 promoted oxLDL uptake, decreased plasma oxLDL, and inhibited the progression of atherosclerosis in ApoE-deficient mice. 345 Hence, LOX-1 is also a key regulator in the mechanisms of atherosclerotic plaque formation, progression and instability which may need further investigation.

Currently, some natural products, such as Tanshinone II-A, curcumin and Gingko biloba extract, have been shown to prevent atherosclerosis through LOX-1 inhibition. 346 , 347 , 348 The LOX-1 molecule consists of a hydrophobic channel that is the primary binding site for the phospholipid moiety of oxLDL. 349 Chemically synthesized small molecules targeting this channel can effectively reduce oxLDL uptake in vitro. 350 In addition to chemically synthesized inhibitors, many monoclonal antibodies are available to block LOX-1 activity. However, these antibodies are currently limited to cell and animal experiments because LOX-1 molecule contains a highly conserved C-type lectin-like domain in mammals, making it challenging to develop human LOX-1 antibodies. 351 At present, the research of chimeric LOX-1 antibody is still in progress.

SR-BI is a member of the scavenger receptor family. Liver SR-BI regulates RCT by taking up HDL-C and transporting cholesterol to bile. Liver SR-BI regulates HDL composition, mediates cholesterol efflux, and reduces inflammation and oxidation through selective uptake of HDL lipids. In macrophages and ECs, SR-BI is important in inhibiting atherosclerosis and reducing foam cell formation by regulating cholesterol transport. 352 Therefore, SR-BI is a potential multifunctional target for inhibiting atherosclerosis.

The current study has identified the protective role of SR-BI in mice with atherosclerosis. Genomic analysis reveals increased risk of CVD in loss-of-function carriers of scavenger receptor class B member 1 ( SCARB1 ) variant, which encodes SR-BI, suggesting the protective role of SR-BI in atherosclerosis. 353 Given the recent appreciation of endothelial SR-BI in LDL transcytosis, SR-BI targeted therapies need to be assessed with caution. 354 At present, the mechanism by which SR-BI works in human body is still unclear, so exploring its detailed mechanism is crucial for the development of new treatments for atherosclerosis.

LCAT is the only enzyme in plasma that esterifies cholesterol, and its activity is a major determinant of HDL-C levels. 355 LCAT plays a central role in HDL metabolism and RCT, so it is generally considered to be anti-atherosclerotic. However, studies in humans and animals obtained different results, so whether its activity can improve the function of HDL is controversial. 356 , 357 This may be related to the levels of LDL-C, the presence or absence of CETP and SR-BI, and the degree of overexpression of LCAT. 356

AlphaCore Pharmaceuticals developed the original recombinant human LCAT (rhLCAT) for clinical testing. In a phase 1 clinical trial, this early rhLCAT formulation, ACP501, increased plasma HDL-C by 50% and promoted cholesterol efflux without serious adverse reactions. 358 Since then, a new formulation of rhLCAT, MEDI6012, has been developed, which can raise plasma HDL-C in patients with atherosclerosis by injection three times a week. 359 However, it was abandoned in phase 2 for safety or efficacy reasons. Compound A is the first identified small molecular activator of LCAT that can covalently bind to residue C31 of LCAT, and has been shown to increase LCAT activity in vitro with unclear function on atherosclerosis. 360 , 361

In addition, another class of activators bind LCAT in a non-covalent and reversible manner. Previous studies have shown that such activators stabilize the open, active conformation of the enzyme, thereby facilitating lipid transport to the active site. 362 DS-8190a is an orally bioavailable and novel small-molecular LCAT activator that can directly interact with human LCAT. It inhibited atherosclerosis in mice expressing human LCAT, which was associated with enhanced the RCT process. Oral administration of DS-8190A also stimulated RCT process in primate cynomolgus monkeys. 363 These studies suggest that LCAT activation may help to reduce residual risk of ASCVD.

MiR-33 and miR-122

MicroRNAs (miRNAs) belong to a family of endogenous noncoding RNAs that can regulate gene expression post-transcriptionally. By binding to the 3′-untranslated region (3′UTR) of target genes, miRNAs promote translational repression or mRNA degradation. 364 Recent studies have shown that miRNAs are involved in cholesterol uptake, synthesis, and efflux, and are expected to be potential targets for regulating cholesterol metabolism. 365 , 366 , 367

miRNA-33 (miR-33) is composed of miR-33a and miR-33b, located in the SREBP2 and SREBP1 gene introns, respectively, and co-expressed under different stimulation conditions. 368 , 369 miR-33 inhibits expression of the genes involved in cholesterol efflux and HDL synthesis, such as ABCA1 and ABCG1 . 370 Studies have shown that inhibition of miR-33 induces hepatic ABCA1 expression, thereby increasing plasma HDL-C levels, and the inhibition also promotes RCT in macrophages and regression of atherosclerosis. 371 , 372 In addition, some studies have investigated the role of miR-33 on VLDL/LDL metabolism. It has been reported that global knockout of miR-33 in mice increases plasma LDL-C/VLDL-C levels. 373 However, mice may experience these effects due to their genetic background. The levels of VLDL-C and VLDL-TG were increased in LDLR deficient mice but not ApoE deficient mice fed Western diet after miR-33 knockout, which may be due to a high basal level of VLDL in ApoE deficient mice. 374 , 375 Based on the existing studies, although inhibition of miR-33 can effectively improve cholesterol efflux and HDL synthesis, its side effects remain to be clarified.

miRNA-122 (miR-122) is the most abundant hepatic miRNA. Its levels are positively correlated to human plasma cholesterol levels, suggesting that miR-122 can be involved in regulation of cholesterol metabolism. 376 miR-122 inhibitors have been reported to reduce plasma TC levels in mice and non-human primates. 377 , 378 , 379 However, miR-122 deletion is accompanied by significant hepatic steatosis, so the safety of miR-122 treatment remains to be investigated. 380 Moreover, to designate miR-122 as a potential therapeutic target for regulating cholesterol metabolism, the further elucidation on its physiological role is required.

Prekallikrein

Recently, the coagulation factor PK [encoded by the kallikrein B1 ( KLKB1 ) gene] was identified as a binding protein of LDLR. 140 In this study, it was found that PK binds to LDLR and causes LDLR lysosomal degradation, while plasma PK concentrations in humans are positively correlated to LDL-C levels. Loss of KLKB1 increases hepatic LDLR and reduces FC, attenuating atherosclerosis progression in multiple rodent models. In addition, the use of anti-competitive neutralizing antibodies can also reduce plasma lipids by up-regulating liver LDLR. This study suggests that PK may represent a potential treatment target for ASCVD.

Benefits of improving cholesterol homeostasis in other diseases

In addition to ASCVD, cholesterol metabolic disorders are also involved in the pathogenesis of other diseases and cholesterol lowering can ameliorate them. Interestingly, improving cholesterol homeostasis may be beneficial to several diseases even the role of cholesterol in these diseases remains unclear.

NAFLD is a chronic liver disease caused by excessive lipid deposition in liver cells without significant alcohol intake. 381 NAFLD includes nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). 382 The accumulation of FC in the liver is also relevant to the pathogenesis of NAFLD. 383 , 384 Epidemiological studies have found that intake of excess dietary cholesterol significantly increases the risk of NAFL and NASH. 385 , 386 A study of lipidomic analysis of liver biopsies from patients with NAFLD showed that hepatic FC level was positively correlated to the severity of liver histopathology. 382 Animal studies also showed that exogenous induction of FC accumulation in the liver can promote the progression of NAFL to NASH. 387 , 388

In NAFLD, hepatic cholesterol homeostasis is imbalanced, resulting in elevated levels of hepatic cholesterol. 389 This dysregulation may involve multiple metabolic pathways, including activation of cholesterol biosynthetic pathway (elevated expression and activity of SREBP2 and HMGCR), and cholesterol de-esterification (enhanced hydrolysis of CE to FC by hepatic neutral CE hydrolase), and reduced cholesterol export and BA synthesis (reduced expression of ABCG8 and CYP7A1). 70 , 384 , 390 , 391 However, the contributions of these pathways to NAFLD need to be further explored.

The exact mechanism of excess cholesterol toxicity in NAFLD remains incompletely described. Excess cholesterol accumulation in hepatocytes stimulates the formation of cholesterol crystals. 392 The presence of cholesterol crystals in hepatocytes activates NLRP3 inflammation, ultimately leads to hepatocyte death. Küpffer cells (KCs) aggregate around necrotic hepatocytes and trigger the formation of “crown-like structures”. Subsequently, KCs process these cholesterol crystals released from the dead hepatocytes and transform into foam cells. 383 , 392 Meanwhile, cholesterol crystals-induced activation of KCs triggers the activation of hepatic stellate cells (HSCs) by releasing inflammatory cytokines and transforming growth factor β, further accelerating the progression of NASH to fibrosis. 393 Furthermore, transcriptional coactivator with PDZ-binding motif (TAZ) is a transcriptional regulator that promotes NASH fibrosis and its expression is significantly increased in the NASH process. 394 , 395 , 396 Wang et al. firstly demonstrated that cholesterol prevents TAZ proteasomal degradation via the soluble adenylate cyclase-protein kinase A-inositol trisphosphate receptor-calcium-RhoA pathway. 397 This provides a new mechanism for the importance of hepatocyte cholesterol in the development of NASH. In summary, the cholesterol accumulation in hepatocytes and hepatic non-parenchymal cells accelerates the pathological process of NAFLD.

Clinical data show that statin treatment in patients with NAFLD reduces intrahepatic cholesterol levels. 398 , 399 , 400 Interestingly, the effect of ezetimibe on NAFLD in clinical trials is controversial. Several clinical studies suggest that ezetimibe may be beneficial for NAFLD. 401 , 402 However, a randomized, double-blind, placebo-controlled trial showed that ezetimibe had no significant effect on liver histology in NASH patients, 403 indicating more studies are needed to address the effect of ezetimibe. In addition to classic cholesterol-lowering drugs, other interventions to lower cholesterol may also be beneficial for NAFLD. Lanifibranor is a pan-PPAR agonist. In a recent phase 2b clinical study, lanifibranor not only showed good tolerability but also significantly improved liver fibrosis in NASH patients. 404 Lanifibranor improved NASH may be partially related to lowering cholesterol. Yang et al. found that knockout of E3 ligase SH3 domain-containing ring finger 2 ( SH3RF2 ) in hepatocytes resulted in accumulation of acetyl-CoA, which directly promoted cholesterol synthesis and aggravated the development of NAFLD. 405 Furthermore, miRNAs are key factors in regulating hepatic cholesterol synthesis. 406 Targeting SH3RF2 or miRNAs may be a new approach to alleviate NAFLD by lowering cholesterol.

Obesity is the manifestation of metabolic syndrome in the adipose tissue, which is associated with various chronic diseases, particularly CVD, diabetes, and certain types of cancers. 407 , 408 , 409 Changes in diet composition are one of the main reasons for the increasing trend of obesity. Chung et al. demonstrated that high dietary consumption of cholesterol was sufficient to induce an increase in visceral adipose cholesterol content and promote inflammation with adipose tissue in monkeys. 410 In addition, the genome-wide association studies have found the significant association between NPC1 and obesity. 411 This may provide a new explanation for familial obesity.

Adipose tissue plays a central role in energy metabolism and adaptation to the nutritional environment, and about 25% of the person’s cholesterol is stored in adipose tissues. 412 In obesity, cholesterol imbalance triggers inflammation in adipocytes and fat-resident immune cells, thus disrupting metabolic homeostasis. 413 In the initial stages of obesity, white adipose tissue exhibits physiological expansion and releases acute pro-inflammatory factors in order to store more energy. 414 Therefore, this initial pro-inflammatory response may be only physiologically adaptive. However, when cholesterol crystals accumulate in adipocytes and immune cells, it activates NLRP3 inflammasome, leading to increased inflammation. 415 Meanwhile, local inflammation in adipose tissue may directly affect brown adipocyte thermogenesis and beige adipocyte recruitment, which also hinders thermogenesis. 414 Taken together, excessive accumulation of cholesterol in adipose tissues causes inflammation and adipocyte dysfunction. Therefore, cholesterol-lowering therapies may be beneficial for obesity.

Triiodothyronine (T3) is the biologically active form of thyroid hormone. Grover et al. demonstrated that T3 regulates cholesterol metabolism via acting thyroid hormone receptor β signaling. 416 Both clinical and animal studies have shown that T3 treatment increased the rate of cholesterol metabolism. 416 , 417 However, the pharmacological benefits of T3 are limited by its side effects, particularly on heart rate. A novel strategy preferentially delivers T3 to the liver, thus mitigating its side effects. 418 Some new cholesterol-lowering targets may also be beneficial for obesity. Berbe´e et al. demonstrated that β3-adrenergic receptor-stimulated activation of brown adipose tissue reduces obesity by decreasing plasma cholesterol levels. 419 The selective thyroid hormone receptor modulator GC-1 has been shown to have better cholesterol-lowering efficacy than atorvastatin in animal studies. 420 These observations deserve further studies and hopefully offer new perspective for the treatment of lipid disorders and obesity. Interestingly, diet and lifestyle changes can also lower cholesterol. In a clinical trial with 82 healthy overweight and obese subjects, an isocaloric Mediterranean diet intervention was found to lower plasma cholesterol and alter the microbiome and metabolome. 421 Moreover, dietary and exercise interventions produced better outcomes for obese children. 422 Solving the obesity problem is a daunting challenge that seems to inevitably require multiple interventions. The development of drugs to treat obesity has been underway for more than a century and is continuing. 423 Consequently, for obese patients, lowering cholesterol may need to be used in combination with other interventions.

The relationship between TG and diabetes has been proposed at a fairly early stage. 424 , 425 , 426 However, the role of cholesterol has been underrecognized. The specific cholesterol homeostasis in pancreatic β cells plays a key role in insulin secretion. In 2007, two studies demonstrated that excess cholesterol inhibits insulin secretion from β cells. Brunham et al. reported that mice with specific knockout of ABCA1 in β cells had increased cholesterol levels and impaired glucose-stimulated insulin secretion. 427 Likewise, Hao et al. proved that accumulation of cholesterol in β cells influenced the translocation and activation of glucokinase, further inhibiting insulin secretion. 428 Subsequently, Vergeer et al. confirmed that carriers of loss-of-function mutant ABCA1 have pancreatic β-cell dysfunction. 429 The final step in insulin secretion is the fusion of insulin granules with plasma membrane and then secreted outside the cell through exocytosis. Xu et al. found that excess cholesterol can reduce insulin exocytosis through a dynamic-dependent process activated by phosphatidylinositol 4,5-bisphosphate. 430 Meanwhile, cholesterol accumulation also induces apoptosis of pancreatic β cells by enhancing mitochondrial bioenergetic damage, inflammation, oxidative stress and ER stress. 431 , 432 , 433 In addition, imbalanced cholesterol homeostasis in β cells increases obesity, reduces skeletal muscle mass and causes systemic inflammation. 434 This may provide a new explanation for the link between diabetes and obesity.

Given the harmful effects of cholesterol on β-cell function, cholesterol-lowering therapies may be therapeutically beneficial. In a randomized, double-blinded study, subjects taking a CETP inhibitor significantly increased postprandial insulin secretion. 435 This may be due to increased cholesterol efflux from pancreatic β cells. 435 Surprisingly, there is growing evidence showing that statin therapy could increase the risk of diabetes in a dose-dependent manner. 436 , 437 , 438 A recent animal study explains that atorvastatin impairs β-cell function by modulating small G protein, which subsequently dysregulating islet mTOR signaling and reducing functional β-cell mass. 439 Therefore, statins may need to be combined with other drugs for a better use in diabetic patients with hypercholesterolemia. Interestingly, ezetimibe promotes insulin secretion and protects β-cell function in diabetic mice. 440 Exploring the specific mechanism of ezetimibe to promote insulin secretion will be an interesting future investigation. Moreover, miR-33a and miR-145 can downregulate ABCA1, leading to cholesterol accumulation and reduction of insulin secretion. 441 , 442 Thus, targeting microRNAs or other epigenetic mechanisms may offer a promising therapeutic strategy for diabetes and its complications.

Neurodegenerative diseases

The brain is the cholesterol-rich organ in the body, accounting for approximately 20% of the body’s cholesterol. 443 Cholesterol homeostasis in the brain must be accurately controlled to ensure the brain to work properly. 444 Imbalance of cholesterol homeostasis in the brain is involved in the development of neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD).

Several reviews have linked cholesterol to the pathophysiology of AD, revealing the importance of cholesterol homeostasis in AD. 445 , 446 , 447 In an early clinical study, FH was shown to be an early risk factor for AD. 448 Plasma cholesterol can be oxidized to 27-hydroxycholesterol, which is able to cross the blood-brain barrier (BBB) and reach the central nervous system (CNS). 449 This establishes a critical link between FH and increased brain cholesterol. Xiong et al. stained brain sections from AD patients and found that cholesterol levels increased with disease progression. 450 A recent animal study has shown that a high-cholesterol diet disrupts BBB and impairs cognitive function. 448 Cutler et al. found that oxidative stress induced disturbances in cholesterol metabolism, leading to enrichment of cholesterol in neurons, which exacerbates the process of AD. 451 It is necessary to note that lipoproteins can’t cross the intact BBB. 444 The accumulation of cholesterol in the brain may be due to a disruption of BBB or a disturbance in the brain’s own cholesterol metabolism. However, the exact mechanism needs to be further explored.

Amyloid protein is cleaved to β-amyloid (Aβ) by β and γ-secretase. Aβ aggregation is the predominant pathological marker of AD. 445 Sparks et al. identified the effect of cholesterol on Aβ accumulation in 1994. 452 They found that feeding a cholesterol-rich diet to rabbits for eight weeks led to accumulation of intracellular Aβ in neurons in the hippocampal region. Many subsequent experiments have also demonstrated that cholesterol promotes Aβ accumulation. A key reason for the sensitivity of Aβ to cholesterol is that the activity of β and γ secretase is positively correlated to cholesterol levels. 446 , 453 Furthermore, cholesterol not only promotes Aβ secretion, but also impairs autophagy-mediated clearance of Aβ. Pathological accumulation of phosphorylated Tau (pTau) is another major biochemical marker of AD. Meanwhile, hyperphosphorylation of tau is accompanied with formation of neurofibrillary tangles (NFTs). 454 , 455 Imbalance in cholesterol homeostasis also increases pTau. A case-control study found a significant tau deposition in the brains of Niemann-Pick type C patients. 456 CE are the major storage form of excess cholesterol, and Kant et al. found that CE inhibited pTau degradation by inhibiting proteasome activity. 457 Conversely, Fan et al. demonstrated that cholesterol deficiency also leads to tau hyperphosphorylation, 458 indicating the exact mechanism of cholesterol effects on p-Tau remains to be further explored.

PD is the second most common progressive neurodegenerative disease after AD, and its pathological features include the loss of dopaminergic neurons and the formation of Lewy bodies from the accumulation of α-synuclein. 459 Increasing evidence suggests that cholesterol metabolism may also play a role in the pathogenesis of PD. However, the role of TC in PD is controversial. Some clinical studies found no difference in TC levels between PD patients and healthy controls. 460 , 461 In contrast, other prospective studies even found that high levels of TC were associated with a lower risk of PD. 462 , 463 This may be due to the fact that cholesterol levels decrease with age, and PD usually occurs more often in older age. As reported by Hu et al., the high TC levels increases the risk of PD in individuals aged 25-54 years, but this association is not significant after 55 years. 464 Thus, high TC levels in young and middle-aged individuals may promote PD development, which has been demonstrated in animal models with high-fat diets. 465 , 466

In spite of the unclear role of cholesterol in PD pathogenesis, several possible hypotheses have been proposed. Bar-On et al. treated B103 cells with cholesterol and found more α-synuclein aggregates while statin can reduce the aggregation. 467 The subsequent studies found that α-synuclein has a similar structure to apolipoproteins. 468 , 469 Thus, there is an interaction between cholesterol and α-synuclein. Fantini et al. found that cholesterol promotes α-synuclein insertion into lipid rafts through a virus-like fusion mechanism. 469 Hsiao et al. found that α-synuclein promotes cholesterol efflux in SH-SY5Y cells. 470 However, the relationship between cholesterol and α-synuclein remains to be further explored.

HD is an autosomal dominant neurodegenerative disorder caused by an abnormal expansion of the CAG trinucleotide repeat of the Huntington ( HTT ) gene. 471 Cholesterol homeostasis is altered in HD, which may be an effective disease-modifying strategy in the future. 472 An early investigation showed no significant changes in plasma cholesterol concentrations in HD patients. 473 However, another study found reduced mRNA levels of HMGCR, and 7-dehydrocholesterol reductase in postmortem tissues of HD patients. 474 Subsequently, Leoni et al. reported reduced blood cholesterol levels in HD patients. 475 Similarly, reduced brain cholesterol levels were also found in a variety of HD animal models. 476 , 477 , 478

Interestingly, reduced cholesterol level is more likely a phenomenon in the process of HD pathogenesis. There is evidence showing that mutant Huntington (m HTT ) interferes with SREBP2 activation, leading to reduced expression of HMGCR and cholesterol synthesis. 479 Brain-derived neurotrophic factor (BDNF) can also stimulate cholesterol synthesis. 480 Normal HTT promotes vesicular transport of BDNF vesicles along microtubules. 481 However, this process is inhibited by m HTT , resulting in decreased BDNF levels in the striatum, which may be another pathway leading to reduced cholesterol synthesis. 478 In contrast, cholesterol accumulates in mHTT­expressing neurons despite the downregulation of cholesterol synthesis. 482 Daniel et al. found that mHTT ­expressing neurons show elevated levels of the lipid raft marker ganglioside GM1, suggesting that cholesterol accumulation is associated with an increase in lipid rafts. 483 The present evidence suggests that reduced cholesterol synthesis and cholesterol accumulation in neurons are the main manifestations of imbalanced cholesterol homeostasis in HD. Determining which aspect of cholesterol dysregulation primarily affects the pathological process of HD will be a major challenge in the future.

Based on the reports above, modulation of cholesterol homeostasis could be a potential therapeutic target for neurodegenerative diseases. Lipophilic statins can cross the BBB and have the potential to modulate cholesterol homeostasis in the brain. 484 Several preclinical trials have shown multiple potential benefits of statins in neurodegenerative diseases. 484 , 485 , 486 , 487 Although the protective effects of statins in preclinical trials are consistent, the results of clinical trials remain controversial. Epidemiological studies have shown a 70% reduction in incidence of AD in subjects taking statins. 488 Treatment of subjects with statin at doses used in the clinical management of hypercholesterolemia resulted in a nearly 40% reduction in Aβ production in human plasma. 489 Li et al. reported that NFT burden was significantly reduced in subjects who had taken statins by brain autopsy. 490 By contrast, a cohort study that included 2798 individuals found that statin treatment was not associated with the risk of AD. 491 Similarly, most observational studies have shown that the use of statins reduces the risk of PD, 492 , 493 , 494 whereas some clinical trials have found that statins have no effect on PD or even increase the odds of PD. 495 , 496 However, no clinical trials have been conducted to evaluate the role of statins in HD to date. Due to the specificity of cholesterol homeostasis in HD, the benefit of statins in HD may be through anti-inflammation, anti-oxidative stress, and neuroprotection, rather than the ability to regulate cholesterol metabolism. Therefore, well-designed preclinical trials are needed to prove the effects of statins on HD. Other cholesterol-lowering drugs have also shown protection against neurodegenerative diseases in preclinical animal models. Efavirenz reduces p-Tau in a dose-dependent manner by decreasing CE production. 457 BM15.766, a specific inhibitor of cholesterol synthesis, showed inhibition of Aβ in transgenic AD mice model. 497 In addition, LXRs are major regulators of cholesterol homeostasis and inflammation in the CNS. 498 LXRs agonizts were shown to have alleviating effect in neurodegenerative diseases in preclinical trials. 499 , 500 , 501 β-Cyclodextrin and its derivatives also have a beneficial effect on the neurodegenerative diseases as drugs or drug carriers. 502 , 503 The pathogenesis of neurodegenerative diseases is mediated by a variety of factors, and cholesterol disorders may intricately aggravate the disease process. Considering the importance of cholesterol for the brain cell membrane integrity, cholesterol-lowering drugs should be used precisely with tailored needs. In other words, they are recommended for patients of neurodegenerative diseases with a relatively high cholesterol background.

Cholesterol is an essential neutral lipid which is necessary for membrane integrity and fluidity. 504 The increasing evidence demonstrate that tumor cells need an increased supply of cholesterol and can accumulate it. 505 , 506 , 507 It has been reported that during cancer progression, cholesterol influx and synthesis is increased and cholesterol efflux is decreased. 508 Aberrant activation of SREBPs is the main cause of increased tumor cholesterol synthesis. For example, in hepatocellular carcinoma, the sustained activation of protein kinase B (PKB) phosphorylates phosphoenolpyruvate carboxykinase 1, which in turn activates SREBPs and promotes tumor growth. 509 The alteration of the extracellular microenvironment of tumor cells also leads to activation of SREBPs. In breast cancer models, hypoxia induces PKB phosphorylation, which in turn activates hypoxia-inducible factor 1 and subsequently upregulates expression of SREBPs. 510 In addition, increased inflammatory factors, lower pH and excess glucose in the microenvironment can also activate SREBPs. 510 , 511 LXR promotes expression of cholesterol efflux proteins, ABCA1, ABCG1 and ABCG5, to reduce intracellular cholesterol concentrations. However, LXR is inhibited in tumors, which contributes to cholesterol accumulation in cancer cells. 512 , 513 Interestingly, CE levels were also significantly increased in tumors. 513 , 514 ACAT involves in synthesis of CE, which has been shown to be associated with a variety of tumors. 513 , 515 A latest study found that loss of P53 increased ubiquitin specific peptidase 19, which in turn stabilized ACAT1 and led to CE accumulation. 516 This study provides an important mechanism indicating the involvement of CE in hepatocellular carcinogenesis.

Similar to tumor cells, activation of cholesterol synthesis pathway is necessary to maintain T cell function. However, excessive cholesterol in the tumor microenvironment leads to ER stress in CD8 + T cells. Furthermore, the ER stress sensor X-box-binding protein 1 is activated to regulate transcription of programmed death 1 and natural killer cell receptor 2B4, which ultimately leads to T cell exhaustion. 517 It can be seen that the effect of increased extrinsic supply of cholesterol on T cells seems to be negative in the situation where tumor cells have a greater capacity to absorb cholesterol. In another study, ovarian cancer cells promoted tumor-associated macrophage (TAM) cholesterol efflux by secreting hyaluronic acid, which induced TAM conversion from M1 to M2 type and promoted tumor growth. 518

Statins have been shown to have good inhibitory effects on estrogen receptor-negative breast cancer, multiple myeloma, prostate cancer and some other specific tumors. 519 , 520 , 521 However, in several phase 3 clinical trail studies, treatment of 40 mg/day pravastatin or simvastatin to patients with small cell lung cancer, metastatic colorectal cancer, advanced hepatocellular carcinoma, or advanced gastric cancer had no additional benefit. 522 , 523 , 524 , 525 Therefore, a precision medicine approach is necessary if statins are to be incorporated into the treatment of cancer patients. Avacizimibe, a potent inhibitor of ACAT1, has been shown to affect the survival and proliferation of tumor cells in several preclinical studies. 526 , 527 , 528 The clinical application of Avacizimibe in anti-tumor needs to be further explored. In addition, drugs targeting the absorption and efflux of cholesterol have been tried for cancer treatment. LXR agonist, T0901317, suppressed the development of prostate cancer by upregulating ABCA1 and ABCG1 expression. 529 Ezetimibe significantly inhibited the growth of prostate and liver cancers. 530 , 531 Yuan et al. found that the tumor microenvironment could inhibit LDLR expression in CD8 + T cells via activating PCSK9, which suppressed the antitumor activity of CD8 + T cells. 532 Therefore, PCSK9 may be a novel target for tumor immunotherapy. The anti-tumor effects of PCSK9 inhibitors need to be further explored. In summary, drugs targeting cholesterol metabolic pathways have been demonstrated in many cancers. Considering the complexity of cancer metabolism, there are still many open questions that need to be addressed. For example, at what stage of tumorigenesis do these drugs act specifically, such as tumor metastasis? Do statins affect the function of circulating tumor cells? How do statins affect tumor cell metabolism in tumor microenvironment?

Osteoporosis

Osteoporosis most commonly occurs to postmenopausal women caused by impaired bone formation and/or excessive bone resorption. Bone mineral density (BMD) is considered as the key standard for determining osteoporosis. 533 Vitamin D, one of the important metabolites of cholesterol, induces synthesis of calcium-binding proteins to promote Ca 2+ absorption and enhances BMD. 534 Interestingly, epidemiological evidence indicates that high serum cholesterol levels represent a risk factor for osteoporosis. 535 , 536 , 537 , 538 Also, this phenomenon has been confirmed in several animal experiments. 539 , 540 , 541

Previous studies have given several possible explanations for why cholesterol increases the risk of osteoporosis. Cutillas-Marco et al. found that vitamin D levels were negatively associated with TC and LDL-C levels in a population-based survey. 542 This may be the most important cause of osteoporosis due to high cholesterol. However, the exact mechanism needs to be further explored. Bone homeostasis is maintained by osteoclastic bone resorption and osteoblastic bone formation. Experimental animal studies have shown that osteoclast functions are significantly cholesterol-dependent. 543 , 544 A high cholesterol diet leads to increased osteoclast numbers and bone resorption. 544 Conversely, inhibition of proliferation and differentiation of osteoblast MC3T3-E1 cells by cholesterol was determined in a dose-dependent manner, while resulted in decreased expression of the bone formation markers, bone morphogenetic protein-2 and runt-related transcription factor 2.

The clinical use of statins to prevent and/or treat osteoporosis is controversial. In 2018, an investigation found a reduced risk of osteoporosis in stroke patients using statins. 545 Ann et al. showed that statin increased BMD and appeared to be more effective in men with osteoporosis by meta-analysis. 546 However, in 2019, a cross-sectional retrospective study of healthy subjects reported that high doses of statins significantly increased the risk of osteoporosis. 547 This may indicate that statins are more appropriate for patients with severe hypercholesterolemia and high risk for osteoporosis. Furthermore, less of the statins reach the bone after the drug has been metabolized. This explains the fact that statins are often used at much higher doses than clinical ones to relieve osteoporosis. 548 Consequently, local delivery of statins needs further exploration.

Virus infection

A lipid raft is a subdomain of the plasma membrane enriched in cholesterol and sphingolipids, which also act as vectors for viruses to enter the host cells. 549 , 550 Studies have shown an association between cholesterol levels and virus infections. 551 , 552 , 553 Louie et al. found that additional 2% cholesterol in the diet causes inflammatory imbalance and exacerbates morbidity in mice infected with influenza A virus. 554 Wang et al. proved that pseudorabies virus (PRV) increases self-infection capability by suppressing LXR expression to increase total intracellular cholesterol levels. 555 COVID-19 is caused by an infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Sphingolipid- and cholesterol-rich regions recruit several receptors and molecules involved in pathogen recognition and cell signaling. 556 Angiotensin-converting enzyme 2 (ACE2) can be recruited to these regions as the primary functional receptor for SARS-CoV-2. 556 Therefore, cholesterol may be functionally important as a mediator of COVID-19 infection. Radenkovic et al. suggested that lipid rafts rich in ACE2 receptors may be increased in a state of high cholesterol levels, thus enhancing the endocytosis process of SARS-CoV-2. 557 Sanders et al. proved that SARS-CoV-2 requires cholesterol for viral entry and pathological syncytia formation. 558 Similarly, Li et al. also found that cholesterol depletion impaired virus entry in vitro. 559 , 560 In addition, cholesterol plays a role in binding and altering the SARS-CoV N-terminal fusion peptide oligomeric state, which is required for virus entry into the host cells. 561 Although many reports suggest that cholesterol plays an important role in virus entry, this still needs to be confirmed in vivo. In particular, the effect of SARS-CoV-2 on cholesterol homeostasis remains unclear and the molecular mechanisms need to be further explored.

PCSK9 is another interesting mediator involved in viral infection. Several clinical studies have found that hepatitis C virus (HCV) infection is associated with increased PCSK9 serum levels. 562 , 563 , 564 PCSK9 negatively regulates the hepatocyte surface proteins (LDLR, SR-BI, VLDLR) involved in HCV entry in vitro. 565 Meanwhile, HCV infection upregulates PCSK9 expression. 566 This indicated a complex interaction between PCSK9 and HCV. A recent preclinical study indicated that dengue virus (DENV) infection also induced PCSK9 expression, which led to downregulation of LDLR expression with a sequester of cholesterol in the intracellular space, providing a more favorable environment for virus entry. 567 Therefore, PCSK9 appears to contribute to DENV infection. However, the relationship between PCSK9 and SARS-CoV-2 infection is unclear.

25-hydroxycholesterol (25HC) is one of the metabolites of cholesterol catalyzed by CH25H. 568 Unlike cholesterol, 25HC and its synthetic enzyme CH25H have been shown to have potent broad-spectrum antiviral activity. 569 Li et al. reported that 25HC and CH25H protected hosts from Zika virus infection in a mouse model. 570 Xiang et al. found that 25HC and CH25H inhibited HCV infection by blocking SREBP maturation to inhibit viral genome replication. 571 Similarly, several studies have also shown that 25HC and CH25H inhibit SARS-CoV-2 infection by blocking membrane fusion. 572 , 573 LXR has been shown to induce the activation of interferon-γ (IFN-γ), which stimulates the expression of CH25H. 569 , 574 Interestingly, our studies reported that 25HC can also induce CH25H expression in an LXR-dependent manner, and demonstrated that LXR activation, interaction between CH25H and IFN-γ, and 25HC metabolism may form an antiviral system in which LXR plays a central role. 575 , 576

There is an interaction between COVID-19 infection and CVD. Li et al. reported an increased prevalence of CVD in patients after COVID-19 infection. 577 Similarly, patients infected by COVID-19 who previously experienced CVD had an increased case fatality rate. 578 Thus, lowering cholesterol levels may reduce the risk of COVID-19-induced complications. Statins have been reported to have anti-viral activity. 579 Therefore, they were quickly used in clinical trials for patients with COVID-19 infection. An observational study of hospitalized COVID-19 infected patients indicated that statins might be effective against COVID-19. 580 Similar observations have been reported in several subsequent studies. 581 , 582 , 583 Subir et al. recommended that COVID-19 infected patients at a high CVD risk should continue statin therapy unless absolutely contraindicated. 584 Statins may lower membrane cholesterol levels, thereby decreasing the attachment and internalization of SARS-CoV-2. 557 Surprisingly, Reiner et al. identified several statins as potential SARS-CoV-2 major protease inhibitors by molecular docking, especially pitavastatin with the strongest binding. 585 Therefore, the benefits of statins for patients with COVID-19 may be exerted through their direct cholesterol lowering effects and beyond. Future research is needed to depict the precise mechanism of cholesterol-aimed viral entry, survival and discover the new cholesterol-lowering therapies in COVID-19 patients. In addition, a preclinical study has shown that LXR agonist, T0901317, significantly inhibits herpes simplex virus type 1 infection. 576 Similarly, T0901317 also showed better prevention of PRV infection in mice. 555 A monoclonal antibody of PCSK9 (alirocumab) was shown to inhibit DENV infection in vitro. 567 Boccara et al. firstly evaluated the efficacy and safety of evolocumab in reducing LDL-C levels in HIV patients in a multinational, randomized, double-blind study. 586 However, no clinical trials on the effects of PCSK9 inhibitors in SARS-CoV-2-infected patients to date. Nevertheless, experts believe that use of PCSK9 inhibitors is still beneficial for COVID-19 patients with familial hypercholesterolemia. 587 , 588

Summary and outlook

High circulating cholesterol level is a major risk factor for ASCVD and promotes the progression of atherosclerosis, making key molecules involved in cholesterol homeostasis as the attractive therapeutic targets for ASCVD treatment. By reducing cholesterol biosynthesis and enhancing cholesterol metabolism, statins are used widely to reduce the levels of plasma TC and LDL-C to prevent or reduce CVD. However, due to the side effects and intolerance of statins, non-statin cholesterol-lowering drugs are being developed and more other novel targets than cholesterol lowering have been characterized. Moreover, combination of non-statin cholesterol-lowering drugs (for example, ezetimibe or PCSK9 inhibitors) with statins may be more effective in reducing LDL-C levels. A very exciting development is the concept “the lower the better” of LDL-C reduction, indicating that a lower LDL-C is tightly correlated to a better attenuation of ASCVD. In addition, cholesterol lowering has been demonstrated to be beneficial in many other diseases (Table 3 ). Therefore, cholesterol-lowering therapy is a rapidly developing field with various new targets and drugs.

In the future, the investigations related to cholesterol may face more challenges. For example, characterizing the relationship between inflammation and cholesterol metabolic disorders and developing the specific anti-inflammatory therapeutic intervention in reducing inflammation in ASCVD. Beyond LDL-C, the intervention on other lipoproteins needs more efforts to investigate. Nowadays, various cholesterol-lowering drugs are used in clinics. However, the studies on personalized therapy, lifestyle and targeting the right patient with the right time still need more attention. Moreover, exploring the role of cholesterol in other diseases, especially the complications of metabolic disorders, may accelerate the translation of research to the clinic.

Vance, D. E. & Van den Bosch, H. Cholesterol in the year 2000. Biochim. Biophys. Acta 1529 , 1–8 (2000).

Article   CAS   PubMed   Google Scholar  

Nicholls, M. Adolf otto reinhold windaus. Eur. Heart J. 40 , 2659–2660 (2019).

Kennedy, E. P. & Westheimer, F. H. Nobel laureates: Bloch and Lynen win prize in medicine and physiology. Science 146 , 504–506 (1964).

Brown, M. S. & Goldstein, J. L. Cholesterol feedback: from Schoenheimer’s bottle to Scap’s MELADL. J. Lipid Res. 50 , S15–S27 (2009).

Article   PubMed   PubMed Central   CAS   Google Scholar  

Schoenheimer, R. & Breusch, F. Synthesis and destruction of cholesterol in the organism. J. Biol. Chem. 103 , 439–448 (1933).

Article   CAS   Google Scholar  

Brown, M. S. & Goldstein, J. L. The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell 89 , 331–340 (1997).

Brown, M. S., Ye, J., Rawson, R. B. & Goldstein, J. L. Regulated intramembrane proteolysis: a control mechanism conserved from bacteria to humans. Cell 100 , 391–398 (2000).

Goldstein, J. L. & Brown, M. S. A century of cholesterol and coronaries: from plaques to genes to statins. Cell 161 , 161–172 (2015).

Article   CAS   PubMed   PubMed Central   Google Scholar  

Endo, A. A historical perspective on the discovery of statins. Proc. Jpn Acad. Ser. B Phys. Biol. Sci. 86 , 484–493 (2010).

N., A. Über die veränderungen der kaninchenaorta bei experimenteller cholesterinsteatose. Beitr. Pathol. Anat. 56 , 379–404 (1913).

Google Scholar  

Lee, Y. T. et al. Mouse models of atherosclerosis: a historical perspective and recent advances. Lipids Health Dis. 16 , 12 (2017).

Tall, A. R. & Yvan-Charvet, L. Cholesterol, inflammation and innate immunity. Nat. Rev. Immunol. 15 , 104–116 (2015).

Grebe, A. & Latz, E. Cholesterol crystals and inflammation. Curr. Rheumatol. Rep. 15 , 313 (2013).

Baumer, Y., Mehta, N. N., Dey, A. K., Powell-Wiley, T. M. & Boisvert, W. A. Cholesterol crystals and atherosclerosis. Eur. Heart J. 41 , 2236–2239 (2020).

Rajamaki, K. et al. Cholesterol crystals activate the NLRP3 inflammasome in human macrophages: a novel link between cholesterol metabolism and inflammation. PLoS One 5 , e11765 (2010).

Duewell, P. et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 464 , 1357–1361 (2010).

Janoudi, A., Shamoun, F. E., Kalavakunta, J. K. & Abela, G. S. Cholesterol crystal induced arterial inflammation and destabilization of atherosclerotic plaque. Eur. Heart J. 37 , 1959–1967 (2016).

Soehnlein, O. & Libby, P. Targeting inflammation in atherosclerosis—from experimental insights to the clinic. Nat. Rev. Drug Discov. 20 , 589–610 (2021).

Libby, P., Ridker, P. M. & Maseri, A. Inflammation and atherosclerosis. Circulation 105 , 1135–1143 (2002).

Gofman, J. W., Lindgren, F. T. & Elliott, H. Ultracentrifugal studies of lipoproteins of human serum. J. Biol. Chem. 179 , 973–979 (1949).

Gofman, J. W. & Lindgren, F. The role of lipids and lipoproteins in atherosclerosis. Science 111 , 166–171 (1950).

Gofman, J. W. Serum lipoproteins and the evaluation of atherosclerosis. Ann. N. Y. Acad. Sci. 64 , 590–595 (1956).

Castelli, W. P., Anderson, K., Wilson, P. W. & Levy, D. Lipids and risk of coronary heart disease. framingham study Ann. Epidemiol. 2 , 23–28 (1992).

Müller, C. Xanthomata, hypercholesterolemia, angina pectoris. Acta Med. Scand. 89 , 75–84 (1938).

Khachadurian, A. K. The inheritance of essential familial hypercholesterolemia. Am. J. Med. 37 , 402–407 (1964).

Steinberg, D. Thematic review series: The pathogenesis of atherosclerosis: an interpretive history of the cholesterol controversy, part III: Mechanistically defining the role of hyperlipidemia. J. Lipid Res. 46 , 2037–2051 (2005).

Brown, M. S. & Goldstein, J. L. A receptor-mediated pathway for cholesterol homeostasis. Science 232 , 34–47 (1986).

Grundy, S. M. & Feingold, K. R. Guidelines for the Management of High Blood Cholesterol. in Endotext (eds K. R. Feingold et al.) (2000).

Endo, A., Kuroda, M. & Tanzawa, K. Competitive inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase by ML-236A and ML-236B fungal metabolites, having hypocholesterolemic activity. FEBS Lett. 72 , 323–326 (1976).

Brown, M. S., Faust, J. R., Goldstein, J. L., Kaneko, I. & Endo, A. Induction of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in human fibroblasts incubated with compactin (ML-236B), a competitive inhibitor of the reductase. J. Biol. Chem. 253 , 1121–1128 (1978).

Cho, L. A practical approach to the cholesterol guidelines and ASCVD prevention. Cleve Clin. J. Med. 87 , 15–20 (2020).

Article   PubMed   Google Scholar  

Davidson, M. H. Efficacy of simvastatin and ezetimibe in treating hypercholesterolemia. J. Am. Coll. Cardiol. 42 , 398–399 (2003). author reply 399.

Seidah, N. G. et al. The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): Liver regeneration and neuronal differentiation. Proc. Natl Acad. Sci. USA 100 , 928–933 (2003).

Lagace, T. A. et al. Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice. J. Clin. Investig. 116 , 2995–3005 (2006).

Zhang, D. W. et al. Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation. J. Biol. Chem. 282 , 18602–18612 (2007).

Kim, E. J. & Wierzbicki, A. S. The history of proprotein convertase subtilisin kexin-9 inhibitors and their role in the treatment of cardiovascular disease. Ther. Adv. Chronic Dis. 11 , 2040622320924569 (2020).

Lamb, Y. N. Inclisiran: first approval. Drugs 81 , 389–395 (2021).

Sanjay, K. V. et al. ATP citrate lyase inhibitor Bempedoic acid alleviate long term HFD induced NASH through improvement in glycemic control, reduction of hepatic triglycerides & total cholesterol, modulation of inflammatory & fibrotic genes and improvement in NAS score. Curr. Res Pharm. Drug Discov. 2 , 100051 (2021).

Govindaraju, A. & Sabarathinam, S. Bempedoic acid: a nonstatin drug for the management of hypercholesterolemia. Health Sci. Rep. 4 , e431 (2021).

Article   PubMed   PubMed Central   Google Scholar  

Feng, X., Zhang, L., Xu, S. & Shen, A. Z. ATP-citrate lyase (ACLY) in lipid metabolism and atherosclerosis: an updated review. Prog. Lipid Res. 77 , 101006 (2020).

Kapourchali, F. R., Surendiran, G., Goulet, A. & Moghadasian, M. H. The role of dietary cholesterol in lipoprotein metabolism and related metabolic abnormalities: a mini-review. Crit. Rev. Food Sci. Nutr. 56 , 2408–2415 (2016).

Rosenson, R. S. & Song, W. L. Egg yolk, source of bad cholesterol and good lipids? Am. J. Clin. Nutr. 110 , 548–549 (2019).

Myocardial Infarction Genetics Consortium, I. et al. Inactivating mutations in NPC1L1 and protection from coronary heart disease. N. Engl. J. Med 371 , 2072–2082 (2014).

Iqbal, J. & Hussain, M. M. Intestinal lipid absorption. Am. J. Physiol. Endocrinol. Metab. 296 , E1183–E1194 (2009).

Altmann, S. W. et al. Niemann-Pick C1 Like 1 protein is critical for intestinal cholesterol absorption. Science 303 , 1201–1204 (2004).

Fumeron, F., Bard, J. M. & Lecerf, J. M. Interindividual variability in the cholesterol-lowering effect of supplementation with plant sterols or stanols. Nutr. Rev. 75 , 134–145 (2017).

Cusack, L. K., Fernandez, M. L. & Volek, J. S. The food matrix and sterol characteristics affect the plasma cholesterol lowering of phytosterol/phytostanol. Adv. Nutr. 4 , 633–643 (2013).

Huff, M. W., Pollex, R. L. & Hegele, R. A. NPC1L1: evolution from pharmacological target to physiological sterol transporter. Arterioscler. Thromb. Vasc. Biol. 26 , 2433–2438 (2006).

Dietschy, J. M. & Gamel, W. G. Cholesterol synthesis in the intestine of man: regional differences and control mechanisms. J. Clin. Investig. 50 , 872–880 (1971).

Nestel, P. J. & Poyser, A. Changes in cholesterol synthesis and excretion when cholesterol intake is increased. Metabolism 25 , 1591–1599 (1976).

Rudney, H. & Sexton, R. C. Regulation of cholesterol biosynthesis. Annu. Rev. Nutr. 6 , 245–272 (1986).

Bloch, K. The biological synthesis of cholesterol. Science 150 , 19–28 (1965).

Goldstein, J. L. & Brown, M. S. Regulation of the mevalonate pathway. Nature 343 , 425–430 (1990).

DeBose-Boyd, R. A. Feedback regulation of cholesterol synthesis: sterol-accelerated ubiquitination and degradation of HMG CoA reductase. Cell Res 18 , 609–621 (2008).

Yokoyama, C. et al. SREBP-1, a basic-helix-loop-helix-leucine zipper protein that controls transcription of the low density lipoprotein receptor gene. Cell 75 , 187–197 (1993).

Gong, X. et al. Complex structure of the fission yeast SREBP-SCAP binding domains reveals an oligomeric organization. Cell Res 26 , 1197–1211 (2016).

Brown, M. S., Radhakrishnan, A. & Goldstein, J. L. Retrospective on cholesterol homeostasis: the central role of SCAP. Annu. Rev. Biochem. 87 , 783–807 (2018).

Luo, J., Yang, H. & Song, B. L. Mechanisms and regulation of cholesterol homeostasis. Nat. Rev. Mol. Cell Biol. 21 , 225–245 (2020).

Kober, D. L. et al. SCAP structures highlight key role for rotation of intertwined luminal loops in cholesterol sensing. Cell 184 , 3689–3701 e3622 (2021).

Yan, R. et al. A structure of human SCAP bound to INSIG-2 suggests how their interaction is regulated by sterols. Science 371 , eabb2224 (2021).

Sharpe, L. J., Coates, H. W. & Brown, A. J. Post-translational control of the long and winding road to cholesterol. J. Biol. Chem. 295 , 17549–17559 (2020).

Luskey, K. L. & Stevens, B. Human 3-hydroxy-3-methylglutaryl coenzyme A reductase. Conserved domains responsible for catalytic activity and sterol-regulated degradation. J. Biol. Chem. 260 , 10271–10277 (1985).

Song, B. L., Sever, N. & DeBose-Boyd, R. A. Gp78, a membrane-anchored ubiquitin ligase, associates with INSIG-1 and couples sterol-regulated ubiquitination to degradation of HMG CoA reductase. Mol. Cell 19 , 829–840 (2005).

Cao, J. et al. Ufd1 is a cofactor of gp78 and plays a key role in cholesterol metabolism by regulating the stability of HMG-CoA reductase. Cell Metab. 6 , 115–128 (2007).

Lee, J. N., Song, B., DeBose-Boyd, R. A. & Ye, J. Sterol-regulated degradation of INSIG-1 mediated by the membrane-bound ubiquitin ligase gp78. J. Biol. Chem. 281 , 39308–39315 (2006).

Liu, T. F. et al. Ablation of gp78 in liver improves hyperlipidemia and insulin resistance by inhibiting SREBP to decrease lipid biosynthesis. Cell Metab. 16 , 213–225 (2012).

Lu, X. Y. et al. Feeding induces cholesterol biosynthesis via the mTORC1-USP20-HMGCR axis. Nature 588 , 479–484 (2020).

Clarke, P. R. & Hardie, D. G. Regulation of HMG-CoA reductase: Identification of the site phosphorylated by the AMP-activated protein kinase in vitro and in intact rat liver. EMBO J. 9 , 2439–2446 (1990).

Sato, R., Goldstein, J. L. & Brown, M. S. Replacement of serine-871 of hamster 3-hydroxy-3-methylglutaryl-CoA reductase prevents phosphorylation by AMP-activated kinase and blocks inhibition of sterol synthesis induced by ATP depletion. Proc. Natl Acad. Sci. USA 90 , 9261–9265 (1993).

min, H. K. et al. Increased hepatic synthesis and dysregulation of cholesterol metabolism is associated with the severity of nonalcoholic fatty liver disease. Cell Metab. 15 , 665–674 (2012).

Zhang, X. et al. Thyroid-stimulating hormone decreases HMG-CoA reductase phosphorylation via AMP-activated protein kinase in the liver. J. Lipid Res. 56 , 963–971 (2015).

Rosenson, R. S. et al. Cholesterol efflux and atheroprotection: advancing the concept of reverse cholesterol transport. Circulation 125 , 1905–1919 (2012).

van der Velde, A. E. et al. Direct intestinal cholesterol secretion contributes significantly to total fecal neutral sterol excretion in mice. Gastroenterology 133 , 967–975 (2007).

Article   PubMed   CAS   Google Scholar  

Schwartz, C. C., Vlahcevic, Z. R., Halloran, L. G. & Swell, L. An in vivo evaluation in man of the transfer of esterified cholesterol between lipoproteins and into the liver and bile. Biochim. Biophys. Acta 663 , 143–162 (1981).

Brandts, J. & Ray, K. K. Familial hypercholesterolemia: JACC focus seminar 4/4. J. Am. Coll. Cardiol. 78 , 1831–1843 (2021).

Yu, L. et al. Cholesterol-regulated translocation of NPC1L1 to the cell surface facilitates free cholesterol uptake. J. Biol. Chem. 281 , 6616–6624 (2006).

Wang, J. et al. Membrane topology of human NPC1L1, a key protein in enterohepatic cholesterol absorption. J. Lipid Res. 50 , 1653–1662 (2009).

Infante, R. E. et al. Purified NPC1L1 protein: II. Localization of sterol binding to a 240-amino acid soluble luminal loop. J. Biol. Chem. 283 , 1064–1075 (2008).

Xie, C. et al. Ezetimibe blocks the internalization of NPC1L1 and cholesterol in mouse small intestine. J. Lipid Res. 53 , 2092–2101 (2012).

Li, P. S. et al. The clathrin adaptor Numb regulates intestinal cholesterol absorption through dynamic interaction with NPC1L1. Nat. Med. 20 , 80–86 (2014).

Johnson, T. A. & Pfeffer, S. R. Ezetimibe-sensitive cholesterol uptake by NPC1L1 protein does not require endocytosis. Mol. Biol. Cell 27 , 1845–1852 (2016).

Huang, C. S. et al. Cryo-EM structures of NPC1L1 reveal mechanisms of cholesterol transport and ezetimibe inhibition. Sci. Adv. 6 , eabb1989 (2020).

Hu, M. et al. Structural insights into the mechanism of human NPC1L1-mediated cholesterol uptake. Sci. Adv. 7 , eabg3188 (2021).

Long, T., Liu, Y., Qin, Y., DeBose-Boyd, R. A. & Li, X. Structures of dimeric human NPC1L1 provide insight into mechanisms for cholesterol absorption. Sci. Adv. 7 , eabh3997 (2021).

Clader, J. W. The discovery of ezetimibe: a view from outside the receptor. J. Med. Chem. 47 , 1–9 (2004).

Zhang, R. et al. Niemann-Pick C1-Like 1 inhibitors for reducing cholesterol absorption. Eur. J. Med. Chem. 230 , 114111 (2022).

Jia, L., Betters, J. L. & Yu, L. Niemann-Pick C1-Like 1 (NPC1L1) protein in intestinal and hepatic cholesterol transport. Annu. Rev. Physiol. 73 , 239–259 (2011).

Yan, J. & Horng, T. Lipid metabolism in regulation of macrophage functions. Trends Cell Biol. 30 , 979–989 (2020).

Chistiakov, D. A., Melnichenko, A. A., Myasoedova, V. A., Grechko, A. V. & Orekhov, A. N. Mechanisms of foam cell formation in atherosclerosis. J. Mol. Med. 95 , 1153–1165 (2017).

Dandan, M. et al. Turnover rates of the low-density lipoprotein receptor and PCSK9: added dimension to the cholesterol homeostasis model. Arterioscler Thromb. Vasc. Biol. 41 , 2866–2876 (2021).

Moore, K. J. & Freeman, M. W. Scavenger receptors in atherosclerosis: beyond lipid uptake. Arterioscler. Thromb. Vasc. Biol. 26 , 1702–1711 (2006).

Kzhyshkowska, J., Neyen, C. & Gordon, S. Role of macrophage scavenger receptors in atherosclerosis. Immunobiology 217 , 492–502 (2012).

Kunjathoor, V. V. et al. Scavenger receptors class A-I/II and CD36 are the principal receptors responsible for the uptake of modified low density lipoprotein leading to lipid loading in macrophages. J. Biol. Chem. 277 , 49982–49988 (2002).

Wang, D. et al. Targeting foam cell formation in atherosclerosis: therapeutic potential of natural products. Pharm. Rev. 71 , 596–670 (2019).

Moore, K. J., Sheedy, F. J. & Fisher, E. A. Macrophages in atherosclerosis: a dynamic balance. Nat. Rev. Immunol. 13 , 709–721 (2013).

Melton, E. M. et al. Myeloid Acat1/Soat1 KO attenuates pro-inflammatory responses in macrophages and protects against atherosclerosis in a model of advanced lesions. J. Biol. Chem. 294 , 15836–15849 (2019).

Huang, L. H. et al. Myeloid Acyl-CoA: cholesterol acyltransferase 1 deficiency reduces lesion macrophage content and suppresses atherosclerosis progression. J. Biol. Chem. 291 , 6232–6244 (2016).

Shao, D. et al. Grape seed proanthocyanidins suppressed macrophage foam cell formation by miRNA-9 via targeting ACAT1 in THP-1 cells. Food Funct. 11 , 1258–1269 (2020).

Wang, B., He, P. P., Zeng, G. F., Zhang, T. & Ou Yang, X. P. miR-467b regulates the cholesterol ester formation via targeting ACAT1 gene in RAW 264.7 macrophages. Biochimie 132 , 38–44 (2017).

Meuwese, M. C. et al. ACAT inhibition and progression of carotid atherosclerosis in patients with familial hypercholesterolemia: the CAPTIVATE randomized trial. JAMA 301 , 1131–1139 (2009).

Tardif, J. C. et al. Effects of the acyl coenzyme A: cholesterol acyltransferase inhibitor avasimibe on human atherosclerotic lesions. Circulation 110 , 3372–3377 (2004).

Warner, G. J., Stoudt, G., Bamberger, M., Johnson, W. J. & Rothblat, G. H. Cell toxicity induced by inhibition of acyl coenzyme A: cholesterol acyltransferase and accumulation of unesterified cholesterol. J. Biol. Chem. 270 , 5772–5778 (1995).

Ouimet, M. & Marcel, Y. L. Regulation of lipid droplet cholesterol efflux from macrophage foam cells. Arterioscler. Thromb. Vasc. Biol. 32 , 575–581 (2012).

Zhao, B., Song, J. St., Clair, R. W. & Ghosh, S. Stable overexpression of human macrophage cholesteryl ester hydrolase results in enhanced free cholesterol efflux from human THP1 macrophages. Am. J. Physiol. Cell Physiol. 292 , C405–C412 (2007).

Sekiya, M. et al. Ablation of neutral cholesterol ester hydrolase 1 accelerates atherosclerosis. Cell Metab. 10 , 219–228 (2009).

Favari, E. et al. Cholesterol efflux and reverse cholesterol transport. Handb. Exp. Pharm. 224 , 181–206 (2015).

Adorni, M. P. et al. The roles of different pathways in the release of cholesterol from macrophages. J. Lipid Res. 48 , 2453–2462 (2007).

Yancey, P. G. et al. Importance of different pathways of cellular cholesterol efflux. Arterioscler. Thromb. Vasc. Biol. 23 , 712–719 (2003).

Anastasius, M. et al. Cholesterol efflux capacity: an introduction for clinicians. Am. Heart J. 180 , 54–63 (2016).

Qian, H. et al. Structure of the human lipid exporter ABCA1. Cell 169 , 1228–1239 e1210 (2017).

Wang, N., Lan, D., Chen, W., Matsuura, F. & Tall, A. R. ATP-binding cassette transporters G1 and G4 mediate cellular cholesterol efflux to high-density lipoproteins. Proc. Natl Acad. Sci. USA 101 , 9774–9779 (2004).

Out, R. et al. Combined deletion of macrophage ABCA1 and ABCG1 leads to massive lipid accumulation in tissue macrophages and distinct atherosclerosis at relatively low plasma cholesterol levels. Arterioscler. Thromb. Vasc. Biol. 28 , 258–264 (2008).

Costet, P., Luo, Y., Wang, N. & Tall, A. R. Sterol-dependent transactivation of the ABC1 promoter by the liver X receptor/retinoid X receptor. J. Biol. Chem. 275 , 28240–28245 (2000).

Shen, W. J., Azhar, S. & Kraemer, F. B. SR-BI: A unique multifunctional receptor for cholesterol influx and efflux. Annu. Rev. Physiol. 80 , 95–116 (2018).

Lim, H. Y. et al. Lymphatic vessels are essential for the removal of cholesterol from peripheral tissues by SR-BI-mediated transport of HDL. Cell Metab. 17 , 671–684 (2013).

Phillips, M. C. Molecular mechanisms of cellular cholesterol efflux. J. Biol. Chem. 289 , 24020–24029 (2014).

De Lalla, O. F. & Gofman, J. W. Ultracentrifugal analysis of serum lipoproteins. Methods Biochem. Anal. 1 , 459–478 (1954).

Kontush, A. et al. Structure of HDL: particle subclasses and molecular components. Handb. Exp. Pharm. 224 , 3–51 (2015).

Marques, L. R. et al. Reverse cholesterol transport: molecular mechanisms and the non-medical approach to enhance HDL cholesterol. Front. Physiol. 9 , 526 (2018).

Glickman, R. M., Green, P. H., Lees, R. S. & Tall, A. Apoprotein A-I synthesis in normal intestinal mucosa and in Tangier disease. N. Engl. J. Med. 299 , 1424–1427 (1978).

Dieplinger, H., Zechner, R. & Kostner, G. M. The in vitro formation of HDL2 during the action of LCAT: The role of triglyceride-rich lipoproteins. J. Lipid Res. 26 , 273–282 (1985).

Vaughan, A. M. & Oram, J. F. ABCG1 redistributes cell cholesterol to domains removable by high density lipoprotein but not by lipid-depleted apolipoproteins. J. Biol. Chem. 280 , 30150–30157 (2005).

Ji, Y. et al. Scavenger receptor BI promotes high density lipoprotein-mediated cellular cholesterol efflux. J. Biol. Chem. 272 , 20982–20985 (1997).

Fielding, C. J., Shore, V. G. & Fielding, P. E. A protein cofactor of lecithin: cholesterol acyltransferase. Biochem. Biophys. Res. Commun. 46 , 1493–1498 (1972).

Jonas, A. Lecithin-cholesterol acyltransferase in the metabolism of high-density lipoproteins. Biochim. Biophys. Acta 1084 , 205–220 (1991).

Bruce, C., Beamer, L. J. & Tall, A. R. The implications of the structure of the bactericidal/permeability-increasing protein on the lipid-transfer function of the cholesteryl ester transfer protein. Curr. Opin. Struct. Biol. 8 , 426–434 (1998).

Group, H. T. C. et al. Effects of extended-release niacin with laropiprant in high-risk patients. N. Engl. J. Med. 371 , 203–212 (2014).

Davidson, M. H. HDL and CETP inhibition: will this define the future? Curr. Treat. Options Cardiovasc. Med. 14 , 384–390 (2012).

Furtado, J. D. et al. Pharmacological inhibition of CETP (cholesteryl ester transfer protein) increases HDL (high-density lipoprotein) that contains APOC3 and other HDL subspecies associated with higher risk of coronary heart disease. Arterioscler. Thromb. Vasc. Biol. 42 , 227–237 (2022).

Rousset, X., Shamburek, R., Vaisman, B., Amar, M. & Remaley, A. T. Lecithin cholesterol acyltransferase: an anti- or pro-atherogenic factor? Curr. Atheroscler. Rep. 13 , 249–256 (2011).

Pownall, H. J., Rosales, C., Gillard, B. K. & Gotto, A. M. Jr High-density lipoproteins, reverse cholesterol transport and atherogenesis. Nat. Rev. Cardiol. 18 , 712–723 (2021).

Madsen, C. M., Varbo, A. & Nordestgaard, B. G. Extreme high high-density lipoprotein cholesterol is paradoxically associated with high mortality in men and women: two prospective cohort studies. Eur. Heart J. 38 , 2478–2486 (2017).

Hamer, M., O’Donovan, G. & Stamatakis, E. High-density lipoprotein cholesterol and mortality: too much of a good thing? Arterioscler. Thromb. Vasc. Biol. 38 , 669–672 (2018).

Nordestgaard, B. G. & Tybjaerg-Hansen, A. IDL, VLDL, chylomicrons and atherosclerosis. Eur. J. Epidemiol. 8 , 92–98 (1992).

Barter, P. J. et al. Cholesteryl ester transfer protein: a novel target for raising HDL and inhibiting atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 23 , 160–167 (2003).

Brown, M. S. & Goldstein, J. L. How LDL receptors influence cholesterol and atherosclerosis. Sci. Am. 251 , 58–66 (1984).

Shu, H. et al. A novel indel variant in LDLR responsible for familial hypercholesterolemia in a Chinese family. PLoS One 12 , e0189316 (2017).

Jiang, L. et al. Analysis of LDLR variants from homozygous FH patients carrying multiple mutations in the LDLR gene. Atherosclerosis 263 , 163–170 (2017).

Calkin, A. C. et al. FERM-dependent E3 ligase recognition is a conserved mechanism for targeted degradation of lipoprotein receptors. Proc. Natl Acad. Sci. USA 108 , 20107–20112 (2011).

Wang, J. K. et al. Ablation of plasma prekallikrein decreases low-density lipoprotein cholesterol by stabilizing low-density lipoprotein receptor and protects against atherosclerosis. Circulation 145 , 675–687 (2022).

Liscum, L. & Underwood, K. W. Intracellular cholesterol transport and compartmentation. J. Biol. Chem. 270 , 15443–15446 (1995).

Simons, K. & Ikonen, E. How cells handle cholesterol. Science 290 , 1721–1726 (2000).

Harris, J. S., Epps, D. E., Davio, S. R. & Kezdy, F. J. Evidence for transbilayer, tail-to-tail cholesterol dimers in dipalmitoylglycerophosphocholine liposomes. Biochemistry 34 , 3851–3857 (1995).

Mukherjee, S. & Chattopadhyay, A. Membrane organization at low cholesterol concentrations: a study using 7-nitrobenz-2-oxa-1,3-diazol-4-yl-labeled cholesterol. Biochemistry 35 , 1311–1322 (1996).

Tulenko, T. N., Chen, M., Mason, P. E. & Mason, R. P. Physical effects of cholesterol on arterial smooth muscle membranes: evidence of immiscible cholesterol domains and alterations in bilayer width during atherogenesis. J. Lipid Res. 39 , 947–956 (1998).

Simons, K. & Ikonen, E. Functional rafts in cell membranes. Nature 387 , 569–572 (1997).

Xu, X. & London, E. The effect of sterol structure on membrane lipid domains reveals how cholesterol can induce lipid domain formation. Biochemistry 39 , 843–849 (2000).

Pucadyil, T. J. & Chattopadhyay, A. Role of cholesterol in the function and organization of G-protein coupled receptors. Prog. Lipid Res. 45 , 295–333 (2006).

Hong, C. & Tontonoz, P. Liver X receptors in lipid metabolism: opportunities for drug discovery. Nat. Rev. Drug Discov. 13 , 433–444 (2014).

Radhakrishnan, A., Ikeda, Y., Kwon, H. J., Brown, M. S. & Goldstein, J. L. Sterol-regulated transport of SREBPs from endoplasmic reticulum to Golgi: oxysterols block transport by binding to INSIG. Proc. Natl Acad. Sci. USA 104 , 6511–6518 (2007).

Mitton, J. R., Scholan, N. A. & Boyd, G. S. The oxidation of cholesterol in rat liver sub-cellular particles. The cholesterol-7-alpha-hydroxylase enzyme system. Eur. J. Biochem. 20 , 569–579 (1971).

Cali, J. J. & Russell, D. W. Characterization of human sterol 27-hydroxylase. A mitochondrial cytochrome P-450 that catalyzes multiple oxidation reaction in bile acid biosynthesis. J. Biol. Chem. 266 , 7774–7778 (1991).

Lund, E. G., Kerr, T. A., Sakai, J., Li, W. P. & Russell, D. W. cDNA cloning of mouse and human cholesterol 25-hydroxylases, polytopic membrane proteins that synthesize a potent oxysterol regulator of lipid metabolism. J. Biol. Chem. 273 , 34316–34327 (1998).

Lappano, R. et al. The cholesterol metabolite 25-hydroxycholesterol activates estrogen receptor α-mediated signaling in cancer cells and in cardiomyocytes. PLoS One 6 , e16631 (2011).

Miller, W. L. & Strauss, J. F. III Molecular pathology and mechanism of action of the steroidogenic acute regulatory protein, StAR. J. Steroid Biochem. Mol. Biol. 69 , 131–141 (1999).

Temel, R. E. & Brown, J. M. A new model of reverse cholesterol transport: enTICEing strategies to stimulate intestinal cholesterol excretion. Trends Pharm. Sci. 36 , 440–451 (2015).

Yu, X. H. et al. ABCG5/ABCG8 in cholesterol excretion and atherosclerosis. Clin. Chim. Acta 428 , 82–88 (2014).

Li, G., Gu, H. M. & Zhang, D. W. ATP-binding cassette transporters and cholesterol translocation. IUBMB Life 65 , 505–512 (2013).

Vrins, C. et al. The sterol transporting heterodimer ABCG5/ABCG8 requires bile salts to mediate cholesterol efflux. FEBS Lett. 581 , 4616–4620 (2007).

Johnson, B. J., Lee, J. Y., Pickert, A. & Urbatsch, I. L. Bile acids stimulate ATP hydrolysis in the purified cholesterol transporter ABCG5/G8. Biochemistry 49 , 3403–3411 (2010).

Norlin, M. & Wikvall, K. Enzymes in the conversion of cholesterol into bile acids. Curr. Mol. Med. 7 , 199–218 (2007).

de Aguiar Vallim, T. Q., Tarling, E. J. & Edwards, P. A. Pleiotropic roles of bile acids in metabolism. Cell Metab. 17 , 657–669 (2013).

Ridlon, J. M., Alves, J. M., Hylemon, P. B. & Bajaj, J. S. Cirrhosis, bile acids and gut microbiota: unraveling a complex relationship. Gut Microbes 4 , 382–387 (2013).

Lee, J. Y. et al. Crystal structure of the human sterol transporter ABCG5/ABCG8. Nature 533 , 561–564 (2016).

Back, S. S. et al. Cooperative transcriptional activation of atp-binding cassette sterol transporters ABCG5 and ABCG8 genes by nuclear receptors including Liver-X-Receptor. BMB Rep. 46 , 322–327 (2013).

van der Veen, J. N. et al. Activation of the liver X receptor stimulates trans-intestinal excretion of plasma cholesterol. J. Biol. Chem. 284 , 19211–19219 (2009).

van der Velde, A. E., Brufau, G. & Groen, A. K. Transintestinal cholesterol efflux. Curr. Opin. Lipido 21 , 167–171 (2010).

de Boer, J. F. et al. Transintestinal and biliary cholesterol secretion both contribute to macrophage reverse cholesterol transport in rats-brief report. Arterioscler Thromb. Vasc. Biol. 37 , 643–646 (2017).

Jakulj, L. et al. Transintestinal cholesterol transport is active in mice and humans and controls ezetimibe-induced fecal neutral sterol excretion. Cell Metab. 24 , 783–794 (2016).

Temel, R. E. et al. Biliary sterol secretion is not required for macrophage reverse cholesterol transport. Cell Metab. 12 , 96–102 (2010).

Stoger, J. L. et al. Deleting myeloid IL-10 receptor signalling attenuates atherosclerosis in LDLR−/− mice by altering intestinal cholesterol fluxes. Thromb. Haemost. 116 , 565–577 (2016).

Stender, S., Frikke-Schmidt, R., Nordestgaard, B. G. & Tybjaerg-Hansen, A. The ABCG5/8 cholesterol transporter and myocardial infarction versus gallstone disease. J. Am. Coll. Cardiol. 63 , 2121–2128 (2014).

Vrins, C. L. J. et al. Trans-intestinal cholesterol efflux is not mediated through high density lipoprotein. J. Lipid Res. 53 , 2017–2023 (2012).

Le May, C. et al. Transintestinal cholesterol excretion is an active metabolic process modulated by PCSK9 and statin involving ABCB1. Arterioscler. Thromb. Vasc. Biol. 33 , 1484–1493 (2013).

Stange, E. F. & Dietschy, J. M. Cholesterol synthesis and low density lipoprotein uptake are regulated independently in rat small intestinal epithelium. Proc. Natl Acad. Sci. USA 80 , 5739–5743 (1983).

Tonini, C. et al. Inhibition of bromodomain and extraterminal domain (BET) proteins by JQ1 unravels a novel epigenetic modulation to control lipid homeostasis. Int. J. Mol. Sci . 21 (2020).

Malhotra, P. et al. Epigenetic modulation of intestinal cholesterol transporter Niemann-Pick C1-Like 1 (NPC1L1) gene expression by DNA methylation. J. Biol. Chem. 289 , 23132–23140 (2014).

Li, X. J. et al. Deficiency of histone methyltransferase SET domain-containing 2 in liver leads to abnormal lipid metabolism and HCC. Hepatology 73 , 1797–1815 (2021).

Fan, Z. et al. Brahma related gene 1 (BRG1) regulates cellular cholesterol synthesis by acting as a Co-factor for SREBP2. Front. Cell Dev. Biol. 8 , 259 (2020).

Kim, H., Choi, S. Y., Lim, J., Lindroth, A. M. & Park, Y. J. EHMT2 inhibition induces cell death in human non-small cell lung cancer by altering the cholesterol biosynthesis pathway. Int. J. Mol. Sci. 21 , 1002 (2020).

Article   CAS   PubMed Central   Google Scholar  

Meaney, S. Epigenetic regulation of cholesterol homeostasis. Front. Genet. 5 , 311 (2014).

Smith, Z., Ryerson, D. & Kemper, J. K. Epigenomic regulation of bile acid metabolism: emerging role of transcriptional cofactors. Mol. Cell Endocrinol. 368 , 59–70 (2013).

Chanda, D., Xie, Y. B. & Choi, H. S. Transcriptional corepressor SHP recruits SIRT1 histone deacetylase to inhibit LRH-1 transactivation. Nucleic Acids Res 38 , 4607–4619 (2010).

Shafaati, M., O’Driscoll, R., Bjorkhem, I. & Meaney, S. Transcriptional regulation of cholesterol 24-hydroxylase by histone deacetylase inhibitors. Biochem. Biophys. Res. Commun. 378 , 689–694 (2009).

Blanc, M. et al. The transcription factor STAT-1 couples macrophage synthesis of 25-hydroxycholesterol to the interferon antiviral response. Immunity 38 , 106–118 (2013).

Gold, E. S. et al. ATF3 protects against atherosclerosis by suppressing 25-hydroxycholesterol-induced lipid body formation. J. Exp. Med. 209 , 807–817 (2012).

Libby, P. et al. Atherosclerosis. Nat. Rev. Dis. Prim. 5 , 56 (2019).

Yu, X. H., Zhang, D. W., Zheng, X. L. & Tang, C. K. Cholesterol transport system: an integrated cholesterol transport model involved in atherosclerosis. Prog. Lipid Res. 73 , 65–91 (2019).

Tabas, I., Williams, K. J. & Boren, J. Subendothelial lipoprotein retention as the initiating process in atherosclerosis: update and therape.utic implications. Circulation 116 , 1832–1844 (2007).

Huang, L. et al. SR-BI drives endothelial cell LDL transcytosis via DOCK4 to promote atherosclerosis. Nature 569 , 565–569 (2019).

Tabas, I. Macrophage death and defective inflammation resolution in atherosclerosis. Nat. Rev. Immunol. 10 , 36–46 (2010).

Xu, S. et al. Endothelial dysfunction in atherosclerotic cardiovascular diseases and beyond: from mechanism to pharmacotherapies. Pharm. Rev. 73 , 924–967 (2021).

Bobryshev, Y. V. Monocyte recruitment and foam cell formation in atherosclerosis. Micron 37 , 208–222 (2006).

Li, A. C. & Glass, C. K. The macrophage foam cell as a target for therapeutic intervention. Nat. Med. 8 , 1235–1242 (2002).

Dickhout, J. G., Basseri, S. & Austin, R. C. Macrophage function and its impact on atherosclerotic lesion composition, progression, and stability: the good, the bad, and the ugly. Arterioscler. Thromb. Vasc. Biol. 28 , 1413–1415 (2008).

Hutchins, P. M. & Heinecke, J. W. Cholesterol efflux capacity, macrophage reverse cholesterol transport and cardioprotective HDL. Curr. Opin. Lipido 26 , 388–393 (2015).

Lao, K. H., Zeng, L. & Xu, Q. Endothelial and smooth muscle cell transformation in atherosclerosis. Curr. Opin. Lipido 26 , 449–456 (2015).

Lusis, A. J. Atherosclerosis. Nature 407 , 233–241 (2000).

Ho-Tin-Noe, B. et al. Cholesterol crystallization in human atherosclerosis is triggered in smooth muscle cells during the transition from fatty streak to fibroatheroma. J. Pathol. 241 , 671–682 (2017).

Abela, G. S. et al. Effect of statins on cholesterol crystallization and atherosclerotic plaque stabilization. Am. J. Cardiol. 107 , 1710–1717 (2011).

Vani, A. & Underberg, J. A. Lowering LDL-cholesterol and CV benefits: Is there a limit to how low ldl-c needs to be for optimal health benefits? Clin. Pharm. Ther. 104 , 290–296 (2018).

Packard, C., Chapman, M. J., Sibartie, M., Laufs, U. & Masana, L. Intensive low-density lipoprotein cholesterol lowering in cardiovascular disease prevention: opportunities and challenges. Heart 107 , 1369–1375 (2021).

Yu, D. & Liao, J. K. Emerging views of statin pleiotropy and cholesterol lowering. Cardiovasc. Res. 118 , 413–423 (2022).

Giugliano, R. P. et al. Cognitive function in a randomized trial of evolocumab. N. Engl. J. Med. 377 , 633–643 (2017).

Collins, R. et al. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet 388 , 2532–2561 (2016).

Ray, K. K. et al. Reductions in atherogenic lipids and major cardiovascular events: a pooled analysis of 10 ODYSSEY trials comparing alirocumab with control. Circulation 134 , 1931–1943 (2016).

Cholesterol Treatment Trialists, C. et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 376 , 1670–1681 (2010).

Endo, A., Kuroda, M. & Tsujita, Y. ML-236A, ML-236B, and ML-236C, new inhibitors of cholesterogenesis produced by penicillium citrinium. J. Antibiot. 29 , 1346–1348 (1976).

Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4s). Lancet 344 , 1383–1389 (1994).

Endo, A. Drugs inhibiting HMG-CoA reductase. Pharm. Ther. 31 , 257–267 (1985).

Sirtori, C. R. The pharmacology of statins. Pharm. Res. 88 , 3–11 (2014).

Welder, G. et al. High-dose atorvastatin causes a rapid sustained increase in human serum PCSK9 and disrupts its correlation with LDL cholesterol. J. Lipid Res. 51 , 2714–2721 (2010).

Careskey, H. E. et al. Atorvastatin increases human serum levels of proprotein convertase subtilisin/kexin type 9. J. Lipid Res. 49 , 394–398 (2008).

Boekholdt, S. M. et al. Very low levels of atherogenic lipoproteins and the risk for cardiovascular events: a meta-analysis of statin trials. J. Am. Coll. Cardiol. 64 , 485–494 (2014).

Cholesterol Treatment Trialists, C. Efficacy and safety of statin therapy in older people: a meta-analysis of individual participant data from 28 randomised controlled trials. Lancet 393 , 407–415 (2019).

Article   Google Scholar  

Cholesterol Treatment Trialists, C. et al. Efficacy and safety of ldl-lowering therapy among men and women: meta-analysis of individual data from 174,000 participants in 27 randomised trials. Lancet 385 , 1397–1405 (2015).

Cholesterol Treatment Trialists, C. et al. The effects of lowering ldl cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet 380 , 581–590 (2012).

Davignon, J. Beneficial cardiovascular pleiotropic effects of statins. Circulation 109 , III39–III43 (2004).

Oesterle, A., Laufs, U. & Liao, J. K. Pleiotropic effects of statins on the cardiovascular system. Circ. Res. 120 , 229–243 (2017).

Barter, P. J., Brandrup-Wognsen, G., Palmer, M. K. & Nicholls, S. J. Effect of statins on HDL-C: a complex process unrelated to changes in LDL-C: analysis of the VOYAGER database. J. Lipid Res. 51 , 1546–1553 (2010).

Puri, R. et al. The beneficial effects of raising high-density lipoprotein cholesterol depends upon achieved levels of low-density lipoprotein cholesterol during statin therapy: implications for coronary atheroma progression and cardiovascular events. Eur. J. Prev. Cardiol. 23 , 474–485 (2016).

Mortensen, M. B. et al. Statin trials, cardiovascular events, and coronary artery calcification: implications for a trial-based approach to statin therapy in mesa. JACC Cardiovasc . Imaging 11 , 221–230 (2018).

Pedersen, T. R. Pleiotropic effects of statins: evidence against benefits beyond LDLl-cholesterol lowering. Am. J. Cardiovasc. Drugs 10 , 10–17 (2010).

Hadjiphilippou, S. & Ray, K. K. Cholesterol-lowering agents. Circ. Res. 124 , 354–363 (2019).

Thompson, P. D., Panza, G., Zaleski, A. & Taylor, B. Statin-associated side effects. J. Am. Coll. Cardiol. 67 , 2395–2410 (2016).

Stroes, E. S. et al. Statin-associated muscle symptoms: impact on statin therapy-european atherosclerosis society consensus panel statement on assessment, aetiology and management. Eur. Heart J. 36 , 1012–1022 (2015).

Howard, J. P. et al. Side effect patterns in a crossover trial of statin, placebo, and no treatment. J. Am. Coll. Cardiol. 78 , 1210–1222 (2021).

NICE Clinical Guidelines, No. 181. Cardiovascular disease: Risk assessment and reduction, including lipid modification National institute for health and care excellence: Guidelines (2016).

Wanner, C. & Tonelli, M. Kidney Disease: Improving Global Outcomes Lipid Guideline Development Work Group, M. KDIGI Clinical Practice Guideline for Lipid Management in CKD: summary of recommendation statements and clinical approach to the patient. Kidney Int 85 , 1303–1309 (2014).

Paseban, M., Butler, A. E. & Sahebkar, A. Mechanisms of statin-induced new-onset diabetes. J. Cell Physiol. 234 , 12551–12561 (2019).

Taylor, F. C., Huffman, M. & Ebrahim, S. Statin therapy for primary prevention of cardiovascular disease. JAMA 310 , 2451–2452 (2013).

Tavazzi, L. et al. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet 372 , 1231–1239 (2008).

Moriarty, P. M. et al. Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: the ODYSSEY ALTERNATIVE randomized trial. J. Clin. Lipido 9 , 758–769 (2015).

Stroes, E. et al. Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab. J. Am. Coll. Cardiol. 63 , 2541–2548 (2014).

Mach, F. et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur. Heart J. 41 , 111–188 (2020).

Knopp, R. H. et al. Effects of ezetimibe, a new cholesterol absorption inhibitor, on plasma lipids in patients with primary hypercholesterolemia. Eur. Heart J. 24 , 729–741 (2003).

Phan, B. A., Dayspring, T. D. & Toth, P. P. Ezetimibe therapy: mechanism of action and clinical update. Vasc. Health Risk Manag 8 , 415–427 (2012).

CAS   PubMed   PubMed Central   Google Scholar  

Dumas, L. S. et al. Evaluation of antiatherogenic properties of ezetimibe using (3)h-labeled low-density-lipoprotein cholesterol and (99m)tc-cabvcam1-5 spect in apoe(-/-) mice fed the paigen diet. J. Nucl. Med. 58 , 1088–1093 (2017).

Lin, X., Racette, S. B., Ma, L., Wallendorf, M. & Ostlund, R. E. Jr. Ezetimibe increases endogenous cholesterol excretion in humans. Arterioscler. Thromb. Vasc. Biol. 37 , 990–996 (2017).

Pandor, A. et al. Ezetimibe monotherapy for cholesterol lowering in 2,722 people: systematic review and meta-analysis of randomized controlled trials. J. Intern. Med. 265 , 568–580 (2009).

Ouchi, Y. et al. Ezetimibe lipid-lowering trial on prevention of atherosclerotic cardiovascular disease in 75 or older (EWTOPIA 75): a randomized, controlled trial. Circulation 140 , 992–1003 (2019).

Honda, K. et al. Lipid-lowering therapy with ezetimibe decreases spontaneous atherothrombotic occlusions in a rabbit model of plaque erosion: a role of serum oxysterols. Arterioscler. Thromb. Vasc. Biol. 38 , 757–771 (2018).

Katzmann, J. L. et al. Non-statin lipid-lowering therapy over time in very-high-risk patients: effectiveness of fixed-dose statin/ezetimibe compared to separate pill combination on LDL-C. Clin. Res. Cardiol. 111 , 243–252 (2022).

Ballantyne, C. M. et al. Bempedoic acid plus ezetimibe fixed-dose combination in patients with hypercholesterolemia and high CVD risk treated with maximally tolerated statin therapy. Eur. J. Prev. Cardiol. 27 , 593–603 (2020).

Jones, M. R. & Nwose, O. M. Role of colesevelam in combination lipid-lowering therapy. Am. J. Cardiovasc. Drugs 13 , 315–323 (2013).

Nissen, S. E. et al. Efficacy and tolerability of evolocumab vs ezetimibe in patients with muscle-related statin intolerance: the GAUSS-3 randomized clinical trial. JAMA 315 , 1580–1590 (2016).

Kosoglou, T. et al. Ezetimibe: a review of its metabolism, pharmacokinetics and drug interactions. Clin. Pharmacokinet. 44 , 467–494 (2005).

Norata, G. D., Tibolla, G. & Catapano, A. L. Targeting PCSK9 for hypercholesterolemia. Annu. Rev. Pharm. Toxicol. 54 , 273–293 (2014).

Ding, Z. et al. Cross-talk between LOX-1 and PCSK9 in vascular tissues. Cardiovasc. Res 107 , 556–567 (2015).

Ding, Z. et al. PCSK9 regulates expression of scavenger receptors and ox-LDL uptake in macrophages. Cardiovasc. Res 114 , 1145–1153 (2018).

Tsouka, A. N., Tellis, C. C. & Tselepis, A. D. Pharmacology of PCSK9 inhibitors: current status and future perspectives. Curr. Pharm. Des. 24 , 3622–3633 (2018).

Migliorati, J. M., Jin, J. & Zhong, X. B. siRNA drug Leqvio (inclisiran) to lower cholesterol. Trends Pharmacol. Sci. 43 , 455–456 (2022).

AlTurki, A. et al. Meta-analysis of randomized controlled trials assessing the impact of proprotein convertase subtilisin/kexin type 9 antibodies on mortality and cardiovascular outcomes. Am. J. Cardiol. 124 , 1869–1875 (2019).

Jalloh, M. A., Doroudgar, S. & Ip, E. J. What is the impact of the 2017 cochrane systematic review and meta-analysis that evaluated the use of PCSK9 inhibitors for lowering cardiovascular disease and mortality? Expert Opin. Pharmacother. 19 , 739–741 (2018).

Karatasakis, A. et al. Effect of PCSK9 inhibitors on clinical outcomes in patients with hypercholesterolemia: a meta-analysis of 35 randomized controlled trials. J. Am. Heart Assoc . 6 (2017).

Turgeon, R. D., Tsuyuki, R. T., Gyenes, G. T. & Pearson, G. J. Cardiovascular efficacy and safety of PCSK9 inhibitors: systematic review and meta-analysis including the odyssey outcomes trial. Can. J. Cardiol. 34 , 1600–1605 (2018).

Ray, K. K. et al. Two phase 3 trials of inclisiran in patients with elevated LDL cholesterol. N. Engl. J. Med. 382 , 1507–1519 (2020).

Wang, Z., Chen, X., Liu, J., Wang, Y. & Zhang, S. Inclisiran inhibits oxidized low-density lipoprotein-induced foam cell formation in Raw264.7 macrophages via activating the PPARγ pathway. Autoimmunity 55 , 223–232 (2022).

Cicero, A. F., Tartagni, E. & Ertek, S. Safety and tolerability of injectable lipid-lowering drugs: a review of available clinical data. Expert Opin. Drug Saf. 13 , 1023–1030 (2014).

Markham, A. Bempedoic acid: first approval. Drugs 80 , 747–753 (2020).

Corsini, A. & Scicchitano, P. Bempedoic acid: mechanism of action. G. Ital. Cardiol. 22 , 9S–14S (2021).

Pinkosky, S. L. et al. Liver-specific ATP-citrate lyase inhibition by bempedoic acid decreases ldl-c and attenuates atherosclerosis. Nat. Commun. 7 , 13457 (2016).

Laufs, U. et al. Efficacy and safety of bempedoic acid in patients with hypercholesterolemia and statin intolerance. J. Am. Heart Assoc. 8 , e011662 (2019).

Samsoondar, J. P. et al. Prevention of diet-induced metabolic dysregulation, inflammation, and atherosclerosis in LDLR -/- mice by treatment with the ATP-citrate lyase inhibitor bempedoic acid. Arterioscler. Thromb. Vasc. Biol. 37 , 647–656 (2017).

Ballantyne, C. M. et al. Efficacy and safety of bempedoic acid added to ezetimibe in statin-intolerant patients with hypercholesterolemia: a randomized, placebo-controlled study. Atherosclerosis 277 , 195–203 (2018).

Goldberg, A. C. et al. Effect of bempedoic acid vs placebo added to maximally tolerated statins on low-density lipoprotein cholesterol in patients at high risk for cardiovascular disease: the CLEAR Wisdom Randomized Clinical Trial. JAMA 322 , 1780–1788 (2019).

Thompson, P. D. et al. Treatment with ETC-1002 alone and in combination with ezetimibe lowers LDL cholesterol in hypercholesterolemic patients with or without statin intolerance. J. Clin. Lipido 10 , 556–567 (2016).

Powell, J. & Piszczatoski, C. Bempedoic acid: a new tool in the battle against hyperlipidemia. Clin. Ther. 43 , 410–420 (2021).

Ray, K. K. et al. Safety and efficacy of bempedoic acid to reduce LDL cholesterol. N. Engl. J. Med. 380 , 1022–1032 (2019).

Pirillo, A. & Catapano, A. L. New insights into the role of bempedoic acid and ezetimibe in the treatment of hypercholesterolemia. Curr. Opin. Endocrinol. Diabetes Obes. 29 , 161–166 (2022).

Feng, Y., Li, Q., Ou, G., Yang, M. & Du, L. Bile acid sequestrants: a review of mechanism and design. J. Pharm. Pharm. 73 , 855–861 (2021).

Ross, S. et al. Effect of bile acid sequestrants on the risk of cardiovascular events: a mendelian randomization analysis. Circ. Cardiovasc. Genet. 8 , 618–627 (2015).

The lipid research clinics coronary primary prevention trial. Results of 6 years of post-trial follow-up. The lipid research clinics investigators. Arch. Intern. Med 152 , 1399–1410 (1992).

The lipid research clinics coronary primary prevention trial results. I. Reduction in incidence of coronary heart disease. JAMA 251 , 351–364 (1984).

The Lipid Research Clinics Program. Pre-entry characteristics of participants in the lipid research clinics’ coronary primary prevention trial. J. Chronic Dis. 36 , 467–479 (1983).

He, L. et al. Lack of effect of colesevelam HCL on the single-dose pharmacokinetics of aspirin, atenolol, enalapril, phenytoin, rosiglitazone, and sitagliptin. Diabetes Res. Clin. Pract. 104 , 401–409 (2014).

Blom, D. J. et al. Long-term efficacy and safety of the microsomal triglyceride transfer protein inhibitor lomitapide in patients with homozygous familial hypercholesterolemia. Circulation 136 , 332–335 (2017).

Alonso, R., Cuevas, A. & Mata, P. Lomitapide: a review of its clinical use, efficacy, and tolerability. Core Evid. 14 , 19–30 (2019).

d’Erasmo, L. et al. Efficacy and safety of lomitapide in homozygous familial hypercholesterolemia: the pan-european retrospective observational study. Eur. J. Prev. Cardiol. 29 , 832–841 (2021).

Cuchel, M. et al. Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study. Lancet 381 , 40–46 (2013).

Ahmad, Z. et al. Inhibition of angiopoietin-like protein 3 with a monoclonal antibody reduces triglycerides in hypertriglyceridemia. Circulation 140 , 470–486 (2019).

In LiverTox: clinical and research information on drug-induced liver injury (2012).

Hurt-Camejo, E. ANGPTL3, PCSK9, and statin therapy drive remarkable reductions in hyperlipidemia and atherosclerosis in a mouse model. J. Lipid Res. 61 , 272–274 (2020).

Pouwer, M. G. et al. Alirocumab, evinacumab, and atorvastatin triple therapy regresses plaque lesions and improves lesion composition in mice. J. Lipid Res. 61 , 365–375 (2020).

Ling, P. et al. Targeting angiopoietin-like 3 in atherosclerosis: from bench to bedside. Diabetes Obes. Metab. 23 , 2020–2034 (2021).

Hua, H. et al. PPARα-independent action against metabolic syndrome development by fibrates is mediated by inhibition of STAT3 signalling. J. Pharm. Pharm. 70 , 1630–1642 (2018).

Chapman, M. J., Redfern, J. S., McGovern, M. E. & Giral, P. Niacin and fibrates in atherogenic dyslipidemia: pharmacotherapy to reduce cardiovascular risk. Pharm. Ther. 126 , 314–345 (2010).

Bruckert, E., Labreuche, J., Deplanque, D., Touboul, P. J. & Amarenco, P. Fibrates effect on cardiovascular risk is greater in patients with high triglyceride levels or atherogenic dyslipidemia profile: a systematic review and meta-analysis. J. Cardiovasc. Pharm. 57 , 267–272 (2011).

Lee, M., Saver, J. L., Towfighi, A., Chow, J. & Ovbiagele, B. Efficacy of fibrates for cardiovascular risk reduction in persons with atherogenic dyslipidemia: a meta-analysis. Atherosclerosis 217 , 492–498 (2011).

Fruchart, J. C. Pemafibrate (K-877), a novel selective peroxisome proliferator-activated receptor alpha modulator for management of atherogenic dyslipidaemia. Cardiovasc. Diabetol. 16 , 124 (2017).

Davidson, M. H., Armani, A., McKenney, J. M. & Jacobson, T. A. Safety considerations with fibrate therapy. Am. J. Cardiol. 99 , 3C–18C (2007).

van Wijk, D. F. et al. Nonpharmacological lipoprotein apheresis reduces arterial inflammation in familial hypercholesterolemia. J. Am. Coll. Cardiol. 64 , 1418–1426 (2014).

Thompson, G. & Parhofer, K. G. Current role of lipoprotein apheresis. Curr. Atheroscler. Rep. 21 , 26 (2019).

Hegele, R. A. & Tsimikas, S. Lipid-lowering agents. Circ. Res. 124 , 386–404 (2019).

Zvintzou, E. et al. Pleiotropic effects of apolipoprotein C3 on HDL functionality and adipose tissue metabolic activity. J. Lipid Res. 58 , 1869–1883 (2017).

Yao, Z. Human apolipoprotein C-III - a new intrahepatic protein factor promoting assembly and secretion of very low density lipoproteins. Cardiovasc. Hematol. Disord. Drug Targets 12 , 133–140 (2012).

Gordts, P. L. et al. Apoc-III inhibits clearance of triglyceride-rich lipoproteins through LDL family receptors. J. Clin. Investig. 126 , 2855–2866 (2016).

Lee, S. J., Campos, H., Moye, L. A. & Sacks, F. M. LDL containing apolipoprotein CIII is an independent risk factor for coronary events in diabetic patients. Arterioscler. Thromb. Vasc. Biol. 23 , 853–858 (2003).

Sacks, F. M. et al. VLDL, apolipoproteins B, CIII, and E, and risk of recurrent coronary events in the cholesterol and recurrent events (CARE) trial. Circulation 102 , 1886–1892 (2000).

Wyler von Ballmoos, M. C., Haring, B. & Sacks, F. M. The risk of cardiovascular events with increased apolipoprotein CIII: a systematic review and meta-analysis. J. Clin. Lipido 9 , 498–510 (2015).

Scheffer, P. G. et al. Increased plasma apolipoprotein C-III concentration independently predicts cardiovascular mortality: the Hoorn Study. Clin. Chem. 54 , 1325–1330 (2008).

Pollin, T. I. et al. A null mutation in human APOC3 confers a favorable plasma lipid profile and apparent cardioprotection. Science 322 , 1702–1705 (2008).

Jorgensen, A. B., Frikke-Schmidt, R., Nordestgaard, B. G. & Tybjaerg-Hansen, A. Loss-of-function mutations in APOC3 and risk of ischemic vascular disease. N. Engl. J. Med 371 , 32–41 (2014).

Gaudet, D. et al. Antisense inhibition of apolipoprotein C-III in patients with hypertriglyceridemia. N. Engl. J. Med. 373 , 438–447 (2015).

Alexander, V. J. et al. N-acetyl galactosamine-conjugated antisense drug to APOC3 mRNA, triglycerides and atherogenic lipoprotein levels. Eur. Heart J. 40 , 2785–2796 (2019).

Authors/Task Force, M., Guidelines, E. S. C. C. F. P. & Societies, E. S. C. N. C. 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Atherosclerosis 290 , 140–205 (2019).

Nordestgaard, B. G. & Langsted, A. Lipoprotein (a) as a cause of cardiovascular disease: Insights from epidemiology, genetics, and biology. J. Lipid Res. 57 , 1953–1975 (2016).

Kamstrup, P. R. Lipoprotein(a) and cardiovascular disease. Clin. Chem. 67 , 154–166 (2021).

Thanassoulis, G. Lipoprotein (a) in calcific aortic valve disease: from genomics to novel drug target for aortic stenosis. J. Lipid Res. 57 , 917–924 (2016).

Emerging Risk Factors, C. et al. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA 302 , 412–423 (2009).

Kamstrup, P. R., Benn, M., Tybjaerg-Hansen, A. & Nordestgaard, B. G. Extreme lipoprotein(a) levels and risk of myocardial infarction in the general population: the copenhagen city heart study. Circulation 117 , 176–184 (2008).

Clarke, R. et al. Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N. Engl. J. Med. 361 , 2518–2528 (2009).

Boffa, M. B., Marcovina, S. M. & Koschinsky, M. L. Lipoprotein(a) as a risk factor for atherosclerosis and thrombosis: mechanistic insights from animal models. Clin. Biochem. 37 , 333–343 (2004).

Deb, A. & Caplice, N. M. Lipoprotein(a): new insights into mechanisms of atherogenesis and thrombosis. Clin. Cardiol. 27 , 258–264 (2004).

Langsted, A., Nordestgaard, B. G. & Kamstrup, P. R. Elevated lipoprotein(a) and risk of ischemic stroke. J. Am. Coll. Cardiol. 74 , 54–66 (2019).

Nielsen, L. B. Atherogenecity of lipoprotein(a) and oxidized low density lipoprotein: insight from in vivo studies of arterial wall influx, degradation and efflux. Atherosclerosis 143 , 229–243 (1999).

Thompson, G. R. The scientific basis and future of lipoprotein apheresis. Ther. Apher. Dial. 26 , 32–36 (2022).

Parish, S. et al. Impact of apolipoprotein(a) isoform size on lipoprotein(a) lowering in the HPS2-THRIVE Study. Circ. Genom. Precis. Med 11 , e001696 (2018).

Santos, R. D. et al. Long-term efficacy and safety of mipomersen in patients with familial hypercholesterolaemia: 2-year interim results of an open-label extension. Eur. Heart J. 36 , 566–575 (2015).

O’Donoghue, M. L. et al. Lipoprotein(a), PCSK9 inhibition, and cardiovascular risk. Circulation 139 , 1483–1492 (2019).

Tsimikas, S. et al. Lipoprotein(a) reduction in persons with cardiovascular disease. N. Engl. J. Med. 382 , 244–255 (2020).

Tsimikas, S., Moriarty, P. M. & Stroes, E. S. Emerging RNA therapeutics to lower blood levels of Lp(a): JACC focus seminar 2/4. J. Am. Coll. Cardiol. 77 , 1576–1589 (2021).

Yvan-Charvet, L. et al. Combined deficiency of ABCA1 and ABCG1 promotes foam cell accumulation and accelerates atherosclerosis in mice. J. Clin. Investig. 117 , 3900–3908 (2007).

Wang, X. et al. Macrophage ABCA1 and ABCG1, but not SR-BI, promote macrophage reverse cholesterol transport in vivo. J. Clin. Investig. 117 , 2216–2224 (2007).

Naik, S. U. et al. Pharmacological activation of liver X receptors promotes reverse cholesterol transport in vivo. Circulation 113 , 90–97 (2006).

Joseph, S. B., Castrillo, A., Laffitte, B. A., Mangelsdorf, D. J. & Tontonoz, P. Reciprocal regulation of inflammation and lipid metabolism by liver X receptors. Nat. Med. 9 , 213–219 (2003).

Chen, J. et al. Liver X receptor activation attenuates plaque formation and improves vasomotor function of the aortic artery in atherosclerotic ApoE -/- mice. Inflamm. Res. 61 , 1299–1307 (2012).

Joseph, S. B. et al. Synthetic LXR ligand inhibits the development of atherosclerosis in mice. Proc. Natl Acad. Sci. USA 99 , 7604–7609 (2002).

Repa, J. J. et al. Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRα and LXRβ. Genes Dev. 14 , 2819–2830 (2000).

Yasuda, T. et al. Tissue-specific liver X receptor activation promotes macrophage reverse cholesterol transport in vivo. Arterioscler. Thromb. Vasc. Biol. 30 , 781–786 (2010).

Li, N. et al. Identification of a novel liver X receptor agonist that regulates the expression of key cholesterol homeostasis genes with distinct pharmacological characteristics. Mol. Pharm. 91 , 264–276 (2017).

Chen, Y. et al. Inhibition of ERK1/2 and activation of LXR synergistically reduce atherosclerotic lesions in ApoE-deficient mice. Arterioscler. Thromb. Vasc. Biol. 35 , 948–959 (2015).

Ma, C. et al. Functional interplay between liver X receptor and AMP-activated protein kinase α inhibits atherosclerosis in apolipoprotein E-deficient mice—a new anti-atherogenic strategy. Br. J. Pharm. 175 , 1486–1503 (2018).

Ma, C. et al. Targeting macrophage liver X receptors by hydrogel-encapsulated T0901317 reduces atherosclerosis without effect on hepatic lipogenesis. Br. J. Pharm. 178 , 1620–1638 (2021).

Villard, E. F. et al. Endogenous CETP activity as a predictor of cardiovascular risk: determination of the optimal range. Atherosclerosis 227 , 165–171 (2013).

Zhang, J. et al. Deficiency of cholesteryl ester transfer protein protects against atherosclerosis in rabbits. Arterioscler. Thromb. Vasc. Biol. 37 , 1068–1075 (2017).

Barter, P. J. et al. Effects of torcetrapib in patients at high risk for coronary events. N. Engl. J. Med. 357 , 2109–2122 (2007).

Schwartz, G. G. et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N. Engl. J. Med 367 , 2089–2099 (2012).

Lincoff, A. M. et al. Evacetrapib and cardiovascular outcomes in high-risk vascular disease. N. Engl. J. Med. 376 , 1933–1942 (2017).

Group, H. T. R. C. et al. Effects of anacetrapib in patients with atherosclerotic vascular disease. N. Engl. J. Med. 377 , 1217–1227 (2017).

Hovingh, G. K. et al. Cholesterol ester transfer protein inhibition by TA-8995 in patients with mild dyslipidaemia (TULIP): A randomised, double-blind, placebo-controlled phase 2 trial. Lancet 386 , 452–460 (2015).

Mehta, J. L., Chen, J., Hermonat, P. L., Romeo, F. & Novelli, G. Lectin-like, oxidized low-density lipoprotein receptor-1 (LOX-1): a critical player in the development of atherosclerosis and related disorders. Cardiovasc. Res. 69 , 36–45 (2006).

Hinagata, J. et al. Oxidized LDL receptor LOX-1 is involved in neointimal hyperplasia after balloon arterial injury in a rat model. Cardiovasc. Res. 69 , 263–271 (2006).

Hu, C. et al. LOX-1 deletion decreases collagen accumulation in atherosclerotic plaque in low-density lipoprotein receptor knockout mice fed a high-cholesterol diet. Cardiovasc. Res. 79 , 287–293 (2008).

Ishigaki, Y. et al. Impact of plasma oxidized low-density lipoprotein removal on atherosclerosis. Circulation 118 , 75–83 (2008).

Xu, S. et al. Tanshinone II-A inhibits oxidized LDL-induced LOX-1 expression in macrophages by reducing intracellular superoxide radical generation and NF-κB activation. Transl. Res 160 , 114–124 (2012).

Kang, B. Y. et al. Curcumin reduces angiotensin II-mediated cardiomyocyte growth via LOX-1 inhibition. J. Cardiovasc. Pharm. 55 , 176–183 (2010).

Ou, H. C. et al. Ginkgo biloba extract attenuates oxLDL-induced oxidative functional damages in endothelial cells. J. Appl. Physiol. 106 , 1674–1685 (2009).

Francone, O. L. et al. The hydrophobic tunnel present in LOX-1 is essential for oxidized ldl recognition and binding. J. Lipid Res. 50 , 546–555 (2009).

Thakkar, S. et al. Structure-based design targeted at LOX-1, a receptor for oxidized low-density lipoprotein. Sci. Rep. 5 , 16740 (2015).

Pothineni, N. V. K. et al. LOX-1 in atherosclerosis and myocardial ischemia: biology, genetics, and modulation. J. Am. Coll. Cardiol. 69 , 2759–2768 (2017).

Linton, M. F., Tao, H., Linton, E. F. & Yancey, P. G. SR-BI: a multifunctional receptor in cholesterol homeostasis and atherosclerosis. Trends Endocrinol. Metab. 28 , 461–472 (2017).

Zanoni, P. et al. Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease. Science 351 , 1166–1171 (2016).

Zhang, X. & Fernandez-Hernando, C. The Janus-faced role of SR-BI in atherosclerosis. Nat. Metab. 1 , 586–587 (2019).

Vitali, C. & Cuchel, M. Controversial role of lecithin: cholesterol acyltransferase in the development of atherosclerosis: new insights from an LCAT activator. Arterioscler. Thromb. Vasc. Biol. 41 , 377–379 (2021).

CAS   PubMed   Google Scholar  

Kunnen, S. & Van Eck, M. Lecithin: cholesterol acyltransferase: old friend or foe in atherosclerosis? J. Lipid Res. 53 , 1783–1799 (2012).

Oldoni, F. et al. Complete and partial lecithin: cholesterol acyltransferase deficiency is differentially associated with atherosclerosis. Circulation 138 , 1000–1007 (2018).

Shamburek, R. D. et al. Safety and tolerability of ACP-501, a recombinant human lecithin: cholesterol acyltransferase, in a phase 1 single-dose escalation study. Circ. Res. 118 , 73–82 (2016).

Bonaca, M. P. et al. Recombinant human lecithin-cholesterol acyltransferase in patients with atherosclerosis: phase 2a primary results and phase 2b design. Eur. Heart J. Cardiovasc. Pharmacother. 8 , 243–252 (2021).

Freeman, L. A. et al. Lecithin: cholesterol acyltransferase activation by sulfhydryl-reactive small molecules: role of cysteine-31. J. Pharm. Exp. Ther. 362 , 306–318 (2017).

Chen, Z. et al. Small molecule activation of lecithin cholesterol acyltransferase modulates lipoprotein metabolism in mice and hamsters. Metabolism 61 , 470–481 (2012).

Manthei, K. A. et al. Molecular basis for activation of lecithin: cholesterol acyltransferase by a compound that increases HDL cholesterol. Elife 7 , e41604 (2018).

Sasaki, M. et al. Novel LCAT (Lecithin: cholesterol acyltransferase) activator DS-8190a prevents the progression of plaque accumulation in atherosclerosis models. Arterioscler. Thromb. Vasc. Biol. 41 , 360–376 (2021).

Krol, J., Loedige, I. & Filipowicz, W. The widespread regulation of microrna biogenesis, function and decay. Nat. Rev. Genet. 11 , 597–610 (2010).

Canfran-Duque, A., Lin, C. S., Goedeke, L., Suarez, Y. & Fernandez-Hernando, C. Micro-RNAs and high-density lipoprotein metabolism. Arterioscler. Thromb. Vasc. Biol. 36 , 1076–1084 (2016).

Goedeke, L., Wagschal, A., Fernandez-Hernando, C. & Naar, A. M. miRNA regulation of LDL-cholesterol metabolism. Biochim. Biophys. Acta 1861 , 2047–2052 (2016).

Goedeke, L., Aranda, J. F. & Fernandez-Hernando, C. microRNA regulation of lipoprotein metabolism. Curr. Opin. Lipido 25 , 282–288 (2014).

Najafi-Shoushtari, S. H. et al. MicroRNA-33 and the SREBP host genes cooperate to control cholesterol homeostasis. Science 328 , 1566–1569 (2010).

Rayner, K. J. et al. MiR-33 contributes to the regulation of cholesterol homeostasis. Science 328 , 1570–1573 (2010).

Marquart, T. J., Allen, R. M., Ory, D. S. & Baldan, A. MiR-33 links SREBP-2 induction to repression of sterol transporters. Proc. Natl Acad. Sci. USA 107 , 12228–12232 (2010).

Horie, T. et al. MicroRNA-33 encoded by an intron of sterol regulatory element-binding protein 2 (SREBP2) regulates HDL in vivo. Proc. Natl Acad. Sci. USA 107 , 17321–17326 (2010).

Rottiers, V. et al. Pharmacological inhibition of a microRNA family in nonhuman primates by a seed-targeting 8-mer antimiR. Sci. Transl. Med. 5 , 212ra162 (2013).

Price, N. L. et al. Genetic ablation of miR-33 increases food intake, enhances adipose tissue expansion, and promotes obesity and insulin resistance. Cell Rep. 22 , 2133–2145 (2018).

Price, N. L. et al. Genetic dissection of the impact of miR-33a and miR-33b during the progression of atherosclerosis. Cell Rep. 21 , 1317–1330 (2017).

Horie, T. et al. MicroRNA-33 deficiency reduces the progression of atherosclerotic plaque in ApoE -/- mice. J. Am. Heart Assoc. 1 , e003376 (2012).

Willeit, P. et al. Circulating microRNA-122 is associated with the risk of new-onset metabolic syndrome and type 2 diabetes. Diabetes 66 , 347–357 (2017).

Esau, C. et al. MiR-122 regulation of lipid metabolism revealed by in vivo antisense targeting. Cell Metab. 3 , 87–98 (2006).

Elmen, J. et al. LNA-mediated microRNA silencing in non-human primates. Nature 452 , 896–899 (2008).

Castoldi, M. et al. The liver-specific microRNA miR-122 controls systemic iron homeostasis in mice. J. Clin. Investig. 121 , 1386–1396 (2011).

Hsu, S. H. et al. Essential metabolic, anti-inflammatory, and anti-tumorigenic functions of miR-122 in liver. J. Clin. Investig. 122 , 2871–2883 (2012).

Chalasani, N. et al. The diagnosis and management of non-alcoholic fatty liver disease: practice Guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology. Gastroenterology 142 , 1592–1609 (2012).

Puri, P. et al. A lipidomic analysis of nonalcoholic fatty liver disease. Hepatology 46 , 1081–1090 (2007).

Ioannou, G. N. The role of cholesterol in the pathogenesis of nash. Trends Endocrinol. Metab. 27 , 84–95 (2016).

Musso, G., Gambino, R. & Cassader, M. Cholesterol metabolism and the pathogenesis of non-alcoholic steatohepatitis. Prog. Lipid Res. 52 , 175–191 (2013).

Yasutake, K. et al. Nutritional investigation of non-obese patients with non-alcoholic fatty liver disease: the significance of dietary cholesterol. Scand. J. Gastroenterol. 44 , 471–477 (2009).

Musso, G. et al. Dietary habits and their relations to insulin resistance and postprandial lipemia in nonalcoholic steatohepatitis. Hepatology 37 , 909–916 (2003).

Savard, C. et al. Synergistic interaction of dietary cholesterol and dietary fat in inducing experimental steatohepatitis. Hepatology 57 , 81–92 (2013).

Wouters, K. et al. Intrahepatic cholesterol influences progression, inhibition and reversal of non-alcoholic steatohepatitis in hyperlipidemic mice. FEBS Lett. 584 , 1001–1005 (2010).

Li, H., Yu, X. H., Ou, X., Ouyang, X. P. & Tang, C. K. Hepatic cholesterol transport and its role in non-alcoholic fatty liver disease and atherosclerosis. Prog. Lipid Res. 83 , 101109 (2021).

Caballero, F. et al. Enhanced free cholesterol, SREBP-2 and StAR expression in human NASH. J. Hepatol. 50 , 789–796 (2009).

Simonen, P. et al. Cholesterol synthesis is increased and absorption decreased in non-alcoholic fatty liver disease independent of obesity. J. Hepatol. 54 , 153–159 (2011).

Ioannou, G. N. et al. Cholesterol crystallization within hepatocyte lipid droplets and its role in murine NASH. J. Lipid Res. 58 , 1067–1079 (2017).

Wallace, M. C., Friedman, S. L. & Mann, D. A. Emerging and disease-specific mechanisms of hepatic stellate cell activation. Semin. Liver Dis. 35 , 107–118 (2015).

Khajehahmadi, Z. et al. Downregulation of hedgehog ligands in human simple steatosis may protect against nonalcoholic steatohepatitis: Is TAZ a crucial regulator? IUBMB Life 71 , 1382–1390 (2019).

Mooring, M. et al. Hepatocyte stress increases expression of yes-associated protein and transcriptional coactivator with PDZ-binding motif in hepatocytes to promote parenchymal inflammation and fibrosis. Hepatology 71 , 1813–1830 (2020).

Wang, X. et al. Hepatocyte TAZ/WWTR1 promotes inflammation and fibrosis in nonalcoholic steatohepatitis. Cell Metab. 24 , 848–862 (2016).

Wang, X. et al. Cholesterol stabilizes TAZ in hepatocytes to promote experimental non-alcoholic steatohepatitis. Cell Metab. 31 , 969–986 e967 (2020).

Musso, G., Cassader, M. & Gambino, R. Cholesterol-lowering therapy for the treatment of nonalcoholic fatty liver disease: an update. Curr. Opin. Lipido 22 , 489–496 (2011).

Tziomalos, K. Lipid-lowering agents in the management of nonalcoholic fatty liver disease. World J. Hepatol. 6 , 738–744 (2014).

Pastori, D. et al. The efficacy and safety of statins for the treatment of non-alcoholic fatty liver disease. Dig. Liver Dis. 47 , 4–11 (2015).

Musso, G. Ezetimibe in the balance: can cholesterol-lowering drugs alone be an effective therapy for NAFLD? Diabetologia 57 , 850–855 (2014).

Takeshita, Y. et al. The effects of ezetimibe on non-alcoholic fatty liver disease and glucose metabolism: a randomised controlled trial. Diabetologia 57 , 878–890 (2014).

Loomba, R. et al. Ezetimibe for the treatment of nonalcoholic steatohepatitis: Aassessment by novel magnetic resonance imaging and magnetic resonance elastography in a randomized trial (MOZART trial). Hepatology 61 , 1239–1250 (2015).

Francque, S. M. et al. A randomized, controlled trial of the pan-PPAR agonist lanifibranor in NASH. N. Engl. J. Med. 385 , 1547–1558 (2021).

Yang, X. et al. Hepatocyte SH3RF2 deficiency is a key aggravator for NAFLD. Hepatology 74 , 1319–1338 (2021).

Rottiers, V. & Naar, A. M. MicroRNAs in metabolism and metabolic disorders. Nat. Rev. Mol. Cell Biol. 13 , 239–250 (2012).

Haslam, D. W. & James, W. P. Obesity. Lancet 366 , 1197–1209 (2005).

Kim, M., Lee, C. & Park, J. Extracellular matrix remodeling facilitates obesity-associated cancer progression. Trends Cell Biol . https://doi.org/10.1016/j.tcb.2022.02.008 (2022).

Salem, V. et al. Prevalence, risk factors, and interventions for obesity in Saudi Arabia: a systematic review. Obes. Rev. 23 , e13448 (2022).

Chung, S. et al. Dietary cholesterol promotes adipocyte hypertrophy and adipose tissue inflammation in visceral, but not in subcutaneous, fat in monkeys. Arterioscler. Thromb. Vasc. Biol. 34 , 1880–1887 (2014).

Lamri, A., Pigeyre, M., Garver, W. S. & Meyre, D. The extending spectrum of NPC1-related human disorders: from Niemann-Pick C1 disease to obesity. Endocr. Rev. 39 , 192–220 (2018).

The adipocyte and obesity: cellular and molecular mechanisms. Abstracts from an international conference, university of toronto, 28 and 29 june, 1982. Int. J. Obes. 7 , 373 (1983).

Gregor, M. F. & Hotamisligil, G. S. Inflammatory mechanisms in obesity. Annu. Rev. Immunol. 29 , 415–445 (2011).

Villarroya, F., Cereijo, R., Gavalda-Navarro, A., Villarroya, J. & Giralt, M. Inflammation of brown/beige adipose tissues in obesity and metabolic disease. J. Intern. Med 284 , 492–504 (2018).

Curley, S., Gall, J., Byrne, R., Yvan-Charvet, L. & McGillicuddy, F. C. Metabolic inflammation in obesity-at the crossroads between fatty acid and cholesterol metabolism. Mol. Nutr. Food Res. 65 , e1900482 (2021).

Grover, G. J. et al. Selective thyroid hormone receptor-beta activation: a strategy for reduction of weight, cholesterol, and lipoprotein (a) with reduced cardiovascular liability. Proc. Natl Acad. Sci. USA 100 , 10067–10072 (2003).

Barbe, P. et al. Triiodothyronine-mediated up-regulation of UCP2 and UCP3 mRNA expression in human skeletal muscle without coordinated induction of mitochondrial respiratory chain genes. FASEB J. 15 , 13–15 (2001).

Finan, B. et al. Chemical hybridization of glucagon and thyroid hormone optimizes therapeutic impact for metabolic disease. Cell 167 , 843–857 e814 (2016).

Berbee, J. F. et al. Brown fat activation reduces hypercholesterolaemia and protects from atherosclerosis development. Nat. Commun. 6 , 6356 (2015).

Baxter, J. D., Webb, P., Grover, G. & Scanlan, T. S. Selective activation of thyroid hormone signaling pathways by GC-1: a new approach to controlling cholesterol and body weight. Trends Endocrinol. Metab. 15 , 154–157 (2004).

Meslier, V. et al. Mediterranean diet intervention in overweight and obese subjects lowers plasma cholesterol and causes changes in the gut microbiome and metabolome independently of energy intake. Gut 69 , 1258–1268 (2020).

Ho, M. et al. Impact of dietary and exercise interventions on weight change and metabolic outcomes in obese children and adolescents: a systematic review and meta-analysis of randomized trials. JAMA Pediatr. 167 , 759–768 (2013).

Marcus, F., Gontero, B., Harrsch, P. B. & Rittenhouse, J. Amino acid sequence homology among fructose-1,6-bisphosphatases. Biochem. Biophys. Res. Commun. 135 , 374–381 (1986).

Goldberg, R. B. Lipid disorders in diabetes. Diabetes Care 4 , 561–572 (1981).

Wilson, F. P. & Williams, O. T. Note on the occurrence and constitution on lipoid material in diabetic blood. Biochem. J. 2 , 20–24 (1907).

Henderson, A. M. A case of diabetes mellitus with hyperlipaemia and hypercholesterolaemia. Med. J. Aust. 1 , 513 (1946).

Brunham, L. R. et al. Beta-cell ABCA1 influences insulin secretion, glucose homeostasis and response to thiazolidinedione treatment. Nat. Med. 13 , 340–347 (2007).

Hao, M., Head, W. S., Gunawardana, S. C., Hasty, A. H. & Piston, D. W. Direct effect of cholesterol on insulin secretion: a novel mechanism for pancreatic beta-cell dysfunction. Diabetes 56 , 2328–2338 (2007).

Vergeer, M. et al. Carriers of loss-of-function mutations in ABCA1 display pancreatic beta-cell dysfunction. Diabetes Care 33 , 869–874 (2010).

Xu, Y., Toomre, D. K., Bogan, J. S. & Hao, M. Excess cholesterol inhibits glucose-stimulated fusion pore dynamics in insulin exocytosis. J. Cell Mol. Med. 21 , 2950–2962 (2017).

Carrasco-Pozo, C. et al. The deleterious effect of cholesterol and protection by quercetin on mitochondrial bioenergetics of pancreatic beta-cells, glycemic control and inflammation: in vitro and in vivo studies. Redox Biol. 9 , 229–243 (2016).

Zhao, Y. F. et al. Cholesterol induces mitochondrial dysfunction and apoptosis in mouse pancreatic beta-cell line MIN6 cells. Endocrine 37 , 76–82 (2010).

Chen, Z. Y. et al. Atorvastatin helps preserve pancreatic β cell function in obese C57BL/6 J mice and the effect is related to increased pancreas proliferation and amelioration of endoplasmic-reticulum stress. Lipids Health Dis. 13 , 98 (2014).

Cochran, B. J. et al. Impact of perturbed pancreatic β-cell cholesterol homeostasis on adipose tissue and skeletal muscle metabolism. Diabetes 65 , 3610–3620 (2016).

Siebel, A. L. et al. Effects of high-density lipoprotein elevation with cholesteryl ester transfer protein inhibition on insulin secretion. Circ. Res. 113 , 167–175 (2013).

Cederberg, H. et al. Increased risk of diabetes with statin treatment is associated with impaired insulin sensitivity and insulin secretion: a 6 year follow-up study of the metsim cohort. Diabetologia 58 , 1109–1117 (2015).

Preiss, D. et al. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis. JAMA 305 , 2556–2564 (2011).

Sattar, N. et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet 375 , 735–742 (2010).

Shen, L. et al. Atorvastatin targets the islet mevalonate pathway to dysregulate mtor signaling and reduce β-cell functional mass. Diabetes 69 , 48–59 (2020).

Zhong, Y. et al. Effect of ezetimibe on insulin secretion in db/db diabetic mice. Exp. Diabetes Res. 2012 , 420854 (2012).

Wijesekara, N. et al. MiR-33a modulates ABCA1 expression, cholesterol accumulation, and insulin secretion in pancreatic islets. Diabetes 61 , 653–658 (2012).

Kang, M. H. et al. Regulation of ABCA1 protein expression and function in hepatic and pancreatic islet cells by miR-145. Arterioscler. Thromb. Vasc. Biol. 33 , 2724–2732 (2013).

Zhang, J. & Liu, Q. Cholesterol metabolism and homeostasis in the brain. Protein Cell 6 , 254–264 (2015).

Li, D., Zhang, J. & Liu, Q. Brain cell type-specific cholesterol metabolism and implications for learning and memory. Trends Neurosci. 45 , 401–414 (2022).

Leduc, V., Jasmin-Belanger, S. & Poirier, J. ApoE and cholesterol homeostasis in Alzheimer’s disease. Trends Mol. Med. 16 , 469–477 (2010).

Wolozin, B. Cholesterol and the biology of Alzheimer’s disease. Neuron 41 , 7–10 (2004).

Shobab, L. A., Hsiung, G. Y. & Feldman, H. H. Cholesterol in Alzheimer’s disease. Lancet Neurol. 4 , 841–852 (2005).

Zambon, D. et al. Higher incidence of mild cognitive impairment in familial hypercholesterolemia. Am. J. Med. 123 , 267–274 (2010).

Silva, T., Teixeira, J., Remiao, F. & Borges, F. Alzheimer’s disease, cholesterol, and statins: the junctions of important metabolic pathways. Angew. Chem. Int. Ed. Engl. 52 , 1110–1121 (2013).

Xiong, H. et al. Cholesterol retention in alzheimer’s brain is responsible for high beta- and gamma-secretase activities and abeta production. Neurobiol. Dis. 29 , 422–437 (2008).

Cutler, R. G. et al. Involvement of oxidative stress-induced abnormalities in ceramide and cholesterol metabolism in brain aging and Alzheimer’s disease. Proc. Natl Acad. Sci. USA 101 , 2070–2075 (2004).

Sparks, D. L. et al. Induction of Alzheimer-like beta-amyloid immunoreactivity in the brains of rabbits with dietary cholesterol. Exp. Neurol. 126 , 88–94 (1994).

Poirier, J. & Apolipoprotein, E. and cholesterol metabolism in the pathogenesis and treatment of Alzheimer’s disease. Trends Mol. Med. 9 , 94–101 (2003).

Gao, Y., Tan, L., Yu, J. T. & Tan, L. Tau in Alzheimer’s disease: mechanisms and therapeutic strategies. Curr. Alzheimer Res. 15 , 283–300 (2018).

Knopman, D. S. et al. Alzheimer disease. Nat. Rev. Dis. Prim. 7 , 33 (2021).

Villemagne, V. L. et al. Imaging of tau deposits in adults with Niemann-Pick type C disease: a case-control study. Eur. J. Nucl. Med. Mol. Imaging 46 , 1132–1138 (2019).

van der Kant, R. et al. Cholesterol metabolism is a druggable axis that independently regulates tau and amyloid-β in iPSC-derived Alzheimer’s disease neurons. Cell Stem Cell 24 , 363–375 e369 (2019).

Fan, Q. W., Yu, W., Senda, T., Yanagisawa, K. & Michikawa, M. Cholesterol-dependent modulation of tau phosphorylation in cultured neurons. J. Neurochem. 76 , 391–400 (2001).

Kalia, L. V. & Lang, A. E. Parkinson’s disease. Lancet 386 , 896–912 (2015).

Sohmiya, M. et al. Redox status of plasma coenzyme Q10 indicates elevated systemic oxidative stress in Parkinson’s disease. J. Neurol. Sci. 223 , 161–166 (2004).

Teunissen, C. E. et al. Combination of serum markers related to several mechanisms in Alzheimer’s disease. Neurobiol. Aging 24 , 893–902 (2003).

de Lau, L. M., Koudstaal, P. J., Hofman, A. & Breteler, M. M. Serum cholesterol levels and the risk of Parkinson’s disease. Am. J. Epidemiol. 164 , 998–1002 (2006).

Rozani, V. et al. Higher serum cholesterol and decreased Parkinson’s disease risk: a statin-free cohort study. Mov. Disord. 33 , 1298–1305 (2018).

Hu, G., Antikainen, R., Jousilahti, P., Kivipelto, M. & Tuomilehto, J. Total cholesterol and the risk of Parkinson disease. Neurology 70 , 1972–1979 (2008).

de Oliveira, J. et al. Diphenyl diselenide prevents cortico-cerebral mitochondrial dysfunction and oxidative stress induced by hypercholesterolemia in LDL receptor knockout mice. Neurochem. Res. 38 , 2028–2036 (2013).

Thirumangalakudi, L. et al. High cholesterol-induced neuroinflammation and amyloid precursor protein processing correlate with loss of working memory in mice. J. Neurochem. 106 , 475–485 (2008).

Bar-On, P. et al. Statins reduce neuronal alpha-synuclein aggregation in in vitro models of Parkinson’s disease. J. Neurochem. 105 , 1656–1667 (2008).

Kruger, R. et al. Increased susceptibility to sporadic Parkinson’s disease by a certain combined alpha-synuclein/apolipoprotein E genotype. Ann. Neurol. 45 , 611–617 (1999).

Fantini, J., Carlus, D. & Yahi, N. The fusogenic tilted peptide (67-78) of α-synuclein is a cholesterol binding domain. Biochim. Biophys. Acta 1808 , 2343–2351 (2011).

Hsiao, J. T., Halliday, G. M. & Kim, W. S. α-synuclein regulates neuronal cholesterol efflux. Molecules 22 , 1769 (2017).

Article   PubMed Central   CAS   Google Scholar  

Walker, F. O. Huntington’s disease. Lancet 369 , 218–228 (2007).

Kacher, R., Mounier, C., Caboche, J. & Betuing, S. Altered cholesterol homeostasis in Huntington’s disease. Front. Aging Neurosci. 14 , 797220 (2022).

Hooghwinkel, G. J., Borri, P. F. & Bruyn, G. W. Biochemical studies in Huntington’s chorea. II. Composition of blood lipids. Acta Neurol. Scand. 42 , 213–220 (1966).

Sipione, S. et al. Early transcriptional profiles in Huntingtin-inducible striatal cells by microarray analyses. Hum. Mol. Genet. 11 , 1953–1965 (2002).

Leoni, V. et al. Whole body cholesterol metabolism is impaired in Huntington’s disease. Neurosci. Lett. 494 , 245–249 (2011).

Valenza, M. et al. Cholesterol biosynthesis pathway is disturbed in YAC128 mice and is modulated by huntingtin mutation. Hum. Mol. Genet. 16 , 2187–2198 (2007).

Valenza, M. et al. Progressive dysfunction of the cholesterol biosynthesis pathway in the R6/2 mouse model of huntington’s disease. Neurobiol. Dis. 28 , 133–142 (2007).

Valenza, M. et al. Cholesterol defect is marked across multiple rodent models of Huntington’s disease and is manifest in astrocytes. J. Neurosci. 30 , 10844–10850 (2010).

Valenza, M. et al. Dysfunction of the cholesterol biosynthetic pathway in Huntington’s disease. J. Neurosci. 25 , 9932–9939 (2005).

Suzuki, S. et al. Brain-derived neurotrophic factor regulates cholesterol metabolism for synapse development. J. Neurosci. 27 , 6417–6427 (2007).

Gauthier, L. R. et al. Huntingtin controls neurotrophic support and survival of neurons by enhancing BDNF vesicular transport along microtubules. Cell 118 , 127–138 (2004).

Karasinska, J. M. & Hayden, M. R. Cholesterol metabolism in Huntington disease. Nat. Rev. Neurol. 7 , 561–572 (2011).

del Toro, D. et al. Altered cholesterol homeostasis contributes to enhanced excitotoxicity in Huntington’s disease. J. Neurochem. 115 , 153–167 (2010).

Sierra, S. et al. Statins as neuroprotectants: a comparative in vitro study of lipophilicity, blood-brain-barrier penetration, lowering of brain cholesterol, and decrease of neuron cell death. J. Alzheimers Dis. 23 , 307–318 (2011).

van der Most, P. J., Dolga, A. M., Nijholt, I. M., Luiten, P. G. & Eisel, U. L. Statins: mechanisms of neuroprotection. Prog. Neurobiol. 88 , 64–75 (2009).

Kumar, A., Sharma, N., Mishra, J. & Kalonia, H. Synergistical neuroprotection of rofecoxib and statins against malonic acid induced Huntington’s disease like symptoms and related cognitive dysfunction in rats. Eur. J. Pharm. 709 , 1–12 (2013).

Yan, J., Sun, J., Huang, L., Fu, Q. & Du, G. Simvastatin prevents neuroinflammation by inhibiting N-methyl-D-aspartic acid receptor 1 in 6-hydroxydopamine-treated PC12 cells. J. Neurosci. Res. 92 , 634–640 (2014).

Jick, H., Zornberg, G. L., Jick, S. S., Seshadri, S. & Drachman, D. A. Statins and the risk of dementia. Lancet 356 , 1627–1631 (2000).

Friedhoff, L. T., Cullen, E. I., Geoghagen, N. S. & Buxbaum, J. D. Treatment with controlled-release lovastatin decreases serum concentrations of human beta-amyloid (A beta) peptide. Int. J. Neuropsychopharmacol. 4 , 127–130 (2001).

Li, G. et al. Statin therapy is associated with reduced neuropathologic changes of Alzheimer disease. Neurology 69 , 878–885 (2007).

Rea, T. D. et al. Statin use and the risk of incident dementia: the cardiovascular health study. Arch. Neurol. 62 , 1047–1051 (2005).

Wolozin, B. et al. Simvastatin is associated with a reduced incidence of dementia and Parkinson’s disease. BMC Med 5 , 20 (2007).

Bykov, K., Yoshida, K., Weisskopf, M. G. & Gagne, J. J. Confounding of the association between statins and parkinson disease: systematic review and meta-analysis. Pharmacoepidemiol. Drug Saf. 26 , 294–300 (2017).

Lee, Y. C. et al. Discontinuation of statin therapy associates with parkinson disease: a population-based study. Neurology 81 , 410–416 (2013).

Liu, G. et al. Statins may facilitate Parkinson’s disease: insight gained from a large, national claims database. Mov. Disord. 32 , 913–917 (2017).

Rozani, V. et al. Statin adherence and the risk of Parkinson’s disease: a population-based cohort study. PLoS One 12 , e0175054 (2017).

Refolo, L. M. et al. A cholesterol-lowering drug reduces β-amyloid pathology in a transgenic mouse model of Alzheimer’s disease. Neurobiol. Dis. 8 , 890–899 (2001).

Whitney, K. D. et al. Regulation of cholesterol homeostasis by the liver X receptors in the central nervous system. Mol. Endocrinol. 16 , 1378–1385 (2002).

Chen, J. Y. et al. Partial amelioration of peripheral and central symptoms of Huntington’s disease via modulation of lipid metabolism. J. Huntingt. Dis. 5 , 65–81 (2016).

Xu, P. et al. LXR agonists: new potential therapeutic drug for neurodegenerative diseases. Mol. Neurobiol. 48 , 715–728 (2013).

Cermenati, G. et al. Liver X receptors, nervous system, and lipid metabolism. J. Endocrinol. Investig. 36 , 435–443 (2013).

CAS   Google Scholar  

Yao, J. et al. Neuroprotection by cyclodextrin in cell and mouse models of Alzheimer disease. J. Exp. Med. 209 , 2501–2513 (2012).

Bar-On, P. et al. Effects of the cholesterol-lowering compound methyl-beta-cyclodextrin in models of alpha-synucleinopathy. J. Neurochem. 98 , 1032–1045 (2006).

Ikonen, E. Cellular cholesterol trafficking and compartmentalization. Nat. Rev. Mol. Cell Biol. 9 , 125–138 (2008).

Mooberry, L. K., Sabnis, N. A., Panchoo, M., Nagarajan, B. & Lacko, A. G. Targeting the SR-BI receptor as a gateway for cancer therapy and imaging. Front. Pharm. 7 , 466 (2016).

Ahn, J. et al. Prediagnostic total and high-density lipoprotein cholesterol and risk of cancer. Cancer Epidemiol. Biomark. Prev. 18 , 2814–2821 (2009).

Riscal, R., Skuli, N. & Simon, M. C. Even cancer cells watch their cholesterol! Mol. Cell 76 , 220–231 (2019).

Tosi, M. R. & Tugnoli, V. Cholesteryl esters in malignancy. Clin. Chim. Acta 359 , 27–45 (2005).

Xu, D. et al. The gluconeogenic enzyme PCK1 phosphorylates INSIG1/2 for lipogenesis. Nature 580 , 530–535 (2020).

Furuta, E. et al. Fatty acid synthase gene is up-regulated by hypoxia via activation of Akt and sterol regulatory element binding protein-1. Cancer Res 68 , 1003–1011 (2008).

Huang, B., Song, B. L. & Xu, C. Cholesterol metabolism in cancer: mechanisms and therapeutic opportunities. Nat. Metab. 2 , 132–141 (2020).

Pontini, L. & Marinozzi, M. Shedding light on the roles of liver X receptors in cancer by using chemical probes. Br. J. Pharm. 178 , 3261–3276 (2021).

Xu, H., Zhou, S., Tang, Q., Xia, H. & Bi, F. Cholesterol metabolism: new functions and therapeutic approaches in cancer. Biochim. Biophys. Acta Rev. Cancer 1874 , 188394 (2020).

Han, M. et al. Therapeutic implications of altered cholesterol homeostasis mediated by loss of CYP46A1 in human glioblastoma. EMBO Mol. Med. 12 , e10924 (2020).

Oni, T. E. et al. SOAT1 promotes mevalonate pathway dependency in pancreatic cancer. J. Exp. Med. 217 , e20192389 (2020).

Zhu, Y. et al. P53 deficiency affects cholesterol esterification to exacerbate hepatocarcinogenesis. Hepatology . https://doi.org/10.1002/hep.32518 (2022).

Ma, X. et al. Cholesterol induces CD8 + T cell exhaustion in the tumor microenvironment. Cell Metab. 30 , 143–156 e145 (2019).

Goossens, P. et al. Membrane cholesterol efflux drives tumor-associated macrophage reprogramming and tumor progression. Cell Metab. 29 , 1376–1389 e1374 (2019).

Garwood, E. R. et al. Fluvastatin reduces proliferation and increases apoptosis in women with high grade breast cancer. Breast Cancer Res. Treat. 119 , 137–144 (2010).

Clendening, J. W. et al. Exploiting the mevalonate pathway to distinguish statin-sensitive multiple myeloma. Blood 115 , 4787–4797 (2010).

Longo, J. et al. An actionable sterol-regulated feedback loop modulates statin sensitivity in prostate cancer. Mol. Metab. 25 , 119–130 (2019).

Seckl, M. J. et al. Multicenter, phase III, randomized, double-blind, placebo-controlled trial of pravastatin added to first-line standard chemotherapy in small-cell lung cancer (LUNGSTAR). J. Clin. Oncol. 35 , 1506–1514 (2017).

Lim, S. H. et al. A randomised, double-blind, placebo-controlled multi-centre phase III trial of XELIRI/FOLFIRI plus simvastatin for patients with metastatic colorectal cancer. Br. J. Cancer 113 , 1421–1426 (2015).

Jouve, J. L. et al. Pravastatin combination with sorafenib does not improve survival in advanced hepatocellular carcinoma. J. Hepatol. 71 , 516–522 (2019).

Kim, S. T. et al. Simvastatin plus capecitabine-cisplatin versus placebo plus capecitabine-cisplatin in patients with previously untreated advanced gastric cancer: a double-blind randomised phase 3 study. Eur. J. Cancer 50 , 2822–2830 (2014).

Luo, Y., Liu, L., Li, X. & Shi, Y. Avasimibe inhibits the proliferation, migration and invasion of glioma cells by suppressing linc00339. Biomed. Pharmacother. 130 , 110508 (2020).

Bemlih, S., Poirier, M. D. & El Andaloussi, A. Acyl-coenzyme A: cholesterol acyltransferase inhibitor Avasimibe affect survival and proliferation of glioma tumor cell lines. Cancer Biol. Ther. 9 , 1025–1032 (2010).

Jiang, Y. et al. Proteomics identifies new therapeutic targets of early-stage hepatocellular carcinoma. Nature 567 , 257–261 (2019).

Pommier, A. J. et al. Liver X receptor activation downregulates AKT survival signaling in lipid rafts and induces apoptosis of prostate cancer cells. Oncogene 29 , 2712–2723 (2010).

Solomon, K. R. et al. Ezetimibe is an inhibitor of tumor angiogenesis. Am. J. Pathol. 174 , 1017–1026 (2009).

Miura, K. et al. Ezetimibe suppresses development of liver tumors by inhibiting angiogenesis in mice fed a high-fat diet. Cancer Sci. 110 , 771–783 (2019).

Yuan, J. et al. Potentiating CD8 + T cell antitumor activity by inhibiting PCSK9 to promote LDLR-mediated tcr recycling and signaling. Protein Cell 12 , 240–260 (2021).

Song, S., Guo, Y., Yang, Y. & Fu, D. Advances in pathogenesis and therapeutic strategies for osteoporosis. Pharm. Ther. 237 , 108168 (2022).

Paschalis, E. P. et al. Vitamin D and calcium supplementation for three years in postmenopausal osteoporosis significantly alters bone mineral and organic matrix quality. Bone 95 , 41–46 (2017).

Yamaguchi, T. et al. Plasma lipids and osteoporosis in postmenopausal women. Endocr. J. 49 , 211–217 (2002).

Yerges-Armstrong, L. M. et al. Decreased bone mineral density in subjects carrying familial defective apolipoprotein B-100. J. Clin. Endocrinol. Metab. 98 , E1999–E2005 (2013).

Jeong, T. D. et al. Relationship between serum total cholesterol level and serum biochemical bone turnover markers in healthy pre- and postmenopausal women. Biomed. Res. Int. 2014 , 398397 (2014).

Tarakida, A. et al. Hypercholesterolemia accelerates bone loss in postmenopausal women. Climacteric 14 , 105–111 (2011).

Parhami, F. et al. Atherogenic high-fat diet reduces bone mineralization in mice. J. Bone Min. Res. 16 , 182–188 (2001).

You, L. et al. High cholesterol diet increases osteoporosis risk via inhibiting bone formation in rats. Acta Pharm. Sin. 32 , 1498–1504 (2011).

Pelton, K. et al. Hypercholesterolemia promotes an osteoporotic phenotype. Am. J. Pathol. 181 , 928–936 (2012).

Cutillas-Marco, E., Prosper, A. F., Grant, W. B. & Morales-Suarez-Varela, M. M. Vitamin D status and hypercholesterolemia in spanish general population. Dermatoendocrinology 5 , 358–362 (2013).

Luegmayr, E. et al. Osteoclast formation, survival and morphology are highly dependent on exogenous cholesterol/lipoproteins. Cell Death Differ. 11 , S108–S118 (2004).

Sanbe, T. et al. Oral administration of vitamin C prevents alveolar bone resorption induced by high dietary cholesterol in rats. J. Periodontol. 78 , 2165–2170 (2007).

Lin, S. M., Wang, J. H., Liang, C. C. & Huang, H. K. Statin use is associated with decreased osteoporosis and fracture risks in stroke patients. J. Clin. Endocrinol. Metab. 103 , 3439–3448 (2018).

An, T. et al. Efficacy of statins for osteoporosis: a systematic review and meta-analysis. Osteoporos. Int. 28 , 47–57 (2017).

Leutner, M. et al. Diagnosis of osteoporosis in statin-treated patients is dose-dependent. Ann. Rheum. Dis. 78 , 1706–1711 (2019).

Oryan, A., Kamali, A. & Moshiri, A. Potential mechanisms and applications of statins on osteogenesis: current modalities, conflicts and future directions. J. Control Release 215 , 12–24 (2015).

Brown, D. A. & London, E. Structure and function of sphingolipid- and cholesterol-rich membrane rafts. J. Biol. Chem. 275 , 17221–17224 (2000).

Ripa, I., Andreu, S., Lopez-Guerrero, J. A. & Bello-Morales, R. Membrane rafts: portals for viral entry. Front. Microbiol. 12 , 631274 (2021).

Schroeder, C. Cholesterol-binding viral proteins in virus entry and morphogenesis. Subcell. Biochem. 51 , 77–108 (2010).

Osuna-Ramos, J. F., Reyes-Ruiz, J. M. & Del Angel, R. M. The role of host cholesterol during flavivirus infection. Front. Cell Infect. Microbiol. 8 , 388 (2018).

Palmer, M. Cholesterol and the activity of bacterial toxins. FEMS Microbiol. Lett. 238 , 281–289 (2004).

Louie, A. Y. et al. Dietary cholesterol causes inflammatory imbalance and exacerbates morbidity in mice infected with influenza A virus. J. Immunol. 208 , 2523–2539 (2022).

Wang, Y. et al. Pseudorabies virus inhibits expression of liver X receptors to assist viral infection. Viruses 14 (2022).

Palacios-Rapalo, S. N. et al. Cholesterol-rich lipid rafts as platforms for SARS-CoV-2 entry. Front Immunol. 12 , 796855 (2021).

Radenkovic, D., Chawla, S., Pirro, M., Sahebkar, A. & Banach, M. Cholesterol in relation to COVID-19: Should we care about it? J. Clin. Med. 9 , 1909 (2020).

Sanders, D. W. et al. SARS-CoV-2 requires cholesterol for viral entry and pathological syncytia formation. Elife 10 , e65962 (2021).

Lu, Y., Liu, D. X. & Tam, J. P. Lipid rafts are involved in SARS-CoV entry into Vero E6 cells. Biochem. Biophys. Res. Commun. 369 , 344–349 (2008).

Li, G. M., Li, Y. G., Yamate, M., Li, S. M. & Ikuta, K. Lipid rafts play an important role in the early stage of severe acute respiratory syndrome-coronavirus life cycle. Microbes Infect. 9 , 96–102 (2007).

Meher, G., Bhattacharjya, S. & Chakraborty, H. Membrane cholesterol modulates oligomeric status and peptide-membrane interaction of severe acute respiratory syndrome coronavirus fusion peptide. J. Phys. Chem. B 123 , 10654–10662 (2019).

Fasolato, S. et al. PCSK9 levels are raised in chronic HCV patients with hepatocellular carcinoma. J. Clin. Med. 9 , 3134 (2020).

Andriulli, A. et al. Meta-analysis: the outcome of anti-viral therapy in HCV genotype 2 and genotype 3 infected patients with chronic hepatitis. Aliment. Pharm. Ther. 28 , 397–404 (2008).

Hyrina, A. et al. Treatment-induced viral cure of hepatitis C virus-infected patients involves a dynamic interplay among three important molecular players in lipid homeostasis: circulating microRNA (miR)-24, miR-223, and proprotein convertase subtilisin/kexin type 9. EBioMedicine 23 , 68–78 (2017).

Li, Z. & Liu, Q. Proprotein convertase subtilisin/kexin type 9 inhibits hepatitis C virus replication through interacting with NS5A. J. Gen. Virol. 99 , 44–61 (2018).

Li, Z. & Liu, Q. Hepatitis C virus regulates proprotein convertase subtilisin/kexin type 9 promoter activity. Biochem. Biophys. Res. Commun. 496 , 1229–1235 (2018).

Gan, E. S. et al. Dengue virus induces PCSK9 expression to alter antiviral responses and disease outcomes. J. Clin. Investig. 130 , 5223–5234 (2020).

Diczfalusy, U. On the formation and possible biological role of 25-hydroxycholesterol. Biochimie 95 , 455–460 (2013).

Liu, S. Y. et al. Interferon-inducible cholesterol-25-hydroxylase broadly inhibits viral entry by production of 25-hydroxycholesterol. Immunity 38 , 92–105 (2013).

Li, C. et al. 25-hydroxycholesterol protects host against zika virus infection and its associated microcephaly in a mouse model. Immunity 46 , 446–456 (2017).

Xiang, Y. et al. Identification of cholesterol 25-hydroxylase as a novel host restriction factor and a part of the primary innate immune responses against hepatitis C virus infection. J. Virol. 89 , 6805–6816 (2015).

Zu, S. et al. 25-hydroxycholesterol is a potent SARS-CoV-2 inhibitor. Cell Res 30 , 1043–1045 (2020).

Zang, R. et al. Cholesterol 25-hydroxylase suppresses SARS-CoV-2 replication by blocking membrane fusion. Proc. Natl Acad. Sci. USA 117 , 32105–32113 (2020).

Wang, Q. et al. Identification of interferon-gamma as a new molecular target of liver X receptor. Biochem. J. 459 , 345–354 (2014).

Liu, Y. et al. Activation of liver X receptor plays a central role in antiviral actions of 25-hydroxycholesterol. J. Lipid Res. 59 , 2287–2296 (2018).

Liu, Y. et al. 25-hydroxycholesterol activates the expression of cholesterol 25-hydroxylase in an LXR-dependent mechanism. J. Lipid Res. 59 , 439–451 (2018).

Li, B. et al. Prevalence and impact of cardiovascular metabolic diseases on COVID-19 in china. Clin. Res. Cardiol. 109 , 531–538 (2020).

Wu, Z. & McGoogan, J. M. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: Summary of a report of 72314 cases from the Chinese center for disease control and prevention. JAMA 323 , 1239–1242 (2020).

Gorabi, A. M. et al. Antiviral effects of statins. Prog. Lipid Res. 79 , 101054 (2020).

Zhang, X. J. et al. In-hospital use of statins is associated with a reduced risk of mortality among individuals with COVID-19. Cell Metab. 32 , e174 (2020).

Proto, M. C. et al. Lipid homeostasis and mevalonate pathway in COVID-19: basic concepts and potential therapeutic targets. Prog. Lipid Res. 82 , 101099 (2021).

Torres-Pena, J. D. et al. Prior treatment with statins is associated with improved outcomes of patients with COVID-19: Data from the semi-COVID-19 registry. Drugs 81 , 685–695 (2021).

Huang, W., Xiao, J., Ji, J. & Chen, L. Association of lipid-lowering drugs with COVID-19 outcomes from a mendelian randomization study. Elife 10 , e73873 (2021).

Subir, R., Jagat, J. M. & Kalyan, K. G. Pros and cons for use of statins in people with coronavirus disease-19 (COVID-19). Diabetes Metab. Syndr. 14 , 1225–1229 (2020).

Reiner, Z. et al. Statins and the COVID-19 main protease: in silico evidence on direct interaction. Arch. Med. Sci. 16 , 490–496 (2020).

Boccara, F. et al. Evolocumab in HIV-infected patients with dyslipidemia: primary results of the randomized, double-blind BEIJERINCK study. J. Am. Coll. Cardiol. 75 , 2570–2584 (2020).

Vuorio, A., Watts, G. F. & Kovanen, P. T. Familial hypercholesterolaemia and COVID-19: triggering of increased sustained cardiovascular risk. J. Intern. Med. 287 , 746–747 (2020).

Vuorio, A. & Kovanen, P. T. Prevention of endothelial dysfunction and thrombotic events in COVID-19 patients with familial hypercholesterolemia. J. Clin. Lipido 14 , 617–618 (2020).

Download references

Acknowledgements

The work was funded by the National Natural Science Foundation of China (NSFC) Grants 81973316 to J.H., 82173807 to Y.D. Tianjin Municipal Science and Technology Commission of China Grant 20JCZDJC00710 and the Fundamental Research Funds for the Central Universities (Nankai University) 63211045 to J.H.

Author information

Authors and affiliations.

Department of Cardiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China

Yajun Duan & Suowen Xu

Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China

Yajun Duan, Ke Gong, Feng Zhang, Xianshe Meng & Jihong Han

College of Life Sciences, Key Laboratory of Bioactive Materials of Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China

You can also search for this author in PubMed   Google Scholar

Contributions

Y.D. and J.H. designed and wrote the manuscript. Y.D., K.G., F.Z., and X.M. completed the literature search, wrote the text and drafted figures. S.X. and J.H. revised and edited manuscript. All authors listed have made a substantial contribution to this work. All authors have read and approved the content.

Corresponding author

Correspondence to Jihong Han .

Ethics declarations

Competing interests.

The authors declare no competing interests.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ .

Reprints and permissions

About this article

Cite this article.

Duan, Y., Gong, K., Xu, S. et al. Regulation of cholesterol homeostasis in health and diseases: from mechanisms to targeted therapeutics. Sig Transduct Target Ther 7 , 265 (2022). https://doi.org/10.1038/s41392-022-01125-5

Download citation

Received : 30 April 2022

Revised : 04 July 2022

Accepted : 12 July 2022

Published : 02 August 2022

DOI : https://doi.org/10.1038/s41392-022-01125-5

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

This article is cited by

Pcsk9 inhibitors and osteoporosis: mendelian randomization and meta-analysis.

• Ding-Qiang Chen

BMC Musculoskeletal Disorders (2024)

Exploring the causal effect between lipid-modifying drugs and idiopathic pulmonary fibrosis: a drug-target Mendelian randomization study

• Gexiang Cai
• Jingjing Liu
• Lianyou Shao

Lipids in Health and Disease (2024)

Collagen I-induced VCAN/ERK signaling and PARP1/ZEB1-mediated metastasis facilitate OSBPL2 defect to promote colorectal cancer progression

Cell Death & Disease (2024)

Metabolic memory: mechanisms and diseases

• Yuezhang Sun

Signal Transduction and Targeted Therapy (2024)

Neutrophil extracellular traps: a catalyst for atherosclerosis

• Cuiping Wang

Molecular and Cellular Biochemistry (2024)

Quick links

• Explore articles by subject
• Guide to authors
• Editorial policies

Why ‘good’ cholesterol may not always be good

February 16, 2022 – For decades, it’s been known that, when it comes to heart disease risk, there’s a difference between so-called “bad cholesterol”—also known as low-density lipoprotein or LDL, which can clog up the artery walls—and “good cholesterol,” known as high-density lipoprotein or HDL, which helps clear cholesterol out of the system. Recently, drugs have been developed that increase the amount of HDL in the blood, but disappointingly failed to reduce the risk of cardiovascular disease and were never brought to market. A December paper co-authored by Harvard T.H. Chan School of Public Health researchers Jeremy Furtado , Frank Sacks , and colleagues, helps explain why the drugs didn’t work. In this Big 3 Q&A, Furtado elaborates on their findings.

Q: People call HDL “good cholesterol” because it helps remove cholesterol out of the body—but you seem to say that’s not always the case. Why is that moniker not entirely accurate?

A: In the middle of the last century, total cholesterol was an important biomarker used to assess heart disease risk. Then, in the 1970s and 1980s, researchers discovered that total cholesterol is actually made up of two very different systems, the LDL and HDL, with opposing relationships with heart disease risk. Generally speaking, cholesterol in LDL is linked to increased risk while cholesterol in HDL is associated with protection against heart disease. More recently, our group here at Harvard Chan School found that within HDL there are different subspecies that have different types of proteins on their surfaces that make them function differently from each other in the body. Given these functional differences, why should we expect that they are all protective or operate the same way? Recently, we’ve been studying 16 out of the potentially 200 or so different protein-defined HDL subspecies and found that while some are associated with a reduced risk of cardiovascular disease as you’d expect, some show no association or are even associated with increased risk. In particular, we found that HDL that contains a protein called apolipoprotein C3 (apoC3) is associated with a higher risk of cardiovascular disease, including stroke and heart attack, and type 2 diabetes . We also found that HDL that contains Complement C3 or alpha-2-Macroglobulin (α2M) is also associated with higher risk. HDLs that lack these proteins are more protective than total HDL. Conversely, HDL that contains apolipoprotein E (apoE) or apolipoprotein C1 (apoC1) is more protective against heart disease.

Q: In your study, you looked at a class of drugs called CETP inhibitors, specifically evacetrapib (Eli Lilly) and torcetrapib (Pfizer). What happened to cholesterol levels and cardiovascular disease when people took these medications?

A: CETP is a protein that moves cholesterol from HDL into LDL, so these CETP inhibitor drugs increase HDL cholesterol. While they succeeded in this, phase three clinical trials showed that there wasn’t a significant decrease in cardiovascular disease outcomes, including heart attack. So CETP inhibition wasn’t having the intended effect of reducing mortality and heart disease. The failure of these trials and trials like them, coupled with other studies that showed that naturally occurring genetic mutations that resulted in high HDL cholesterol also did not confer any protection against heart disease, implied to some that HDL was not truly an actor in the disease. Our hypothesis was that maybe the different protein-defined subspecies have different relationships with disease, some bad and some good, and perhaps these drugs didn’t work because even though they increased overall HDL cholesterol, it was the bad kinds that went up. And, in fact, we found the types of HDL that went up the most were the ones that were the worst, including those that contained apoC3.

Q: What are the health implications of these findings? Is there a way that pharma companies could retool these drugs, or other things that people can do to increase their good good cholesterol?

A: One of the most important things to come out of this study is to underscore the need to learn more about HDL subspecies to find out what functions these proteins perform. HDL isn’t just a cholesterol transporter. It also has anti-inflammatory, antioxidant, immunological, and other actions that affect disease risk. We need to find out which HDL subspecies are protective and which ones are detrimental. Once we know that, we can work to produce therapies that will target increases of the good types of HDL or reductions of the bad. And it’s not just drug therapies. Our group will soon publish new research on the effects of healthy diets associated with reduced risk of heart disease that increase HDL cholesterol, and do so by increasing the good HDL subspecies and not the bad. Stay tuned!

– Michael Blanding

• Cholesterol & Triglycerides
• Cholesterol
• Triglycerides
• Causes & Risks
• Tests & Diagnosis
• Overview of Treatment
• Drug Therapy
• Complementary & Alternative Treatment
• Diet & Exercise
• Mental & Emotional Health
• Complications
• Appointment Prep
• View Full Guide

Cholesterol: Latest Research

High cholesterol raises your risk of heart disease , heart attack , and stroke . A healthy diet and lifestyle can improve your levels. Medication can help, too. Still, doctors and scientists keep studying cholesterol to see what else they can learn about it.

Here’s some progress they’ve made in the ways they think about, prevent, and treat high cholesterol.

A More Personal Approach

Doctors used to think everyone’s cholesterol level should be about the same. Now, your doctor will look at your numbers along with other risk factors you have for heart disease. Those factors include blood pressure , blood sugar , age, and weight . The higher your risk for heart issues, the lower your doctor may suggest you try to get your cholesterol levels .

Prescription for Exercise

If you have high cholesterol and mildly high blood pressure , but you have a low overall risk of heart disease, your doctor may not prescribe medication right away. New guidelines from the American Heart Association advise sitting less and moving more as the first treatment.

Physical activity can reduce LDL (low-density lipoprotein, or “bad”) cholesterol by 3 to 6 milligrams per deciliter (mg/dL) in your blood. It also lowers your blood pressure.

About 150 minutes of moderate exercise per week is ideal. But you could see a difference in your cholesterol levels with as few as 5 to 10 minutes of movement each day.

Beyond Statins

Doctors often prescribe statins to treat high cholesterol, but not everyone does well on these drugs. People who don’t respond to this type of medicine, or who have unpleasant side effects, now have some other options, such as:

• PCSK9 inhibitors: PCSK9 is a protein that your liver makes. The more you have, the harder it is for your body to get rid of LDL cholesterol . A new class of drugs called PCSK9 inhibitors can block PCSK9. That way, it won’t interfere with cholesterol. You can take these medications by themselves or with statins . You get them through a shot, usually about every 2 weeks.

If you have a genetic condition called familial hypercholesterolemia , PCSK9 inhibitors may work better for you than statins do.

• SiRNA therapy: SiRNA (small interfering RNA) therapy can treat some health conditions by changing how some of your genes work. A new medication called inclisiran ( Leqvio ) uses this technology to treat adults with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease (ASCVD) who need additional LDL lowering. It lowers your LDL levels by disrupting the gene that makes PCSK9. Inclisiran comes in the form of shots, taken several months apart. You can use this medication along with other cholesterol-lowering treatments or alone.
• Bempedoic acid: Like statins, this new medication makes it harder for cholesterol to form in your body. Bempedoic acid, which is a pill you swallow, may lower your LDL levels by up to 15%. For now, you can get a prescription only if you have a family history of high cholesterol or you have atherosclerotic cardiovascular disease (ACD).

Nanotech That ‘Eats’ Plaque

Cholesterol can cause fatty deposits called plaque to form inside your arteries . Over time, it can start to block your blood flow. This condition, called atherosclerosis , raises your risk of heart problems and stroke . Scientists have recently created a nanoparticle -- a tiny object that the naked eye cannot see -- to eat away at this waxy buildup. It’s still in testing mode, but in the future, a drug that contains this nanoparticle could be part of atherosclerosis treatment.

Gut Health Could Help

Researchers have thought for some time that gut health plays a role in cholesterol levels , but it hasn’t been clear exactly how. But they now know that probiotics (“good” live bacteria) and prebiotics (which feed useful germs in your gut) can lower LDL cholesterol and triglycerides , another type of blood fat. These gut bacteria may also increase high-density lipoprotein (HDL, or “good”) cholesterol.

Talk to your doctor if you’re interested in trying probiotics or prebiotics. The amount you need in order to get results is still under review, and too much could lead to an upset stomach .

Top doctors in ,

Find more top doctors on, related links.

• Cholesterol & Triglycerides News
• Cholesterol & Triglycerides Reference
• Cholesterol & Triglycerides Slideshows
• Cholesterol & Triglycerides Quizzes
• Cholesterol Management Blog
• Find a Doctor
• WebMDRx Savings Card
• Atherosclerosis
• Diet & Nutrition
• Heart Disease
• High Blood Pressure
• High Triglycerides
• Living Healthy
• Metabolic Syndrome
• My Medicine

• Alzheimer's disease & dementia
• Arthritis & Rheumatism
• Attention deficit disorders
• Autism spectrum disorders
• Biomedical technology
• Diseases, Conditions, Syndromes
• Endocrinology & Metabolism
• Gastroenterology
• Gerontology & Geriatrics
• Health informatics
• Inflammatory disorders
• Medical economics
• Medical research
• Medications
• Neuroscience
• Obstetrics & gynaecology
• Oncology & Cancer
• Ophthalmology
• Overweight & Obesity
• Parkinson's & Movement disorders
• Psychology & Psychiatry
• Radiology & Imaging
• Sleep disorders
• Sports medicine & Kinesiology
• Vaccination
• Breast cancer
• Cardiovascular disease
• Chronic obstructive pulmonary disease
• Colon cancer
• Coronary artery disease
• Heart attack
• Heart disease
• High blood pressure
• Kidney disease
• Lung cancer
• Multiple sclerosis
• Myocardial infarction
• Ovarian cancer
• Post traumatic stress disorder
• Rheumatoid arthritis
• Schizophrenia
• Skin cancer
• Type 2 diabetes
• Full List »

share this!

August 14, 2024

This article has been reviewed according to Science X's editorial process and policies . Editors have highlighted the following attributes while ensuring the content's credibility:

fact-checked

peer-reviewed publication

trusted source

Apolipoprotein B test may be more accurate measure of heart disease risk

by UT Southwestern Medical Center

The traditional lipid panel may not give the full picture of cholesterol-related heart disease risk for many Americans, according to a study led by UT Southwestern Medical Center researchers and published in JAMA Cardiology .

There are different types of cholesterol particles that can cause heart disease, including low-density lipoproteins (LDL), very low-density lipoproteins (VLDL), and intermediate-density lipoproteins (IDL). LDL-C is a measure of the weight of cholesterol in LDL particles and is one of the most common tests people use to measure cholesterol risk. Every LDL, VLDL, and IDL particle has a single protein on its surface called apolipoprotein B (apoB).

Prior research has shown that the number of "bad" cholesterol particles, measured by a blood test for apoB, is the most accurate marker for cholesterol risk. However, current guidelines do not recommend testing for apoB in all people. Instead, most only have their LDL-C measured, but that does not test for the total number of LDL particles. Measuring LDL-C alone may not be adequate to find people with high apoB levels, UTSW researchers and colleagues said.

"For most patients, the LDL-C measurement is usually 'good enough' because people with high LDL-C also usually have high apoB and vice versa, but that's not true for everyone," said senior author Ann Marie Navar, M.D., Ph.D., Associate Professor of Internal Medicine in the Division of Cardiology and in the Peter O'Donnell Jr. School of Public Health at UT Southwestern.

"Some people have high apoB but a relatively low LDL-C, so their heart disease risk is underestimated by not measuring apoB. Others may have a high LDL-C but a low or normal apoB, and they aren't at risk."

Because the weight of cholesterol particles can vary from person to person, LDL-C and apolipoprotein B (apoB) measurements don't always line up. When apoB levels vary from estimated values, they're called "discordant."

In the case of patients with low or normal-appearing LDL-C and a high apoB level, LDL-C measurements may offer a false sense of security. This happens more commonly in people with metabolic risk factors such as obesity, diabetes, or high triglycerides. But even people without these conditions can have discordance.

The research team used data from the National Health and Nutrition Examination Survey (NHANES) to assess apoB discordance in the U.S. population. The NHANES database included apoB, LDL-C, high-density lipoprotein cholesterol (HDL-C, or "good" cholesterol), total cholesterol , and triglyceride levels for 12,688 adults measured between 2005 and 2016. To determine the discordance level for each individual, Dr. Navar and her colleagues calculated the difference between observed and expected apoB levels based on LDL-C.

As expected, apoB levels for patients in the study with metabolic risks were higher than predicted values. However, some metabolically healthy patients also had apoB levels that varied significantly from expected measures. Physicians following U.S. guidelines may overlook people who are at higher risk of developing atherosclerosis despite normal metabolic health markers.

"I believe that our results, combined with a lot of other data showing the value of measuring apoB levels, support a revision of the guidelines to recommend apoB testing for everybody, not just those with certain clinical risk factors," Dr. Navar said.

The study includes an online calculator for the public to estimate apoB levels based on the LDL-C level. As Dr. Navar explained, a higher-than-expected apoB level indicates a risk of heart disease that is greater than can be calculated by LDL-C alone.

Explore further

Feedback to editors

Millions now survive cancer—but face discrimination when trying to access loans and insurance

39 minutes ago

Researchers closer to figuring out what causes exercise to boost your brain

43 minutes ago

Can a mouthwash-based test help predict head and neck cancer recurrence?

Giving the peptide ACBP to anorexic mice stimulates eating

'Silent' neurons in the sensory cortex can be recruited to enhance sensory processing

Understanding epigenetic control of antibody responses

Leishmania strain in Brazil shows resistance to key drugs

2 hours ago

Study unveils impact of cardiovascular risk factors on genetic predisposition to heart disease

Perimenopause linked with increased risk of bipolar and major depression

First successful treatment of pediatric high-risk refractory neuroblastoma with PARP inhibition

Related stories.

Testing for ApoB protein may be a more accurate marker for heart disease risk than testing for cholesterol alone

Mar 6, 2023

Team finds rare gene mutations may prevent heart disease

May 13, 2019

New way to identify early risks of cardiovascular disease

Dec 1, 2021

Anagliptin effect on LDL in T2DM via ApoB-100 synthesis

Sep 19, 2017

ApoB levels more closely tied to reduced CVD events than LDL

Aug 29, 2017

Researchers study indicators of coronary obstructions in women with established coronary artery disease

May 24, 2024

Recommended for you

'Hidden' irregular heartbeats may raise risk of death

Aug 13, 2024

Pre-surgical antibody treatment might prevent heart transplant rejection

Aug 12, 2024

MRI technique accurately predicts heart failure risk in general population

Study finds baked potatoes can improve heart health for diabetics

Aug 9, 2024

New study adds to increasing evidence that sugar substitute erythritol raises cardiovascular risk

Aug 8, 2024

Let us know if there is a problem with our content

Use this form if you have come across a typo, inaccuracy or would like to send an edit request for the content on this page. For general inquiries, please use our contact form . For general feedback, use the public comments section below (please adhere to guidelines ).

Please select the most appropriate category to facilitate processing of your request

Thank you for taking time to provide your feedback to the editors.

Your feedback is important to us. However, we do not guarantee individual replies due to the high volume of messages.

E-mail the story

Your email address is used only to let the recipient know who sent the email. Neither your address nor the recipient's address will be used for any other purpose. The information you enter will appear in your e-mail message and is not retained by Medical Xpress in any form.

Newsletter sign up

Get weekly and/or daily updates delivered to your inbox. You can unsubscribe at any time and we'll never share your details to third parties.

More information Privacy policy

Donate and enjoy an ad-free experience

We keep our content available to everyone. Consider supporting Science X's mission by getting a premium account.

E-mail newsletter

An official website of the United States government

The .gov means it’s official. Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

• Publications
• Account settings

Preview improvements coming to the PMC website in October 2024. Learn More or Try it out now .

• Advanced Search
• Journal List
• PMC10285014

Eggs and Cardiovascular Disease Risk: An Update of Recent Evidence

Sharayah carter.

1 Alliance for Research in Exercise, Nutrition and Activity (ARENA), Allied Health & Human Performance, University of South Australia, GPO Box 2471, Adelaide, 5001 Australia

Elizabeth S. Connole

Alison m. hill.

2 Alliance for Research in Exercise, Nutrition and Activity (ARENA), Clinical and Health Sciences, University of South Australia, Adelaide, Australia

Jonathan D. Buckley

Alison m. coates, associated data, purpose of review.

This review summarizes recent evidence published since a previous review in 2018 on the association between egg consumption and risk of cardiovascular disease (CVD) mortality, CVD incidence, and CVD risk factors.

Recent Findings

No recent randomized controlled trials were identified. Evidence from observational studies is mixed, with studies reporting either an increased risk or no association of highest egg consumption with CVD mortality, and a similar spread of increased risk, decreased risk, or no association between egg intake and total CVD incidence. Most studies reported a reduced risk or no association between egg consumption and CVD risk factors. Included studies reported low and high egg intake as between 0 and 1.9 eggs/week and 2 and ≥14 eggs/week, respectively. Ethnicity may influence the risk of CVD with egg consumption, likely due to differences in how eggs are consumed in the diet rather than eggs themselves.

Recent findings are inconsistent regarding the possible relationship between egg consumption and CVD mortality and morbidity. Dietary guidance should focus on improving the overall quality of the diet to promote cardiovascular health.

Supplementary Information

The online version contains supplementary material available at 10.1007/s11883-023-01109-y.

Introduction

Cardiovascular disease (CVD) is the leading cause of mortality globally [ 1 ]. Early studies, which indicated that elevated serum cholesterol was associated with an increased risk of heart disease [ 2 , 3 ], led to the American Heart Association (AHA) recommending limiting dietary cholesterol to less than 300 mg/day with specific recommendations to restrict egg consumption, which are high in cholesterol, to a maximum of three eggs per week [ 4 ]. A later analysis from the Framingham study found no association between egg intake and blood cholesterol or heart disease [ 5 ], and in 2002, the AHA removed its advice to limit egg intake while retaining its recommendation to consume less than 300 mg/day of dietary cholesterol [ 6 ]. During this time, findings surfaced indicating that increased intake of dietary cholesterol was associated with decreased synthesis of endogenous cholesterol [ 7 ], and in 2013, the AHA announced that “there is insufficient evidence to determine whether lowering dietary cholesterol reduces low-density lipoproteins (LDL) cholesterol” [ 8 ]. As a result, the 2015–2020 Dietary Guidelines for Americans removed the recommendation of setting a limit to the maximum intake of 300 mg/day of cholesterol. However, the controversy around the impact of consuming foods high in cholesterol, including eggs, on CVD risk remains.

A possible explanation for the controversy is that foods high in cholesterol are also typically high in saturated fat [ 9 ], which is well documented to increase LDL cholesterol and CVD risk [ 10 ]. Thus, it is difficult to determine the independent effects of dietary cholesterol on the blood lipid profile. Based on nutrient profiles from Australian food databases, eggs are high in cholesterol but low in saturated fat, with the average large whole egg (50 g) containing 244 mg of cholesterol but only 1.2 g of saturated fat [ 11 ]. However, eggs, like any individual food, are not consumed in isolation, but as part of an overall diet, which can influence total cholesterol and saturated fat intake. For example, in the American diet, intakes of cholesterol and saturated fat increase in parallel, which may be due to eggs being frequently consumed with bacon or sausage which are high in saturated fat [ 12 ]. Previous reviews considering egg consumption and blood lipids have reported contradictory findings, with a 2018 review of randomized controlled trials (RCT) finding that consuming eggs does not adversely affect the blood lipid profile [ 13 ]. However, in contrast, a subsequent meta-analysis of RCTs reported a positive relationship between changes in dietary cholesterol (all sources, including eggs) and changes in LDL cholesterol, after controlling for saturated fat [ 14 ], and so, the relationship remains unclear.

When the relationship between egg consumption and CVD risk has been reviewed, there have also been mixed findings. The majority of systematic reviews and meta-analyses observed no association between egg consumption and CVD risk [ 15 – 20 ], but a small number of studies identified an increased risk [ 21 , 22 ], particularly in people with diabetes [ 17 , 18 , 23 ]. These inconsistencies in study findings continue to fuel the controversy around the impact of egg consumption on CVD risk.

This review aims to update current evidence identified from a systematic search and narrative review of observational studies and RCTs from 2019 onwards to explore the association between egg consumption and CVD risk, specifically, CVD mortality, incidence, and risk factors in adults. In addition, confounding factors that may play a role in the associations found will be discussed.

Search Strategy

An electronic search of PubMed, Web of Science, and Embase was conducted from January 1, 2019, to September 14, 2022, to identify the potentially eligible studies recent studies with the following search strategy: “[(egg OR eggs) AND (cardiovascular diseases OR cardiovascular OR coronary heart disease OR CHD OR CVD OR stroke OR myocardial infarction OR ischemic heart disease OR ischemic stroke OR hemorrhagic stroke) AND (randomized control trial OR RCT OR cohort OR prospective OR longitudinal OR follow-up OR case-cohort OR nested case control).” Studies were selected if they met the following inclusion criteria: (i) they were conducted on human adults; (ii) evaluated associations between egg intake and risk of CVD (fatal and nonfatal); (iii) evaluated associations between egg intake and CVD risk factors (e.g., hypertension, blood lipid profile, body fat mass). All references were evaluated by two independent reviewers (all by ESC, half each by SC and AMC) with an independent reviewer (either SC or AMC) resolving any disagreement.

Data Extraction

Data were extracted by two independent reviewers (ESC and SC) from each identified study using a standardized extraction form. The following information was collected: (i) author names; (ii) year of publication; (iii) study cohort name and country; (iv) sample size, sex, and age (mean or range) of participants; (v) study aim and design; (vi) follow-up period; (vii) exposure type/dose/frequency; (viii) CVD outcome measures; (ix) CVD results; (x) covariates used in adjustments.

Out of 269 references published during the four-year search period, 209 abstracts were screened, 75 were eligible for full-text screening, and 30 studies (35 data sets) were identified to review (all observational, no RCTs) (See Fig.  1 ). From the 30 studies, 13 were conducted with data from populations living in the USA [ 24 , 25 ••, 26 – 29 , 30 •, 31 – 34 , 35 •, 36 ], eight from China [ 15 , 35 •, 37 , 38 ••, 39 – 42 ], eight from Europe [ 43 – 50 ], one from Iran [ 51 ], and one was a multinational cohort study [ 52 •].

Flow Diagram of search strategy and included articles

The majority (> 50%) of studies controlled for age, gender, education, smoking status, alcohol consumption, physical activity, energy intake, BMI, hypertension, and diabetes. Two studies (7%) controlled for saturated fat intake [ 25 ••, 30 •], eleven studies (37%) controlled for vegetable intake [ 28 , 29 , 36 , 38 ••, 39 , 41 , 42 , 48 – 50 , 52 •], six studies (20%) controlled for meat intake [ 26 , 38 ••, 39 , 41 , 50 , 52 •] (two (6%) for processed meat [ 26 , 50 ]), three (10%) for Mediterranean diet score [ 28 , 44 , 46 ], three (10%) for dietary approaches to stop hypertension (DASH) score [ 31 – 33 ], and six (20%) for diet quality [ 24 , 26 , 34 , 35 •, 37 , 51 ]. Three (10%) studies which were across multiple countries controlled for center or region but not ethnicity [ 45 , 48 , 52 •].

Eggs and CVD Mortality

In the past 4 years, 11 observational studies [ 15 , 24 , 27 , 29 , 30 •, 34 , 35 •, 43 , 44 , 46 , 52 •] have examined the associations between eggs and CVD mortality (See Supplementary Table 1 ). Of these, six publications reported on CVD mortality [ 24 , 29 , 30 •, 34 , 43 , 46 ], and all except one [ 43 ] reported a higher risk of CVD mortality with the highest egg intake vs. the lowest egg intake (hazard ratio (HR) ranging from 1.14–1.75). Four out of five studies reporting a higher risk were from the USA [ 24 , 29 , 30 •, 34 ] with the remaining study from Italy [ 46 ]. One of these five studies [ 30 •] was a substitution study that reported a reduced risk of CVD mortality (total, heart disease, and stroke [males only]) when 3% of energy from plant protein was substituted for egg protein (HR range 0.72–0.76). In one study [ 24 ], the significant association was lost after adjusting for dietary cholesterol, and no association was found for egg white consumption. Five publications [ 15 , 27 , 35 •, 44 , 52 •] reported no association between eggs and CVD mortality (one reported on heart disease mortality only [ 27 ]). One study [ 35 •], after grouping cardiometabolic subtypes (coronary heart disease (CHD), stroke, and diabetes) together, found that the highest egg intake in the White American cohort was associated with higher cardiometabolic mortality, reduced risk was found with moderate egg intake in the Chinese cohort, and no association was found in the Black American cohort.

Eggs and CVD Incidence (Non-Fatal CVD)

Fifteen observational studies reported on egg consumption and CVD incidence (non-fatal CVD) in the last 4 years [ 25 ••, 26 , 28 , 31 – 34 , 38 ••, 39 , 45 , 48 – 51 , 52 •] (See Supplementary Table 1 ). Eight reported on total CVD incidence [ 25 ••, 26 , 28 , 34 , 38 ••, 39 , 51 , 52 •] with four studies finding an increased incidence (HR ranging from 1.06–1.39) with the highest (≥ 7 eggs/week) vs. lowest egg intake (< 1 egg/week) [ 34 ], high (> 6 eggs/week) and low intake (< 3 eggs/week) [ 38 ••], or with a 0.5 egg/day continuous intake [ 25 ••], noting that in this last study, significance was lost after adjusting for dietary cholesterol. The fourth study was a substitution study that reported that substituting eggs with fish, nuts, legumes, or whole grains was associated with 2–3% lower relative risks for incident CVD when the substitution amount was one serving per week and 15–21% lower relative risks when the substitution amount was one serving per day [ 26 ]. Two studies found a decreased incidence (HR ranging from 0.78–0.89) [ 39 , 52 •] (data from the PURE study [ 52 •]), and three found no association [ 28 , 51 , 52 •] (data from the ONTARGET/TRANSCEND study [ 52 •]).

Five studies reported on egg intake and stroke incidence with three finding no association [ 49 , 51 , 52 •] and two finding an increased risk (HR ranging from 1.07–1.34). One study reported an increased risk of total stroke and ischemic stroke with high and low egg intake (> 6 and < 3 eggs/week for total stroke, and > 6 and < 1 egg/week for ischemic stroke) and an increased risk of hemorrhagic stroke with low egg intake (< 3 eggs/week) [ 38 ••]. The other study found an increased risk of 7% for total stroke and 25% for hemorrhagic stroke with 20 g egg/day continuous intake (total: 95% CI 1.01–1.14, P trend = 0.031, hemorrhagic: 95% CI 1.09–1.43, P trend = 0.002) but no association for ischemic stroke [ 45 ].

Individual studies investigating heart disease reported on the incidence of ischemic heart disease, coronary heart disease, myocardial infarction, or venous thromboembolism. Two studies reported on ischemic heart disease, one reporting an increased association with highest (≥ 7 eggs/week) vs. lowest egg intake (< 1 egg/week) [ 34 ] and the other showing a 7% decreased risk for continuous 20 g egg/day intake (95% CI 0.88–0.99, P trend = 0.023) [ 48 ]. Coronary heart disease incidence was reported in three studies, two finding no association [ 33 , 51 ] except in a sub-analysis where an increased risk of 30% (95% CI 1.03–1.56) was found in the older cohort [ 33 ], and one finding an increased risk with highest (> 6 eggs/week) vs. moderate egg consumption (3 < 6 eggs/week) [ 38 ••]. Three studies reported on myocardial infarction incidence, one reported an 11–13% increased risk [ 32 ], one found no association [ 51 ], and one study with two data sets found a 17% reduced risk (data from the PURE study) and no association (data from the ONTARGET/TRANSCEND study) [ 52 •]. No association was found for the incidence of heart disease [ 52 •] or the incidence of venous thromboembolism [ 50 ].

Eggs and CVD Risk Factors

Nine observational studies [ 15 , 36 , 37 , 40 , 42 , 47 , 49 , 52 •, 53 ] were identified in the last 4 years that examined the associations between egg consumption and CVD risk factors including lipid and lipoprotein concentrations, blood pressure (including the presence of hypertension), and adiposity (See Supplementary Table 1 ). Four publications examined the association between eggs and lipid profile [ 15 , 36 , 37 , 52 •]. Two studies found no association [ 36 , 52 •], one study found a decrease in lipid profile (with no association for high-density lipoprotein (HDL) cholesterol) [ 15 ], and one study found an increase in total cholesterol (TC) and LDL cholesterol but a decrease in triglycerides (TG) and an increase in HDL cholesterol [ 37 ]. One study [ 40 ] reported on the association between eggs and lipoprotein particle concentrations and found reduced risk [ 40 ].

Four studies examined eggs and blood pressure [ 15 , 36 , 49 , 52 •]. Two studies found reduced systolic blood pressure [ 15 , 52 •] (data set from the PURE study [ 52 •]), and three studies found reduced diastolic blood pressure [ 15 , 49 , 52 •] (data set from the PURE study [ 52 •]) with the highest egg intake (> 45 g/day or ≥ 7 eggs/week). In contrast, one study reported increased systolic and diastolic blood pressure (data set from ONTARGET/TRANSCEND study [ 52 •]). One study found no association between eggs and systolic blood pressure [ 49 ], and one study found no association for both diastolic and systolic blood pressure [ 36 ]. Two studies reported on the association between eggs and hypertension [ 42 , 47 ]. No association was found for the highest (≥ 7 eggs/week) vs. the lowest (< 1 egg/week) egg intake, but an increased risk was found for lower egg intakes (2–6.9 eggs/week) [ 47 ]. A decreased risk was noted in a substitution study where eggs were substituted for meat [ 42 ].

Three studies described the associations between eggs and adiposity (BMI, body fat, waist circumference) [ 15 , 36 , 41 ]. One study [ 41 ] completed analysis by sex and found a decreased risk of adiposity for females with the highest (approximately 50 g/day) vs. lowest egg intake (0 g/day) but no association for males, and two studies found no association with eggs and waist circumference [ 15 , 36 ].

The majority of research included in this review was from cohort data collected in three geographical regions, with population ethnicity influencing the direction of associations between egg consumption and CVD outcomes. Thirteen publications were from studies conducted in populations residing in the USA [ 24 , 25 ••, 26 – 29 , 30 •, 31 – 34 , 35 •, 36 ]; twelve studies reported on eggs and non-fatal and fatal CVD [ 24 , 25 ••, 26 – 29 , 30 •, 31 – 34 , 35 •] and one on risk factors [ 36 ], with seven identifying an increased risk [ 24 , 25 ••, 26 , 29 , 30 •, 31 , 34 ], five indicating no association [ 27 , 28 , 32 , 33 , 36 ] and one indicating an increased risk (White Americans) or no association (Black Americans) [ 35 •]. Eight studies used data from cohorts residing in China [ 15 , 35 •, 37 , 38 ••, 39 – 42 ] with four studies reporting on eggs and non-fatal and fatal CVD [ 15 , 35 •, 38 ••, 39 ] and five reporting on eggs and CVD risk factors [ 15 , 37 , 40 – 42 ]. In contrast to the US findings, only one of these studies reported an increased risk [ 38 ••], six showed reduced risk [ 35 •, 37 , 39 – 42 ], and one found no association [ 15 ]. Eight studies used cohort data from Europe reporting on eggs and non-fatal and fatal CVD as well as CVD risk factors [ 43 – 50 ]. Three confirmed an increased risk [ 45 – 47 ], one found a reduced risk [ 43 ], and four found no association [ 44 , 48 – 50 ]. One study from Iran found no association with non-fatal CVD [ 51 ]. A final study including cohort data from 21 countries also found no association between fatal CVD and CVD risk factors [ 52 •].

Eleven studies conducted subgroup analyses on eggs and CVD mortality, incidence, and/or risk factors [ 25 ••, 31 , 32 , 34 , 38 ••, 39 , 46 – 49 , 52 •]. Six studies evaluated sex differences: six for men [ 25 ••, 31 , 38 ••, 39 , 48 , 49 ] and four for women [ 31 , 38 ••, 39 , 48 ]. All but two studies found no association or no difference to the overall study outcomes. One study, which reported no association in the total cohort, found a reduced risk of IHD in males [ 48 ], and another study that reported a reduced risk of total CVD and hypertension in the total cohort found no association for males but confirmed reduced risk for females [ 39 ]. Eight studies assessed BMI in a sub-analysis [ 31 , 32 , 34 , 38 ••, 39 , 46 – 48 ] with the majority (seven studies) reporting no association or no difference to the overall study findings. One study reported an increased risk of MI incidence for people with a BMI over 25 kg/m 2 but found no association in the total cohort [ 32 ]. Nine completed sub-analyses for type 2 diabetes, and all but two found no association [ 25 ••, 31 , 32 , 34 , 38 ••, 46 – 48 ]. The two studies [ 31 ] reporting an increased risk of CVD incidence in persons with type 2 diabetes (one specific to ischemic stroke [ 31 ]) also reported increased risk in their overall findings.

Eggs are a highly nutritious food; they offer a complete source of protein, containing all essential amino acids and a complement of vitamins and minerals [ 54 ]. However, the high cholesterol content in eggs makes them a food of concern, which has led to a plethora of studies over the last few decades investigating egg consumption and the risk of CVD.

In this narrative review (with studies identified by a systematic search), we summarized recent evidence from studies published from 2019 to September 2022 with regard to the impact of egg consumption on CVD risk. The studies were all observational, and the findings were mixed. For CVD mortality, an equal number of studies reported an increased risk or no association with the highest egg intake. This was similar to earlier reviews which also found mixed results. A meta-analysis of 39 observational studies including nearly 2 million individuals found no association between the highest intake of eggs and CVD mortality [ 55 ], and similar findings were presented in another meta-analysis of 24 observational studies of over 11 million individuals that found no association between highest intake of eggs and CVD mortality [ 56 ]. However, contrasting findings were reported in a meta-analysis of 19 observational studies that found a nonlinear dose–response association between egg consumption and CVD mortality, although the certainty of the evidence for these observations was rated as very low [ 57 ]. In this latter review, the majority (80%) of studies reporting an increased risk were studied from US populations. Similarly, in a meta-analysis which found no association in the total population, an increased risk was reported in a sub-analysis by ethnicity in the American population [ 56 ].

It is difficult to study food in isolation without considering the effect of foods consumed in the whole diet and the nutrients they collectively contribute. In Western populations, eggs are typically consumed with meat (often processed) which is high in saturated fat, while in Asian cultures, eggs are frequently consumed in meals with vegetables [ 27 ]. It is also possible that Western populations consume more cholesterol from other sources (e.g., red meat, full-fat dairy, and discretionary foods), as compared to people from Asian cultures [ 12 , 58 , 59 ]. In the American diet for example, due to dietary patterns, dietary cholesterol and saturated fat increase in parallel, e.g., eggs with bacon and sausage [ 12 ]. Cooking methods are also different, with higher temperatures and longer cooking time leading to oxidative damage to vitamins [ 60 ]. Furthermore, while nutrition databases have an average for the cholesterol content of eggs, this commonly differs by country and can be influenced by multiple factors including feed composition [ 61 – 63 ], housing systems (free range vs. caged) [ 64 ], and age of the laying hens [ 65 ]. These factors may contribute to the observed country differences. Very few studies in this review controlled for saturated fat; no studies have considered cooking methods, whether eggs were from free-range or caged chickens, or the feed they were provided; and only 37% controlled for vegetable intake, 20% controlled for red meat, and 6% controlled for processed meat which may confound associations.

Regarding CVD incidence (non-fatal), the findings of this review were also mixed. Almost an equal spread of increase, decrease, and no association between egg intake and total CVD incidence was found. Of the eight studies reporting an increased risk of a CVD event, six (75%) were from the USA, and in two of these studies, the populations were majority (92%) male. Therefore, similar to the mortality findings, there is a potential effect of ethnicity, sex, and dietary patterns. Although not consistently so, studies reporting increased incidence of CVD were often from older cohorts or studies with longer duration and hence an aging cohort, both of which would predispose to an increased risk of CVD incidence. Similar mixed findings have been reported in earlier review studies. A meta-analysis of 17 observational studies found no association with CHD or stroke and an increased risk of heart failure with high compared to low egg consumption [ 16 ]. In a meta-analysis of nine observation studies, eating one egg daily was not associated with an increased risk of ischemic heart disease (IHD) and was associated with a small reduction in stroke [ 15 ]. Similarly, a meta-analysis of 21 observational studies also found no association between egg consumption and CVD risk and found beneficial effects toward stroke risk [ 66 ]. An umbrella review of seven systematic reviews and 15 meta-analyses concluded that increased egg consumption is not associated with CVD risk in the general population [ 67 ].

In this review, most studies assessing egg consumption and CVD risk factors found a reduced risk or no association. Interestingly, the majority (56%) of studies were from Chinese cohorts, and only one study was from the USA. However, due to the exploratory nature of observational studies, these studies are unable to establish a causal relationship between egg intake and CVD risk factors. Randomized controlled trials are required to provide evidence of causation, and as there were no RCTs during the defined period of this review, our discussion will focus on review studies of earlier RCTs that examined eggs and CVD risk factors. A systematic review of 23 RCTs found nonsignificant effects of increasing the consumption of eggs on risk markers for CVD [ 13 ]. In a meta-analysis of 28 RCTs, high egg consumption increased total cholesterol, LDL, and HDL cholesterol, but not LDL-to-HDL or TC-to-HDL ratios or triglycerides compared with low egg control diets [ 68 ]. In another meta-analysis of eight RCTs comparing greater than four eggs/week to less than 4 eggs/week, egg consumption was not associated with differences in blood lipid profile or blood pressure [ 69 ] and in two meta-analyses looking at the effects of different food groups on hypertension, regular egg consumption was associated with a lower risk of hypertension [ 70 , 71 ].

In summary, recent data on the associations between egg consumption and risk of CVD mortality, incidence, and risk factors is mixed. With observational data, it is difficult to assess the relationship of any individual food independently of a dietary pattern. The risk associations reported in the reviewed observational studies are likely to be attributed to the dietary pattern accompanying high egg intake (e.g., eating eggs with bacon and sausage or as part of a meal with vegetables) and/or other risk factors present in people with high egg consumption. For example, in Asian cultures, egg consumption is positively associated with socioeconomic status and physical activity, inversely associated with smoking, and generally correlated with other aspects of a healthy dietary pattern (e.g., higher intake of fiber, vegetables, and fruit) [ 15 ]. In the USA, egg consumption is correlated with low physical activity, smoking, and dietary patterns high in saturated fat (e.g., full-fat dairy, red meat, and processed meat) [ 72 ]. Very few of the studies reviewed adjusted analyses for dietary confounders like meat, processed meat, vegetables, and saturated fat, and this could have impacted outcomes. Therefore, the suggestion that egg consumption by itself promotes the risk and development of CVD is questionable compared with the overall complexity of the dietary pattern, physical activity, and genetic predisposition. There is, however, evidence suggesting higher egg consumption could be associated with a higher risk of CVD in people with diabetes [ 17 , 18 , 73 ], but not all studies confirm these findings, specifically after adjusting for background diet [ 74 ]; further studies are needed. The best evidence for CVD prevention supports adopting a change in overall dietary pattern [ 75 ], and therefore, dietary guidance to reduce CVD risk should focus on implementing a healthy dietary pattern rather than removing a single food, such as eggs.

Below is the link to the electronic supplementary material.

Open Access funding enabled and organized by CAUL and its Member Institutions

Declarations

JDB is currently funded by the American Egg Board’s Egg Nutrition Center. They have also received grant support from the Almond Board of California, the Almond Board of Australia, the International Nut and Dried Fruit Council, and Dried Fruit Australia. AMC is currently funded by the American Egg Board’s Egg Nutrition Center. AMC is the immediate past president of the Nutrition Society of Australia. They have also received grant support from the Almond Board of California, the Almond Board of Australia, the International Nut and Dried Fruit Council, and Dried Fruit Australia. And they have been a consultant for Nuts for Life. AMH is currently funded by the American Egg Board’s Egg Nutrition Center. They have also received grant support from the Almond Board of California, the Almond Board of Australia, the International Nut and Dried Fruit Council, and the Dried Fruit Australia. SC and ESC declare that they have no conflicts of interest or funding to disclose.

The article does not contain any studies with human or animal subjects performed by any of the authors.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

• heart health

7 Myths About Cholesterol, Debunked

Y ou may not recall every lab value from your last physical, but you probably remember one: Your cholesterol level.

If it’s higher than ideal, you’re not alone. According to the U.S. Centers for Disease Control and Prevention, between 2015 and 2018, almost 12% of U.S. adults ages 20 and up had high total cholesterol, defined as above 240 mg/dL. The type that physicians mostly worry about is LDL (or “bad”) cholesterol, which is one component of that total.

Why do doctors care so much about cholesterol ? First, “it predicts risk,” says Dr. Jeffrey Berger, a cardiologist and director of the Center for the Prevention of Cardiovascular Disease at NYU Langone in New York City. “It’s been shown in probably hundreds of studies that higher levels of LDL cholesterol is associated with a higher risk of having a heart attack, stroke, or early death.” And, crucially, it’s possible to modify this risk factor. “Numerous studies have shown that when you lower cholesterol, you decrease the risk of a cardiovascular event,” Berger says.

Doctors’ understanding of cholesterol, including how to best manage it, has evolved over the years. Read on for the latest information from experts.

The myth: Cholesterol is always harmful.

The facts: Cholesterol, which is often described as a fat-like, waxy substance, is essential to the human body, including playing a key role during fetal development. It’s part of cell membranes and prompts production of crucial hormones. But too much can cause problems, namely contributing to clogged arteries and raising the risk of heart problems. When physicians and researchers talk about cholesterol’s harms, they’re usually referring specifically to low-density lipoprotein. LDL transports cholesterol around the body, depositing it in blood vessels, explains Nathalie Pamir, an associate professor in preventive cardiology at the Oregon Health & Science University in Portland. Its smaller cousin, high-density lipoprotein (HDL), has long been thought of as the “good” cholesterol because it typically ferries cholesterol away from other parts of the body to the liver.

More from TIME

Because LDL and HDL are different, doctors no longer focus so closely on the total amount of cholesterol. Instead, they generally ask people to aim for lower levels of LDL (optimally, below 100 mg/dL) and higher levels of HDL (at least 60 mg/dL, and not below 40 md/dL).

The myth: ‘Good’ cholesterol is always protective.

The facts: The story has gotten more complicated. LDL is still considered to be a bad actor: “Based on current research, there is no level where having it really low is dangerous,” says Dr. Leslie Cho, section head of preventive cardiology and rehabilitation at the Cleveland Clinic. In fact, people with heart disease should aim for less than 70 mg/dL, and people with diabetes and those at very high risk of coronary artery disease are advised to aim for less than 55 mg/dL, she says.

But the HDL story is more complex. Trials of experimental drugs for increasing HDL have not actually reduced heart events, and research has cast doubt on the idea that the higher the HDL levels, the better. Pamir and colleagues published a study in November in the Journal of the American College of Cardiology that followed nearly 24,000 adults without heart disease over about a decade to measure biomarkers and track heart attacks and heart attack-related deaths. While LDL, as well as another form of lipid, triglycerides, “modestly predicted” risk in white and Black adults, low HDL levels were associated with increased risk only in white adults. And high levels of HDL weren’t protective for either white or Black adults.

One potential explanation, Pamir says, is that the quality of the HDL’s functioning may matter more than the sheer quantity. There’s some evidence that high levels may indicate harmful inflammation, Wright adds. And excessive alcohol use or metabolic disorders may lead to higher HDL levels but not to better health. For now, there’s no test for the quality of HDL. Research into the intricacies of HDL by Pamir and others continues. Until there are more definitive answers, it’s important for people with high levels of HDL not to assume it will protect them from heart problems, to take the lifestyle steps that are known to improve heart health, and to talk with their physicians about medication if other factors suggest a higher heart disease risk, cardiologists say.

Read More: What to Know About High Cholesterol in Kids

The myth: You don’t need to get your cholesterol checked until you reach the average age for heart attacks.

The facts: Recommendations vary on when to start, but the AHA recommends that all low-risk adults ages 20 and older have their levels checked every four to six years. Screening will likely be more frequent if you have a family history or a personal history of heart disease. And the American Academy of Pediatrics recommends all children be screened for high cholesterol between the ages of 9 and 11—earlier if they have risk factors like a family history of early heart disease.

Cholesterol is measured using a blood draw. According to guidelines published in 2016, it’s usually not necessary to fast before your test. (Ask your doctor ahead of time to make sure.)

The myth: You have no control over your cholesterol levels.

The facts: To be sure, some influences on cholesterol are beyond your control. Infants are born with very low LDL cholesterol and levels “keep going up and up” as we age, Cho says. When women hit menopause and estrogen—which helps regulate lipid levels—wanes, their levels of LDL and triglycerides increase. “It’s an aging process. It’s not a moral failure,” Cho says. There are also racial differences. About 9.2% of Black male adults and 10.5% of Black female adults had high cholesterol between 2015-18, compared to 10.1% for white men and 13.1% for white women, according to a report from the American Heart Association.

But there are definitely some things you can do to keep your cholesterol in check, such as exercising. Regular high-intensity workouts, including running or biking at a good pace, can lower cholesterol by at least 10%, Wright says. Exercise also helps people sleep better and reduce stress, which can improve your heart and overall health. “No medication can replicate the physiological benefits of exercise,” Wright says.

And while weight loss can be difficult, you don’t have to lose much to see a positive effect. A 2016 review of weight-loss studies found that even losing 5-10% of your weight—so 10 to 20 pounds for a 200-pound person—resulted in “significant” reductions in total cholesterol, LDL cholesterol, and triglycerides. (Losing more weight was associated with larger improvements.)

The myth: If you have low cholesterol, you won’t have a heart attack.

The facts: This is “not at all” true, Cho says. Cholesterol is an important risk factor, but it’s not the only one, nor is it a perfect indication. Other heart risk factors include age (older people are more at risk), male gender, diabetes, tobacco use, and obesity, according to the American Heart Association (AHA). And an estimated 20% of total risk for what causes someone to have a heart attack isn’t known,” says Dr. R. Scott Wright, professor of cardiology at Mayo Clinic in Rochester, Minn. So don’t get too laser-focused on that number. “If you could choose between a life of high cholesterol yet a low risk of heart attack and stroke, or the opposite—low circulating LDL cholesterol yet a high risk of heart disease—you’d pick the first one,” Berger says. “You care about whether you’re going to have a heart attack or stroke.”

The myth: To keep your cholesterol low, you should avoid eggs.

The facts: If you’re a certain age, you may remember when “cholesterol-free” was plastered all over food packages. The U.S. Department of Agriculture used to recommend consuming less than 300 mg per dietary cholesterol per day. It stopped recommending a specific level in the 2015-20 nutrition guidelines, in part because Americans were, on average, not significantly exceeding that. In addition, the American Heart Association noted in a 2019 scientific advisory on dietary cholesterol that “evidence from observational studies conducted in several countries generally does not indicate a significant association with cardiovascular disease risk.”

Moreover, eating more cholesterol in your diet doesn’t necessarily translate to higher blood cholesterol for most people. The body also makes its own and can adjust to compensate if you eat more or less. That said, some people are highly sensitive to changes in their dietary cholesterol, and blood levels will fall dramatically if they lower their consumption, Cho says.

What does seem to increase LDL cholesterol are the types of fat that are “solid at room temperature,” Cho says. Those include saturated fats from animal products including meat, butter, and dairy. By contrast, unsaturated fats—which are liquid at room temperature—are beneficial. And eating too many simple carbs can lead to weight gain, Wright says. Rather than singling out specific foods, cardiologists now recommend a healthy eating pattern that incorporates plenty of fruits and vegetables, more healthful proteins such as fish, and monounsaturated fats. The Mediterranean diet fits the bill, cardiologists say, and has been associated with protection against other diseases, including diabetes and cancer.

Read More: How to Lower Your Cholesterol Naturally

The myth: You can always control your cholesterol level without help from medications.

The facts: Not all risk factors can be addressed. You can’t do anything about your age; nor can you change your genetic makeup. An inherited disorder called familial hypercholesterolemia causes about 1 in 200 people to be born with high LDL cholesterol levels, which will continue to rise throughout childhood and adulthood. It usually leads to heart disease, according to the AHA, though it can be treated with lifestyle measures and medications. While it’s a rare condition, other risk factors—such as weight and body type—also have genetic influences.

Even with weight loss and exercise, your physician may advise medications to keep your cholesterol in check. The most common are called statins , which decrease LDL levels. They are routinely prescribed to people who have already had a cardiac event to prevent another one, and also for preventing a heart event in the first place in those who are at increased risk. An updated evidence report from the U.S. Preventive Services Task Force, published in August 2022, found that using statins in at-risk populations was associated with a lower risk of cardiac events and death. The benefits occurred “across diverse demographics and clinical populations,” the review said.

Statins are “by far the most well-known [medication], and have the most amount of data,” Berger says. There are also newer drugs, he says, such as ezetimibe and PCSK9 inhibitors. The decision to prescribe medication is often based on risk calculators that gauge the 10-year risk of heart disease; most recent guidelines put the threshold at a 7.5% risk over the next decade, or 5% if the person has other high-risk features, he says. You should have a detailed conversation with your physician about the benefits and risks of medications.

Still, Berger emphasizes, exercise and diet are the first things to try, not just because they can improve your cholesterol, but because they improve overall health. A study published in the New England Journal of Medicine found that among people with a high genetic risk of heart disease, a healthy lifestyle (including diet and exercise) was associated with a 46% lower relative risk of coronary events than an unfavorable one.

More Must-Reads from TIME

• Heman Bekele Is TIME’s 2024 Kid of the Year
• The Reintroduction of Kamala Harris
• The 7 States That Will Decide the Election
• Why China Won’t Allow Single Women to Freeze Their Eggs
• Is the U.S. Ready for Psychedelics?
• The Rise of a New Kind of Parenting Guru
• The 50 Best Romance Novels to Read Right Now
• Can Food Really Change Your Hormones?

Contact us at [email protected]

REVIEW article

Beyond ldl-c: unravelling the residual atherosclerotic cardiovascular disease risk landscape—focus on hypertriglyceridaemia.

• 1 Faculty of Biology Medicine and Health, University of Manchester, Manchester, United Kingdom
• 2 Department of Endocrinology, Diabetes & Metabolism, Manchester University NHS Foundation Trust, Manchester, United Kingdom
• 3 NIHR/Wellcome Trust Clinical Research Facility, Manchester, United Kingdom
• 4 Department of Clinical Biochemistry, Bristol Royal Infirmary, Bristol, United Kingdom
• 5 Department of Clinical Biochemistry, Central Manchester University Hospitals, NHS Foundation Trust, Manchester, United Kingdom
• 6 Centre for Pharmacoepidemiology and Drug Safety, Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
• 7 Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden
• 8 Clinical Nutrition Unit, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy
• 9 Cardiology Department, Sahlgrenska University Hospital, Gothenburg, Sweden
• 10 Centre for Endocrinology, Diabetes and Preventive Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany

Aims: Historically, atherosclerotic cardiovascular disease (ASCVD) risk profile mitigation has had a predominant focus on low density lipoprotein cholesterol (LDL-C). In this narrative review we explore the residual ASCVD risk profile beyond LDL-C with a focus on hypertriglyceridaemia, recent clinical trials of therapeutics targeting hypertriglyceridaemia and novel modalities addressing other residual ASCVD risk factors.

Findings: Hypertriglyceridaemia remains a significant ASCVD risk despite low LDL-C in statin or proprotein convertase subtilisin/kexin type 9 inhibitor-treated patients. Large population-based observational studies have consistently demonstrated an association between hypertriglyceridaemia with ASCVD. This relationship is complicated by the co-existence of low high-density lipoprotein cholesterol. Despite significantly improving atherogenic dyslipidaemia, the most recent clinical trial outcome has cast doubt on the utility of pharmacologically lowering triglyceride concentrations using fibrates. On the other hand, purified eicosapentaenoic acid (EPA), but not in combination with docosahexaenoic acid (DHA), has produced favourable ASCVD outcomes. The outcome of these trials suggests alternate pathways involved in ASCVD risk modulation. Several other pharmacotherapies have been proposed to address other ASCVD risk factors targeting inflammation, thrombotic and metabolic factors.

Implications: Hypertriglyceridaemia poses a significant residual ASCVD risk in patients already on LDL-C lowering therapy. Results from pharmacologically lowering triglyceride are conflicting. The role of fibrates and combination of EPA and DHA is under question but there is now convincing evidence of ASCVD risk reduction with pure EPA in a subgroup of patients with hypertriglyceridaemia. Clinical guidelines should be updated in line with recent clinical trials evidence. Novel agents targeting non-conventional ASCVD risks need further evaluation.

1 Introduction

Atherosclerotic Cardiovascular Disease (ASCVD) remains the leading cause of morbidity and mortality worldwide despite new mechanistic insights and preventative strategies to mitigate ASCVD risk. Increased prevalence of conditions that predispose to ASCVD events i.e., obesity, diabetes, hypertension and atherogenic dyslipidaemia contributes to the increasing burden of care attributed to ASCVD that costs >200 billion US dollars annually for US and comparable figure for Europe ( 1 , 2 ). Low-density lipoprotein cholesterol (LDL-C) has been demonstrated in large genetic, epidemiological, and clinical studies as a leading cause of atherosclerosis and ASCVD ( 3 , 4 ). A meta-regression analysis of 26 randomised controlled trials (RCTs) has demonstrated a stepwise reduction in ASCVD risk with 22% relative risk reduction with each 1 mmol/L reduction in LDL-C ( 5 ). Patients with higher pre-treatment LDL-C benefit more ( 6 ) and there is no limit below which further LDL-C lowering ceases to confer ASCVD protection ( 7 ). Despite this, there remains significant residual risk in statin treated patients ( 8 – 13 ). Addition of pharmacotherapies like proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition can reduce LDL-C to a very low level. Despite achieving LDL-C of <30 mg/dl (0.7 mmol/L) a substantial number of individuals still experience ASCVD events ( 14 ). In this narrative review, we delve into residual cardiovascular risks that extend beyond LDL-C with a focus on the role of triglyceride rich lipoproteins (TRL) as a residual ASCVD risk factor and on the impact of triglyceride (TG) lowering pharmacotherapy on residual ASCVD risk.

We conducted a comprehensive search across multiple electronic databases, including AMED, Embase, HMIC, Pubmed, Ovid Emcare, Ovid MEDLINE and other relevant papers of interest collected by the authors. Our search strategy utilized the following terms: “HYPERTRIGLYCERIDAEMIA”, “FIBRATES”, “RESIDUAL RISK”, “RANDOMISED CONTROLLED TRIALS”, “OMEGA 3 FATTY ACID”, “CARDIOVASCULAR”, “TRIGLYCERDE RICH LIPOPROTEINS” and “TRIGLYCERIDE”. Boolean operators “AND” and “OR” were employed to combine and separate search terms effectively. Only articles published in the English language were considered for inclusion in this review. Exclusion criteria encompassed articles published in languages other than English, conference abstracts, and case reports. Additionally, only studies involving human participants were included. To supplement our database search, we manually scrutinized the reference lists of identified trials, review articles, and previous meta-analyses to identify any additional relevant data.

3 Residual atherosclerotic cardiovascular disease risk

3.1 residual ascvd risk in clinical trials.

The Further cardiovascular OUtcomes Research with PCSK9 Inhibition subjects with Elevated Risk (FOURIER) trial evaluated patients with known ASCVD with pre-treatment LDL-C of 2.4 mmol/L (92 mg/dl) that was reduced to 0.7 mmol/L (30 mg/dl) with evolocumab, 9.8% of drug recipients still experienced ASCVD events over median followup period of 2.2 years ( 14 ). Similarly, in the Evaluation of Cardiovascular outcomes after Acute coronary syndrome during treatment with Alirocumab (ODYSSEY Outcomes), despite achieving LDL-C as low as 1.7 mmol/L (66 mg/dl), probability estimate of alirocumab recipients to have ASCVD event was 12.8% at 4 years ( 15 ). There were similar results in the Studies of PCSK9 Inhibition and the Reduction of Vascular Events (SPIRE) trials, though the relative percentage of ASCVD events was lower than FOURIER and ODYSSEY Outcomes (2.1% in SPIRE 1 at median followup of 7 months and 3.4% in SPIRE 2 at median followup of 12 months) ( 16 ) In the landmark statin trials where LDL-C lowering reduced the relative risk of ASCVD, participants who received statins still exhibited a significant residual cardiovascular risk. This was 22.4% at 2 years in the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI) study (achieved LDL-C 62 mg/dl, 1.6 mmol/L) ( 17 ), 9.3% over median follow up of 4.8 years in the Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) study (achieved LDL-C 81 mg/dl, 2.1 mmol/L) ( 18 ), and 8.7% over a median follow up of 4.9 years in the Treating to New Targets (TNT) study (achieved LDL-C 77 mg/dl, 1.9 mmol/L) ( 19 ). That a heightened incidence of ASCVD events persists despite attainment of low levels of LDL-C prompted the conceptualisation of residual cardiovascular risk due to additional metabolic, inflammatory, and thrombotic risk factors. The mitigation of ASCVD events necessitates a comprehensive and multifaceted approach addressing these diverse components.

3.2 Lipoproteins in atherosclerosis—limitations of LDL-C calculation

The key initial event in the genesis of atherosclerosis is the entrapment of lipoproteins in vascular intima followed by the engulfment by macrophages. Lipoprotein subfractions other than LDL can be preferentially entrapped and engulfed without the need to be chemically modified and may enhance the process of atherosclerosis. While the conventional clinical approach employs LDL-C as a marker for atherosclerotic risk, many atherogenic particles are relatively deficient in cholesterol and so their atherogenicity is underestimated by cholesterol measurement. In most clinical laboratories, LDL-C is an estimated through the Friedwald formula, dependant on knowledge of the total cholesterol (TC), High density lipoprotein cholesterol (HDL-C) and TG concentration. With TG >4.5 mmol/L (400 mg/dl) an estimate for LDL-C cannot be provided by this formula and even modest excursions in TG concentration, will result in underestimation of LDL-C concentration. Alternative calculators are available that offer LDL-C estimations up to TG levels of 10 mmol/L ( 20 ).

3.3 Apolipoprotein B100 and lipoprotein sub-fractions as a marker for ASCVD risk estimation

Apolipoprotein B100 (ApoB) serves as a comprehensive metric for the total atherogenic particle count. Each atherogenic lipoprotein particle, such as LDL, very low-density lipoprotein (VLDL), and Intermediate Density Lipoprotein (IDL), contains a single ApoB molecule. Consequently, the blood ApoB level provides a direct reflection of the overall number of atherogenic particles, irrespective of their size or density. This establishes ApoB as a more precise indicator of ASCVD risk compared to traditional lipid measurements, which fail to consider particle number or size. The Apolipoprotein-related Mortality Risk (AMORIS) study found that ApoB levels and the ApoB/Apolipoprotein A1 ratio were stronger predictors of ASCVD than LDL-C, whilst TG was found to be an independent risk factor for ASCVD ( 21 ). In the post hoc analysis of the TNT trial, higher levels of TRL (VLDL, IDL and chylomicron remnants) were associated with an increased risk of major ASCVD events independent of LDL-C concentration ( 22 ). Mendelian randomisation studies, epidemiological observations and RCTs of lipid-lowering drugs have implicated cholesterol-rich ApoB particles in addition to LDL i.e., VLDL, IDL and Lipoprotein (a) [Lp(a)] as being directly causal in ASCVD ( 4 ). In a prospective observational study of 4,932 individuals from the Jackson Heart Study and the Framingham Offspring Cohort Study, free of coronary heart disease (CHD) at baseline followed-up for 8 years, remnant lipoprotein cholesterol (RLP-C) was linked to the onset of CHD. After adjusting for other ASCVD risk factors and HDL-C, this association was driven by IDL-C which significantly elevated CHD risk by 25% (HR 1.25, 95% CI 1.07–1.46, P  < 0.001) ( 23 ).

Variations in the Lipoprotein lipase (LPL) gene that augment LPL activity are correlated with reduced TG levels and a concomitant decrease in ApoB concentration. Variations in the low-density lipoprotein receptor (LDLR) gene that enhance the activity of the LDLR are linked to decreased LDL-C concentration and a corresponding reduction in ApoB. For every 10 mg/dl decline in plasma ApoB concentration attributable to LPL score-associated variants, a parallel decrease of 0.8 mmol/L (69.9 mg/dl) in TG concentration is observed, with no discernible alteration in LDL-C, and a diminished risk of CHD (odds ratio (OR), 0.771 [95% CI, 0.741–0.802]). An equivalent 10 mg/dl decrease in plasma ApoB concentration associated with LDLR score-related variants corresponds to a 0.4 mmol/L (14.1 mg/dl) reduction in LDL-C concentration, no alteration in TG, and a similarly decreased risk of CHD [OR 0.773 (95% CI, 0.747–0.801)]. Consequently, despite inducing modifications in distinct lipid profiles, both LPL and LDLR scores exhibit analogous reductions in CHD risk for the same decrement in plasma ApoB concentration ( 24 ). This underscores that in hytriglyceridaemic populations ApoB is a better predictor of cardiovascular risk than cholesterol-based parameters, and a pivotal treatment target ( 25 ). There has been accumulating evidence recently which suggest that the risk attributed to an incremental rise in TRL/remnant cholesterol surpasses that of an equivalent increase in LDL-C ( 26 ). This was elaborated more recently in a Bjornsen et al. in a well characterised population from the UK Biobank. The authors investigated 502,460 participants in the UK Biobank, examining all single nucleotide polymorphisms (SNPs) associated with TRL and LDL-C identified via genome wide association studies and standard lipid profiles, including ApoB. These SNPs were divided into 2 clusters. Cluster 1 included SNPs affecting receptor mediated clearance and hence LDL-C more than TRL/remnant cholesterol, while cluster 2 had SNPs with a stronger impact on lipolysis and hence TRL/remnant cholesterol. The OR for CHD per standard deviation (SD) increase in ApoB was 1.76 (95% CI: 1.58–1.96) in cluster 2, which was significantly higher than the OR in cluster 1 [1.33 (95% CI: 1.26–1.40)]. These findings suggest that the association of ApoB with CHD risk varies depending on the type of particle harbouring ApoB and in this study, TRL/remnant particles demonstrated significantly greater atherogenicity per particle compared to LDL ( 27 ).

Despite low ApoB concentration, rare cases of familial dysbetalipoproteinaemia (FDBL) with ApoE2 homozygosity exhibited heightened ASCVD risk ( 28 ). This is attributed to impaired liver processing of chylomicron remnants, leading to prolonged circulation and abnormal cholesterol enrichment due to cholesteryl ester transfer protein (CETP) mediated lipid exchanges. Generating atherogenic small-dense LDL particles, which does not figure well in LDL-C measurements, in patients with high TG level as well as TG's strong association with atherogenic components of the metabolic syndrome, high-sensitivity C-reactive protein (hsCRP), coagulation are other factors contribute to increased ASCVD risk in hypertriglyceridaemia ( 29 – 34 ). It is now accepted that using ApoB to assess ASCVD risk in hypertriglyceridaemia (2–10 mmol/L) better reflects the total number of atherogenic particles than do LDL-C or non-HDL-C, particularly in patients with hypertriglyceridemia ( 25 , 29 – 36 ).

3.4 Severe hypertriglyceridaemia and ASCVD

There is an apparent paradox that hypertriglyceridaemia >10 mmol/L (885 mg/dl) association with ASCVD risk is less than less severe hypertriglyceridaemia. In the CALIBER study, Patel and colleagues, found no increased risk of myocardial infarction (MI) in individuals with TG >10 mmol/L (885 mg/dl), while increased risk was found in mild to moderate hypertriglyceridaemia (1.7–10.0 mmol/L, 150–885 mg/dl) that persisted despite statin and/or fibrate treatment ( 37 ). This is consistent with the notion that small but numerous TG depleted particles are more atherogenic that large TG rich particles such as chylomicrons. TG >10 mmol/L (885 mg/dl) is often associated with chylomicronaemia with particles enriched in TG relative to ApoB. Monogenic disorders causing severe hypertriglyceridemia have increased chylomicron concentrations with a heightened risk of acute pancreatitis, but generally not of premature atherosclerosis, likely due to the limited ability of chylomicrons to traverse the vascular endothelial barrier ( 38 ). Additionally, in severe hypertriglyceridemia (TG >10.0 mmol/L; 885 mg/dl) ApoB immunoassays are compromised by analytical interference in blood samples due to turbidity caused by large chylomicron and VLDL particles ( 39 ). TG measurement does not, therefore, reflect an increased number of atherogenic particles in these cases. Indeed, chylomicron associated ApoB generally contributes very little to total plasma ApoB.

In addition to various lipid subfractions, other metabolic, inflammatory contribute to and thrombotic pathways also fuel residual ASCVD risk as summarised in Figure 1 .

Figure 1. Residual cardiovascular risk factors. Apo A-I, apolipoprotein A-I; ApoB, apolipoprotein B100; CVD: cardiovascular disease; DM, diabetes mellitus; HDL-C; high-density lipoprotein cholesterol; hsCRP, high sensitivity C reactive protein; ICAM, intercellular adhesion molecule; ILs, interleukins; Lp(a), lipoprotein (a); Lp-PLA 2 , lipoprotein-associated phospholipase A 2 ; MASLD: metabolic dysfunction-associated steatotic liver disease; PAI, plasminogen activator inhibitor; PT, prothrombin time; RP, remanent particles; SAA, serum amyloid A; TG, triglycerides; TPA, tissue plasminogen activator; VCAM; vascular cell adhesion molecule. *Leucocyte count after acute myocardial infarction.

4 Triglycerides as a residual ASCVD risk factor

4.1 definition and measurement of triglycerides.

Despite heterogeneity in the definition of hypertriglyceridaemia, normal levels of fasting TG have been defined at <1.7 mmol/L (<150 mg/dl) ( 40 – 42 ). Persistent hypertriglyceridaemia is defined as a fasting TG ≥1.7 mmol/L (≥150 mg/dl) following a minimum of 4–12 weeks of lifestyle intervention, a stable dose of maximally tolerated statin when indicated as well as evaluation and management of secondary causes of hypertriglyceridaemia ( 41 ). More recently a more stringent criteria of TG <1.2 mmol/L (100 mg/dl) has been proposed to define optimal TG concentration ( 43 ). There has been discrepancy in recommendations between different guidelines regarding fasting or non-fasting lipid measurements for ASCVD risk assessment ( 43 – 46 ). Non-fasting and fasting samples provide comparable results for TC, LDL-C and HDL-C. The concentration of TG is elevated during the postprandial phase ( 40 ) though the increment is modest in majority of patients, between 0.14–0.3 mmol/L (12–27 mg/dl) ( 41 ) Non-fasting rather than fasting TG concentration is independently associated with atherosclerosis and incident future ASCVD events independent of other ASCVD risk factors, lipid parameters and insulin resistance ( 45 , 47 , 48 ). Using non-fasting samples of 6,391 participants in the Women's Health Study, a cut-off of 1.98 mmol/L (175 mg/dl) has been proposed to predict future ASCVD events ( 49 ). Fasting and non-fasting TG was found to be in good agreement in the Anglo-Scandinavian Cardiac Outcome Trial (ASCOT-LLT) with no difference in ASCVD outcomes between both groups ( 50 ). Most of the lipid modification clinical trials in last couple of decades used fasting lipid samples, though the implication of postprandial lipaemia and delayed clearance of TRL in postprandial state on ASCVD risk was conceptualised as early as 1979 ( 51 ) and has been subsequently tested in several clinical studies where postprandial TG was better predictor of ASCVD risk ( 52 – 54 ). This could be due to remnant particles that contribute to atherogenesis and are better captured in non-fasting samples. Humans are in a postprandial state most of the time during the day and therefore, a postprandial lipid profile may prove to be a more reliable and physiological marker of future ASCVD risk.

4.2 Hypertriglyceridaemia and ASCVD—mechanism and implications

With the rising prevalence of obesity, diabetes, insulin resistance and metabolic syndrome, evidence to suggest a causal relationship between hypertriglyceridemia and ASCVD has been accumulating. Catabolism of TRL leads to the liberation of remnant particles, small dense LDL particles (sdLDL), HDL3 and free fatty acids (FFA) ( 55 , 56 ). FFA have a multidimensional role that triggers endothelial dysfunction through oxidative stress, impaired nitric oxide (NO) production, inflammation, and endothelial cell apoptosis ( 57 – 59 ) ( Figure 2 ). Remnant particles, which are lipolytic products of chylomicrons and VLDL, vary in size and composition. They are smaller than their parent molecule and have a greater cholesterol-to-TG ratio. Increased production of VLDL and slower clearance of remnant particles and VLDL due to reduced LPL activity delays their conversion to downstream lipoprotein particles ( 38 ) thereby increasing their circulatory time. Similarly, inability of hepatic receptors to clear them from the circulation e.g., in individuals harbouring homozygous Apolipoprotein E2 isoform (FDBL) increases the time spent in the systemic circulation. With increased circulatory time, they are more likely to be entrapped in vascular intima, and in contrast to LDL, can be taken up by macrophages without chemical modifications, facilitating the process of atherogenesis ( 61 ). Apolipoprotein B48, a lipoprotein-associated with gut-derived chylomicron particles and chylomicron remnants has been found in atherosclerotic plaques derived from human aortic, carotid, and femoral endarterectomy specimens ( 62 , 63 ).

Figure 2. Possible mechanisms of TRLs in the process of the onset and progression of atherosclerosis. Catabolism of TRL leads to the production of FFA, sdLDL and their oxidized products, oxidized FFA and ox-sdLDL and remnant particles. Catabolic products of triglycerides increase the production of ROS, increase oxidative stress, reduce NO production, induce EC apoptosis, effects insulin signalling leading to IR, vascular inflammation the expression of proinflammatory cytokines and upregulate endothelial expression adhesion molecules (ICAM-1 and VCAM-1) facilitating the migration of proinflammatory leucocytes to enhance inflammatory response ( 55 ). Retention of TRL lipoproteins, remanent particles and breakdown products in vascular intima attract monocytes that differentiate into macrophages leading to the production of foam cells after engulfing TRL and remanent particles, which form the core of atherosclerotic plaque. The proinflammatory milieu leads to aggregation and activation of platelets and coagulation cascade, thereby inducing a pro-coagulant state and clot formation ( 55 , 56 , 60 ). CAM, intercellular adhesion molecule; EC, endothelial cells; FFA, free fatty acid; IR, insulin resistance; ICAM, inter-cellular adhesion molecule; LPL, lipoprotein lipase; NO: nitric oxide; ox, oxidised; sdLDL, small dense LDL; TNF, Tumour necrosis factor; TRL, triglyceride rich lipoproteins; TRLR, triglyceride rich lipoprotein remnants; VCAM, vascular cell adhesion molecule.

4.3 Complex association between hypertriglyceridemia and atherosclerotic cardiovascular disease: the confounding role of HDL-C

Despite large-scale epidemiological and population-based studies suggesting the association of hypertriglyceridaemia with ASCVD ( Table 1 ), unlike LDL-C, it has been a challenge to establish the causal role of TG with ASCVD. The difficulty in establishing this causal link partly stems from the inverse relationship between TG and HDL-C ( 73 ) and progressively increasing levels of RLP-C and density of LDL with increasing TG: HDL-C ratio ( 74 ) thereby confounding the independent effect of hypertriglyceridaemia on ASCVD. Recent epidemiological studies have attempted to address this by studying the effect of hypertriglyceridaemia in patients with LDL-C <2.6 mmol/L (100 mg/dl), a routinely accepted target in people who are at moderate risk of future ASCVD event ( 75 ). In a population-based study of 27,953 statin-treated patients from the Pacific Northwest and Southern California, with LDL-C 1.0–2.6 mmol/L (40–100 mg/dl), hypertriglyceridaemia (200–499 mg/dl, 2.2–5.6 mmol/L) was found to independently increase the risk of nonfatal MI and coronary revascularisation over an average follow-up period of 5.3 years ( 70 ). Similar findings were observed in a primary prevention cohort with diabetes ( n  = 28,318) and LDL-C <2.6 mmol/L (100 mg/dl) where the risk of CHD was found to be higher in the cohort with hypertriglyceridaemia (TG >150 mg/dl, 1.7 mmol/L) and low HDL-C (≤50 mg/dl, 1.3 mmol/L and ≤40 mg/dl, 1.0 mmol/L for women and men respectively), [Women: HR 1.35 (1.14–1.60), Men: HR 1.62 (1.43–1.83)]. This difference was significant only in women in the cohort with low HDL-C and high TG and highest in men in the same group when compared to low HDL-C, normal TG or normal HDL-C, high TG ( 76 ). Similarly, hypertriglyceridaemia (>150 mg/dl, 1.7 mmol/L) has been demonstrated to be associated with subclinical atherosclerosis regardless of baseline LDL-C levels, [LDL-C <100 mg/dl, 2.6 mmol/L OR: 1.85 (1.08–3.18), LDL-C >100 mg/dl, 2.6 mmol/L OR: 1.42 (1.11–1.80)] and vascular inflammation ( 12 ).

Table 1. Major studies evaluating the effect of hypertriglyceridaemia on ASCVD outcomes.

Despite the strong association between hypertriglyceridaemia and ASCVD this relationship is not straightforward partly due to other lipid abnormalities, most commonly low HDL-C. Although this has been accounted for in some studies, when the confounding factor of low HDL-C is reflected, the link between hypertriglyceridaemia and ASCVD weakens ( 66 , 69 ). Although ApoB is associated with proatherogenic lipoprotein particles, Apolipoprotein A1 (ApoA1) is found in anti-atherogenic particles e.g., HDL and its subfractions. The ratio of ApoB/ApoA1 have been suggested as a better predictor of ASCVD events as compared to the individual concentration of pro- and anti-atherogenic molecules ( 21 ).

4.3.1 Lessons learnt from Mendelian randomisation

Epidemiological studies, while crucial for identifying associations, often face limitations in establishing causation, particularly in complex phenomena like the relationship between raised TRL and ASCVD. Confounders such as low HDL-C and others factors can obscure direct causative links. Mendelian randomization studies leveraging human genetics present a promising avenue. By exploiting genetic variants as proxies for lifelong exposure to elevated TRL, in a study of 73,513 individuals of Danish descent, genetic variants affecting levels of non fasting remnant cholesterol alone, non-fasting remnant cholesterol combined with HDL-C, HDL-C alone, and LDL-C were investigated for their impact on ischemic heart disease (IHD). The findings revealed a substantial causal risk increase for elevated nonfasting remnant cholesterol, independent of HDL-C levels, suggesting a causal association with a 2.8-fold increased risk of ASCVD. Similarly, the non fasting remnant cholesterol to HDL-C ratio showed a 2.9-fold causal risk increase. Conversely, while observational estimates indicated a 1.6-fold increased risk of ASCVD for each 1-mmol/L decrease in HDL-C, the causal estimate was inconclusive at 0.7-fold. Furthermore, for LDL-C, a 1.5-fold causal risk increase was observed, supporting its known association with ASCVD ( 77 ). These findings underscore the causal role of elevated remnant cholesterol in ASCVD development, independent of low HDL-Clevels. Similar observations were made by Do et al. ( 78 ) and others where SNPs in TG raising alleles e.g., ANGPTL3, APOC2, APOA5, GPIHBP1, LMF1 were found to increase the risk of ASCVD, while conversely, in APOC3 loss of function heterozygosity led to reduction in ASCVD events ( 79 – 81 ).

5 Triglycerides as residual ASCVD risk factor in statin-treated patients

Landmark statin trials that shaped our understanding of cardiovascular risk reduction with intensive LDL-C reduction still displayed residual ASCVD risk (22.4% at 2 years, 9.3% at 4.3 years, and 8.7% at 4.9 years in PROVE IT TIMI, IDEAL and TNT respectively) despite intensive statin treatment and achieving LDL-C of 1.6 mmol/L (62 mg/dl), 2.1 mmol/L (81 mg/dl) and 2.0 mmol/L (77 mg/dl) respectively ( 17 – 19 ). Even though efficacy of statins in primary prevention of ASCVD in type 2 diabetes mellitus (T2DM) was well demonstrated in the Collaborative Atorvastatin Diabetes Study (CARDS), 12.5% of statin recipients had an ASCVD event despite achieving median on-treatment LDL-C 2.0 mmol/L (77 mg/dl) during median follow up of 3.9 years ( 13 ). Clearly, residual ASCVD risk persists even after achieving optimal reductions in LDL-C levels in large statin trials, irrespective of the dosage. The factors that may contribute to residual cardiovascular risk are outlined in Figure 1 .

A post hoc analysis of the PROVE IT TIMI trial focused on secondary prevention. LDL-C levels below 1.8 mmol/L (70 mg/dl) and TG levels below 2.2 mmol/L (200 mg/dl) demonstrated a 40% reduced risk of subsequent ASCVD events when compared to individuals with TG levels exceeding 2.2 mmol/L (200 mg/dl). TG <1.7 mmol/L (150 mg/dl) was independently associated with a 20% reduction in relative risk of CHD after adjustment for LDL-C and other covariates. A combination of TG <1.7 mmol/L (150 mg/dl) and LDL-C <1.8 mmol/L (70 mg/dl) was associated with the lowest ASCVD events, and each 0.1 mmol/L (10 mg/dl) lower TG concentration led to a decline in the rate of recurrent acute coronary syndrome (ACS), MI and death by 1.6% independent of LDL-C concentrations ( 8 ). Similar results were found in the intEnsive statin therapy for hypercholesteroleMic Patients with diAbetic retinopaTHY (EMPATHY) study where serum TG was associated with ASCVD regardless of the intensity of statin therapy. Each 0.1 mmol/L (10 mg/dl) increase in TG was associated with a 2.1% increased risk of ASCVD event and TG >1.5 mmol/L (135 mg/dl) was found to be an independent risk factor for developing ASCVD ( 82 ). In post hoc analyses of TNT and IDEAL study, non-HDL-C and ApoB were found to have a stronger association with future ASCVD events as compared to LDL-C alone. Patients with TG in the highest quantile were predicted to be at 63% increased risk as compared with the lowest quantile. This effect was attenuated but not abolished after adjustment for HDL-C. The probability of ASCVD event was 30% higher in individuals with TG levels >1.7 mmol/L (150 mg/dl), as opposed to those with levels <1.7 mmol/L (150 mg/dl). This association between elevated TG levels and an increased risk of new ASCVD events persisted in individuals with an LDL-C cholesterol concentration below 2.6 mmol/L (100 mg/dl) ( 9 , 10 ). A post hoc analysis of dal-OUTCOMES and Myocardial Ischemia Reduction with Acute Cholesterol Lowering (MIRACL) study reported similar results, where in statin-treated patients, fasting TG was found to be independently associated with short- and long-term risk of developing ASCVD independent of LDL-C. Similar to PROVE IT-TIMI, each 0.1 mmol/L (10 mg/dl) increase in TG was associated with a 1.4%–1.6% increase in the risk of a ASCVD event ( 11 ). In all major statin trials, there is a significant residual ASCVD risk in statin recipients, which is due to atherogenic dyslipidaemia and non-LDL lipoprotein subfractions along with other contributors that constitute residual ASCVD risk profile ( Figure 1 ).

6 Triglycerides and residual ASCVD risk in PCSK9 inhibitor treated patients

The FOURIER and ODYSSEY OUTCOMES trials have demonstrated significant LDL-C reduction that has translated into ASCVD risk reduction. However, despite achieving very low LDL-C, a residual risk of 9.8% and 9.5% respectively remained at 2.2 and 2.8 years respectively. Participants in both trials received moderate or high intensity statin in addition to PCSK9 monoclonal antibodies. In FOURIER, mean LDL-C at the end of the trial period was as low as 0.8 mmol/L (30 mg/dl) in the evolocumab arm. Despite this, a significant proportion of patients had ASCVD events. 9.8% of evolocumab recipients had at least one ASCVD event and 6.1% had a subsequent ASCVD event ( 14 , 83 ). In a prespecified secondary analysis of the FOURIER trial, a monotonic relationship between LDL-C at 4 weeks and ASCVD events was observed, where while high LDL-C was associated with heightened risk, 10.3% of individuals achieving LDL-C <0.5 mmol/L (20 mg/dl) experienced an ASCVD event ( 84 ). TG of 1.3 mmol/L (112.3 mg/dl) at the end of the trial period along with other metabolic and inflammatory factors ( Figure 1 ) might explain the residual ASCVD risk in this group who achieved very low LDL-C. ApoB, which constitutes a composite of all major atherogenic lipoproteins, inclusive of LDL, VLDL, IDL, remnant particles and Lp(a) would be a better therapeutic target to minimize ASCVD risk. This is supported by a recent analysis of the ODYSSEY outcome database by Hagstrom et al. where LDL-C was found to underestimate the ASCVD risk and ApoB levels were found to be a better predictor of future ASCVD events independent of LDL-C levels in a cohort of alirocumab treated patients ( 85 ). Similarly, intensive LDL-C lowering with evolocumab and statins in the “Global Assessment of Plaque Regression With a PCSK9 Antibody as Measured by Intravascular Ultrasound” (GLAGOV) study achieved a significant reduction in plaque atheroma volume (PAV) and total atheroma volume (TAV) with very low LDL-C (36.6 mg/dl, 0.9 mmol/L). Nevertheless, not all the patients achieved plaque regression. In a subgroup of participants with baseline LDL-C of 1.8 mmol/L (70 mg/dl), with a further 50%–55% reduction after treatment, 20% did not have regression in atheroma volume despite achieving very low LDL-C ( 86 ), thereby suggesting a role of TG-rich lipoproteins and other factors ( Figure 1 ) in atheroma development and progression ( 87 ). In addition, 12.2% of evolocumab recipients had ASCVD events suggestive of residual factors other than LDL-C contributing to atherogenesis ( 86 ).

Residual ASCVD risk in statin and PCSK9-treated patients is not confined to non-LDL subfractions. Pradhan et al. have demonstrated a 62% increase in the risk of future ASCVD events (3.6% annual event rate) in statin and PCSK9-treated patients who have achieved median LDL-C of 1.07 mmol/L (41.7 mg/dl) but have raised high-sensitivity C-reactive protein (>3 mg/L) suggesting complex interplay of multiple residual ASCVD risk factors in the pathogenesis of ASCVD ( 88 ).

7 Therapeutic targets

The role of TG in ASCVD is well established from clinical trials ( 8 ), epidemiological ( 69 ) and Mendelian randomisation studies ( 24 , 89 ). Serum TG levels are very sensitive to diet, lifestyle, and secondary factors. Three classes of drugs that preferentially reduce serum TG levels are fibrates, omega-3 fatty acids (FA) and niacin. Despite genetic studies ( 78 ) and post hoc analysis of landmark statin ( 8 ) and PCSK9 trials ( 85 ) suggesting a lower risk of ASCVD with reduced TG, the results from pharmacologically achieved lower TG levels with niacin, fibrates and omega-3 FA have been inconsistent. Major clinical trials of fibrates and Omega-3 FA evaluating ASCVD outcomes are summarised in Tables 2 , 3 respectively.

Table 2. Major fibrate trials, effect on lipid profile and ASCVD outcomes.

Table 3. Major omega 3 fatty acid trials, effect on lipid profile and ASCVD outcomes.

7.1 Diet and lifestyle

TG levels are highly responsive to dietary interventions and physical activity; therefore, the first line of intervention is often diet and lifestyle modifications ( 38 ). Epidemiological and clinical trial data substantiate the correlation between the Mediterranean-style dietary pattern and reduction in TG levels ( 113 , 114 ). Modification of macronutrient composition through dietary interventions, adopting low-carbohydrate diets, and implementing caloric restriction have shown efficacy in improving TG ( 115 ). Notably, the Mediterranean diet emerges as the dietary pattern with the most consistent and robust evidence supporting its efficacy in addressing hypertriglyceridaemia ( 113 ). Additionally, among dietary components, the consumption of omega-3 FA has been the subject of a substantial number of RCTs that have consistently demonstrated their effectiveness in reducing TG levels ( 116 , 117 ). Sea food and oily fish are a rich source of polyunsaturated fatty acids (PUFA) that not only lead to a significant decrease in TG but also improve blood pressure, systemic inflammation and increase HDL-C ( 118 ). In the Framingham Heart Study Offspring Cohort, individuals in the highest quintile for the Mediterranean-style diet exhibited the lowest TG levels over a 7-year follow-up ( 119 ). Additionally, these interventions offer ancillary benefits such as weight loss and reduced waist circumference. A comprehensive approach to lifestyle modification, encompassing dietary strategies with an emphasis on reduced carbohydrate and saturated fat intake, regular physical activity, and weight management, can result in substantial TG reductions ranging from 20% to 50%.

While there exists evidence substantiating the correlation between elevated TG and a heightened susceptibility to ASCVD events, a multitude of clinical trials assessing pharmacological interventions aimed at reducing TG levels have not demonstrated reduction in ASCVD events. The Atherothrombosis Intervention in Metabolic Syndrome with Low HDL-C/High Triglycerides: Impact on Global Health Outcomes (AIM-HIGH) study investigated the impact of niacin on individuals on intensive statin therapy with elevated TG levels and low HDL-C levels. Despite niacin achieving a 31% reduction in TG and 21% increase in HDL-C in a cohort with baseline LDL-C <1.8 mmol/L (70 mg/dl), no difference in the composite primary cardiovascular endpoint emerged between the niacin-administered cohort and the control group ( 120 ). Similar results were replicated later by the Heart Protection Study 2–Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE), which investigated the combined administration of niacin and laropiprant, a prostaglandin D2 receptor 1 antagonist, with simvastatin and/or ezetimibe ( 121 ). A systematic review and metanalysis spanning the preceding six decades and 17 RCTs failed to show ASCVD risk reduction with niacin treatment across all patient cohorts, including those on statin treatment ( 122 ). Consequently, niacin has been withdrawn from the European market.

7.3 Fibrates

Fibrates are synthetic ligands for peroxisome proliferator-activated receptor (PPAR) alpha receptors, through which they exert lipid-lowering and pleiotropic effects via increasing lipolysis by upregulating LPL activity, hepatic FA uptake, increased production of ApoA1, inhibition of apolipoprotein C3 and reduced expression of various pro-inflammatory cytokines and adhesion molecules ( 123 ). Whilst hypertriglyceridaemia is deemed as a risk factor for ASCVD and current guidelines recommend employing additional measures to reduce TG <1.7 mmol/L (150 mg/dl) to mitigate cardiovascular risk ( 75 , 124 ), the addition of fibrates to statins to achieve this has not shown any additional benefit ( Table 2 ). The history of employing fibrates to reduce cardiovascular risk dates to the 1950s when a group of farm workers were found to have low cholesterol after being exposed to an insecticide (phenyl ethyl acetic acid) that led to the synthesis of its analogue, clofibrate ( 125 , 126 ). When clofibrate was employed for the first time in a primary prevention cohort, although showing a significant reduction in nonfatal MI, it failed to demonstrate a significant benefit in cardiovascular mortality. Furthermore, it increased the risk of gallstones and non-cardiovascular mortality ( 91 ) which precluded its use in the modern era. Whilst the outcomes from clofibrate were disappointing, primary, and secondary prevention trials towards the end of 20th century with another fibrate, gemfibrozil demonstrated significant benefits in reducing cardiovascular events ( 92 , 127 ). The secondary prevention trial (VA HIT) included patients only with HDL-C <1.0 mmol/L (39 mg/dl) thereby signalling the benefit of fibrates in individuals with atherogenic dyslipidaemia (high TG, low HDL-C). Intriguingly, the ASCVD benefit was attributed to increased HDL-C rather than a reduction in TG levels. Subgroup analysis of the Helsinki Heart Study (HHS) trial echoed similar results where the greatest benefit was derived in individuals with low HDL-C (<1.08 mmol/L, 42 mg/dl) and high TG (>2.3 mmol/L, 204 mg/dl) ( 128 ). The predominant effect of fibrates in ameliorating ASCVD risk in atherogenic dyslipidaemia, characterized by high TG and low HDL-C, has been replicated in subsequent trials with bezafibrate and fenofibrate where, although these drugs failed to demonstrate significant ASCVD risk reduction across the whole cohort, participants with atherogenic dyslipidaemia derived maximum benefit ( 94 , 98 ) ( Table 2 ). Several meta-analyses have demonstrated ASCVD risk reduction with fibrates only in the setting of atherogenic dyslipidaemia ( 129 , 130 ). In addition to ASCVD risk reduction, fibrates reduce the progression of diabetic retinopathy ( 131 , 132 ).

More recently, a selective PPAR alpha receptor modulator, pemafibrate, has been evaluated for ASCVD risk reduction in hypertriglyceridaemia in a subset of patients with LDL-C <1.8 mmol/L (70 mg/dl) whilst on statins or <2.6 mmol/L (100 mg/dl) in cases of statin intolerance. In addition, the study was focused on individuals with atherogenic dyslipidaemia i.e., with T2DM, TG >2.2 mmol/L (195 mg/dl) and HDL-C <1.0 mmol/L (38 mg/dl). Two-thirds of the study population had prior ASCVD events. This cohort was representative of modern-day residual ASCVD risk profile where intensive LDL-C reduction and background statin therapy have been employed. Pemafibrate is distinct from other fibrates as it is a selective PPAR receptor modulator. Though the lipid-modifying effect of pemafibrate is comparable with fenofibrate, pemafibrate has superior pleiotropic effects and increases HDL's cholesterol efflux capacity in vitro ( 133 ). Nevertheless, despite better pharmacokinetics and achieving a significant reduction in TG, VLDL-C and remnant particles and a comparable HDL-C increase compared to earlier fibrate trials, no significant reduction in major ASCVD events was demonstrated, thereby casting doubt on the utility of TG reduction via fibrates on ASCVD events in statin-treated patients with adequately lowered LDL-C. Safety analysis of pemafibrate also revealed that drug recipients were twice as likely to suffer deep vein thrombosis (DVT) and pulmonary embolism (PE) compared to placebo. Similar findings have been reported with fenofibrate [FIELD trial, RR for venous thromboembolism (VTE) 1.5 (1.1–2.0)] ( 97 ) and clofibrate [Coronary Drug Project, RR for PE 1.8 (1.1–2.8)] ( 90 ). The association of fibrates with VTE has been supported by a French pharmacovigilance database and other case-control studies ( 134 – 137 ). The reason for the increased risk of VTE is not known, though an increased level of homocysteine with or without other contributing factors might explain the increased risk ( 137 ).

Kim and colleagues have recently conducted a meta-analysis and meta-regression analysis of 12 RCTs, including Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes (PROMINENT) trial, employing fibrates for ASCVD risk reduction. While authors demonstrated overall reduction in ASCVD risk, mainly in secondary prevention group, it was found that reduction in ASCVD events was significantly associated with reduction in LDL-C. Each 1 mmol/L reduction in LDL-C level was associated with a reduction in major adverse cardiovascular events (MACE) with a relative risk (RR) 0.71 (95% CI 0.49–0.94, p  = 0.01). On the other hand, a reduction in TG concentration was not associated with a significant reduction in MACE. Change in LDL-C was found to be the main driver of heterogeneity between the studies ( 138 ). Fibrates can reduce LDL-C, however this LDL-C lowering potential is inconsistent ( 139 ) and is significantly dampened with concomitant use of statins ( 140 ). In the meta-analysis by Kim et al. both baseline and LDL-C change were inversely correlated with the year of publication, suggesting better lipid control post-statin era and hence diminished efficacy of fibrates in reducing LDL-C ( 138 ). There also appears a negative correlation between change in LDL-C and baseline LDL-C with Pemafibrate ( 141 ). sdLDL are more atherogenic than large buoyant LDL particles. Using Sampson formula to calculate sdLDL-C, no difference has been shown in its concentration between pemafibrate and placebo group ( 142 ). Likely, low baseline LDL-C levels diminish the role of TG in sdLDL formation. Additionally, Pemafibrate stimulates hepatic TG lipase, potentially enhancing sdLDL production, which could offset the decrease in sdLDL attributed to lower TG levels. In the PROMENENT study Pemafibrate reduced remnant cholesterol and TG, however increased levels of ApoB, a surrogate indicator for LDL particle count. Given the strong correlation between ApoB levels and sdLDL-C levels, the lack of reduction in estimated sdLDL-C levels in the PROMINET trial is not unexpected ( 142 ). The beneficial impact of Pemafibrate on ASCVD might be restricted to individuals with hypertriglyceridemia those with relatively higher LDL-C and would be interesting to investigate the effect of Pemafibrate in a sub-cohort of PROMINENT trial who had higher baseline LDL-C. Moreover, recent advancements in the treatment of diabetes and hypertension, along with the growing utilization of cardioprotective anti-hyperglycaemic medications, high-intensity statins, along with addition of other potent LDL-C lowering drugs may have reduced the remaining cardiovascular risk to such an extent that it becomes challenging to discern notable differences in outcomes solely through triglyceride lowering strategies.

In summary, the use of fibrates to mitigate ASCVD risk was supported by early trials with the greatest benefit being derived for patients with atherogenic dyslipidaemia. However, results from the PROMINENT study ( 99 ) along with an increased propensity to develop VTE with fibrates have cast doubt over their clinical utility for ASCVD risk reduction and they should be administered cautiously in patients, particularly in individuals at high risk of VTE.

7.4 Omega 3 fatty acids

Omega 3 FA are PUFA that cannot be synthesised by humans. They are found in abundance in seafood and hence are also called marine fatty acids. Our understanding of the relationship between increased consumption of PUFA, favourable lipid profile and reduce incidence of CHD dates to the 1970s when Greenland Inuit whose diet was rich in seafood were found to have favourable metabolic profiles as compared to Danish controls ( 143 ). Subsequently, several potential mechanisms via which omega-3 FA can reduce the burden of ASCVD independent of its lipid-lowering potential have been proposed ( 144 ). Despite this, clinical studies have produced divergent results for ASCVD outcomes with omega-3 FA supplementation ( Table 3 ).

The initial landmark trial of omega-3 FA, Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico- Prevenzione trial (GISSI-P) ignited excitement when it showed a 15%–20% reduction in fatal and non-fatal ASCVD events ( 100 ). Similar results were reproduced in Japan EPA lipid Intervention Study (JELIS) where Eicosapentaenoic acid (EPA) supplementation led to a 19% reduction in major ASCVD events ( 101 ). Nonetheless, this earlier excitement waned when subsequent trials failed to reproduce ASCVD benefits ( Table 3 ). Positive outcomes in GISSI-P and JELIS could be due to the diet and lifestyle of the study population from Italy and Japan respectively who consume seafood on a more regular basis and hence may have higher circulating omega-3 FA levels. Attained level of blood EPA is an important factor and may explain the positive outcome of JELIS trial. This perception is supported by findings from two recent trials, Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE-IT) ( 111 ) and Long-Term Outcomes Study to Assess Statin Residual Risk with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridemia (STRENGTH) ( 112 ), where outcomes for REDUCE-IT, like JELIS, were positive after using a higher dose of purified icosapent ethyl (IPA) (4 g/day) leading to a greater increment in its blood levels. However, outcomes were neutral for STRENGTH, where the increment in EPA levels was lower as compared to REDUCE-IT. Baseline EPA level in study participants in JELIS was 97 µg/ml which was significantly higher than REDUCE-IT and STRENGTH, (26.1 µg/ml and 21.0 µg/ml respectively) but achieved EPA levels after supplementation with omega-3 FA were comparable between JELIS (1.8 g/day of purified IPA, 70% increase, 169 µg/ml) and REDUCE-IT (4 g/day of purified IPA, 394% increase, 144 µg/ml) which produced positive outcomes. In STRENGTH however, the achieved EPA levels after supplementation [EPA 1,860 mg + docosahexaenoic acid (DHA) 1,500 mg/day] led to a 269% increment yet the absolute achieved EPA levels remained lower (89.6 µg/ml) than the baseline EPA levels of JELIS participants ( 101 , 111 , 112 ). This suggests employing higher doses of EPA may help in achieving an “effective therapeutic level” of circulating EPA to reduce ASCVD events. Moreover, the mean baseline TG level in JELIS participants was 1.7 mmol/L (150 mg/dl) which, according to current guidelines is defined as normal ( 38 ). This, along with ASCVD risk reduction disproportionate to the amount of TG reduction and failure of fibrates to reduce ASCVD events despite achieving greater TG reduction suggests independent pathways through which EPA exerts its antiatherogenic effects. Trials demonstrating neutral outcomes employed a combination of EPA and DHA while trials demonstrating positive ASCVD outcomes employed purified EPA. This might suggest that any beneficial effect conferred by EPA is partially neutralised by DHA, though there is no mechanistic data to suggest any proatherosclerotic and/or prothrombotic effects of DHA. One plausible explanation could be the low absolute dose of EPA used in EPA + DHA as compared to the higher one used in EPA monotherapy (without DHA) studies.

EPA and DHA are two distinct molecules that have diverse effects on membrane integrity, stability, and cholesterol distribution ( 145 ). While EPA preserves membrane structure, DHA increases membrane fluidity and has fewer antioxidant properties that wane more quickly as compared to EPA ( 146 ). The antioxidant properties of EPA exceed quantitatively those of fibrates which might explain positive ASCVD outcomes despite proportionately less TG reduction ( 146 ). The differential interaction of EPA and DHA with the cell membrane, cholesterol distribution, formation of cholesterol crystals and atherosclerotic plaque, antioxidant capacity and modulation of endothelial dysfunction ( 147 ) might explain the ASCVD protection conferred by EPA-based therapeutics. The application of the INSPIRE biobank registry (formerly known as the Intermountain Heart Collaborative Study) afforded a unique opportunity to explore the relationship between spontaneously acquired levels of omega-3 metabolites and the occurrence of long-term major adverse cardiovascular events (MACE) within a diverse cohort of high-risk individuals encompassing both primary and secondary prevention populations referred for angiography ( 148 ). The findings substantiated the observed cardioprotective impact linked to elevated circulating and acquired levels of EPA, as opposed to DHA. Notably, these results suggested that increased DHA levels and a resultant reduced EPA/DHA ratio might diminish the cardiovascular protective effect of EPA. Elevated plasma concentrations of EPA and the combined EPA + DHA demonstrated a protective effect against incident MACE. However, unadjusted DHA alone did not display a correlation with incident MACE or a protective effect. Furthermore, DHA, when adjusted for EPA, exhibited an almost twofold increased risk of MACE for individuals in the highest quartile compared to the lowest quartile of DHA. These findings, in conjunction with reduced attained EPA serum levels, may contribute to understanding the outcomes observed in recent trials, such as the STRENGTH and REDUCE-IT ( 148 ). The Randomized Trial for Evaluation in Secondary Prevention Efficacy of Combination Therapy - Statin and Eicosapentaenoic Acid (RESPECT-EPA) was a recent open label trial focussed on patients with secondary prevention on background statin therapy. After 6 years, a marginally significant reduction in the primary cardiovascular outcome (10.9% vs. 14.9%, hazard ratio 0.785, p  = 0.0547) and a significant decrease in the composite secondary endpoint (8.0% vs. 11.3%, hazard ratio 0.734, p  = 0.0306) was observed. The trial employed same dose of EPA as in JELIS but the baseline EPA level was half of that of JELIS participants (45 µg/ml vs. 97 µg/ml) and focus on patients with higher chronic inflammation suggested by lower EPA:AA (arachidonic acid) ratio ( 149 , 150 ). Though the details of the study are awaited, like JELIS, higher baseline EPA levels in a Japanese cohort with subsequent higher clinically meaningful levels after treatment might suggest that absolute serum EPA levels govern ASCVD outcomes whereas patients with low baseline EPA might require higher doses of EPA to achieve clinically significant levels. Similar observations had been made in a sub-study of REDUCE-IT where achieved EPA levels in the treatment group were found to be associated with ASCVD events, heart failure and cardiovascular death ( 151 ).

7.5 Weight loss and bariatric surgery

The common dyslipidaemia associated with obesity is marked by elevated TG levels and low HDL-C. Most diet and lifestyle interventions accompanied by some degree of weight loss are translated into improved hypertriglyceridaemia ( 152 ). Pharmacological interventions with glucagon like peptide 1 (GLP1) and gastric inhibitory polypeptide (GIP) receptor agonists are associated with a 20%–25% reduction in TG accompanied by 15%–20% weight loss ( 153 , 154 ). Bariatric surgery (BS) offers another option to attain significant and sustained weight loss that not only improves hypertriglyceridaemia but also improves the qualitative composition of lipoprotein particles ( 155 ). Incidence of hypertriglyceridaemia was significantly reduced after bariatric surgery during the follow up period of 2 years ( 156 ) where TG level remains the strongest univariate predictor of mortality in the Swedish Obese Subject (SOS) study ( 157 ). In a metanalysis of 178 studies, recipients of BS demonstrated a significant decrease in mean TG levels as compared to both baseline and non-surgical controls. Reduction in TG varied depending on type of BS employed with the greatest reduction observed with Roux-en-Y gastric bypass (RYGB), but each procedure displayed significant reductions compared to baseline and controls ( 158 ). We have demonstrated significant reductions in TG along with other atherogenic lipoproteins, markers of systemic inflammation and insulin resistance after BS in patients with and without diabetes ( 159 – 162 ). In T2DM the susceptibility to ASCVD is significantly increased by the existence of microvascular disease that may manifest as nephropathy, neuropathy, or retinopathy ( 163 ). Hypertriglyceridaemia is associated with small nerve fibre damage and cardiac autonomic neuropathy ( 117 , 155 , 164 , 165 ). Our findings, along with those of others, indicate evidence of small nerve fibre regeneration post-bariatric surgery. Additionally, we established a correlation between improvements in neuropathic parameters and reductions in TG levels ( 160 , 166 , 167 ). Notably, the beneficial effects on small nerve fibre structure and function extend beyond patients with T2DM. A similar association of hypertriglyceridaemia is noted in relation to retinopathy and nephropathy ( 38 ).

In addition to lipid-modifying therapy targeting serum TG, several other therapeutic agents have been or are in the process of development, targeting various potential mediators of residual cardiovascular risk with variable success ( Table 4 ). Careful selection of patients, after addressing traditional modifiable risk factors based on clinical features, laboratory values, risk of adverse effects, co-morbidities and patient preferences can aid in defining the choice of novel therapy. The absolute benefit gained by these add-on novel therapies largely depends upon the baseline residual risk after addressing conventional modifiable risks.

Table 4. Therapeutic targets for reducing atherosclerotic cardiovascular disease (ASCVD) risk: summary of clinical trials and outcomes.

8 Conclusion

Historically ASCVD risk reduction measures have predominantly been LDL-centric. Despite significant strides in developing LDL-C lowering agents and their proven benefits in reducing ASCVD risk, a substantial portion of the secondary prevention cohort remains undertreated. Factors such as clinical inertia, discrepancies in access to effective lipid-lowering therapies, and challenges in implementing guidelines contribute to this problem. Even with optimal guideline-based treatment, lipid-related but also lipid-independent residual risk remains a significant contributor to recurrent events, emphasizing the need to identify atherogenic targets beyond LDL-C.

TRL as a risk factor for ASCVD have gained much attention recently supported by epidemiological, genetic, and mechanistic studies. Addressing this TRL-associated risk is challenging, given mixed results from clinical outcome studies evaluating various therapeutic approaches. Fibrates had previously been shown to be of benefit in atherogenic dyslipidaemia but recent results from the PROMINENT trial have cast doubt on their utility in ASCVD risk reduction. Further, increased risk of VTE has been reported inconsistently in earlier fibrate trials and therefore merits careful consideration. ASCVD risk reduction from REDUCE-IT and RESPECT EPA but not from STRENGTH and other studies employing combined EPA and DHA suggest TG-independent pathways to mitigate ASCVD risk with purified EPA products. Patients at high risk of recurrent ASCVD events may benefit from employing additional therapeutic agents to target components of the residual cardiovascular risk profile.

Author contributions

BB: Data curation, Writing – original draft, Writing – review & editing. JS: Writing – original draft, Writing – review & editing. PD: Writing – original draft, Writing – review & editing. MF: Writing – original draft, Writing – review & editing. DA: Writing – original draft, Writing – review & editing. AW: Writing – original draft, Writing – review & editing. SR: Writing – original draft, Writing – review & editing. IG-B: Writing – original draft, Writing – review & editing. AM: Writing – original draft, Writing – review & editing. PD: Writing – original draft, Writing – review & editing. HS: Conceptualization, Supervision, Writing – original draft, Writing – review & editing.

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work is supported by an unrestricted grant from Amarin.

Acknowledgments

The authors acknowledge the support from Manchester National Institute for Health Research (NIHR)/WELLCOME Trust Clinical Research Facility, Lipid disease fund, Hyperlipidaemia Education & Atherosclerosis Research Trust UK (HEART UK).

Conflict of interest

HS: Received personal fees from Amgen, Akcea, Synageva, NAPP, Novartis, Takeda, Sanofi, Pfizer and Kowa & received research grants and donations from Akcea, Pfizer, MSD, AMGEN, Genzyme-Sanofi, Synageva, Amryt, Synageva and Alexion. DA: reports research grants from Boehringer-Ingelheim, Bristol Myers Squibb, Janssen, and the LEO Foundation. JS: received grants and research support from Astra Zeneca, Daiichi-Sankyo, Eli Lilly and Company and Novo Nordisk; speaker fees from Novartis, Astra Zeneca, Daiichi-Sankyo and Sanofi; and consultancy fees from Amgen, Boehringer Ingelheim, Eli Lilly and Company and Sanofi. PD: Received honoraria from Sobi, Novartis, Amgen, Daiichi Sankyo, Sanofi and Amarin. SR: Received honoraria from NOVARTIS, AMGEN, Astra Zeneca, Ultragenyx, Sanofi, Foresite Labs, and research grants from Astra Zeneca. IG-B: received personal honoraria for consulting from Amgen, Regeneron, Aegereon, Akcea Therapeutics, Daiichi-Sankyo, Novartis, Ultragenyx, Sanofi and Amarin.

The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher's note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

1. European Heart Network. European Cardiovascular Disease Statistics 2017 [Internet]. (2017). [cited 2022 Dec 13]. Available online at: https://ehnheart.org/cvd-statistics.html

Google Scholar

2. Centres for Disease Control and Prevention. Health Topics—Heart Disease and Heart Attack [Internet]. (2021). [cited 2022 Dec 13]. Available online at: https://www.cdc.gov/policy/polaris/healthtopics/heartdisease/index.html#print

3. Ference BA, Ginsberg HN, Graham I, Ray KK, Packard CJ, Bruckert E, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European atherosclerosis society consensus panel. Eur Heart J . (2017) 38(32):2459–72. doi: 10.1093/eurheartj/ehx144

PubMed Abstract | Crossref Full Text | Google Scholar

4. Durrington PN. Hyperlipidaemia: Diagnosis and Management . 3rd ed. London: Hodder Arnold (2007).

5. Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, Bhala N, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet . (2010) 376(9753):1670–81. doi: 10.1016/S0140-6736(10)61350-5

6. Soran H, Schofield JD, Durrington PN. Cholesterol, not just cardiovascular risk, is important in deciding who should receive statin treatment. Eur Heart J . (2015) 36(43):2975–83. doi: 10.1093/eurheartj/ehv340

7. Soran H, Kwok S, Adam S, Ho JH, Durrington PN. Evidence for more intensive cholesterol lowering. Curr Opin Lipidol . (2017) 28(4):291–9. doi: 10.1097/MOL.0000000000000433

8. Miller M, Cannon CP, Murphy SA, Qin J, Ray KK, Braunwald E. Impact of triglyceride levels beyond low-density lipoprotein cholesterol after acute coronary syndrome in the PROVE IT-TIMI 22 trial. J Am Coll Cardiol . (2008) 51(7):724–30. doi: 10.1016/j.jacc.2007.10.038

9. Kastelein JJP, van der Steeg WA, Holme I, Gaffney M, Cater NB, Barter P, et al. Lipids, apolipoproteins, and their ratios in relation to cardiovascular events with statin treatment. Circulation . (2008) 117(23):3002–9. doi: 10.1161/CIRCULATIONAHA.107.713438

10. Faergeman O, Holme I, Fayyad R, Bhatia S, Grundy SM, Kastelein JJP, et al. Plasma triglycerides and cardiovascular events in the treating to new targets and incremental decrease in end-points through aggressive lipid lowering trials of statins in patients with coronary artery disease. Am J Cardiol . (2009) 104(4):459–63. doi: 10.1016/j.amjcard.2009.04.008

11. Schwartz GG, Abt M, Bao W, DeMicco D, Kallend D, Miller M, et al. Fasting triglycerides predict recurrent ischemic events in patients with acute coronary syndrome treated with statins. J Am Coll Cardiol . (2015) 65(21):2267–75. doi: 10.1016/j.jacc.2015.03.544

12. Raposeiras-Roubin S, Rosselló X, Oliva B, Fernández-Friera L, Mendiguren JM, Andrés V, et al. Triglycerides and residual atherosclerotic risk. J Am Coll Cardiol . (2021) 77(24):3031–41. doi: 10.1016/j.jacc.2021.04.059

13. Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HAW, Livingstone SJ, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the collaborative atorvastatin diabetes study (CARDS): multicentre randomised placebo-controlled trial. Lancet . (2004) 364(9435):685–96. doi: 10.1016/S0140-6736(04)16895-5

14. Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med . (2017) 376(18):1713–22. doi: 10.1056/NEJMoa1615664

15. Schwartz GG, Steg PG, Szarek M, Bhatt DL, Bittner VA, Diaz R, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med . (2018) 379(22):2097–107. doi: 10.1056/NEJMoa1801174

16. Ridker PM, Revkin J, Amarenco P, Brunell R, Curto M, Civeira F, et al. Cardiovascular efficacy and safety of bococizumab in high-risk patients. N Engl J Med . (2017) 376(16):1527–39. doi: 10.1056/NEJMoa1701488

17. Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med . (2004) 350(15):1495–504. doi: 10.1056/NEJMoa040583

18. Pedersen TR, Faergeman O, Kastelein JJP, Olsson AG, Tikkanen MJ, Holme I, et al. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial. JAMA . (2005) 294(19):2437–45. doi: 10.1001/jama.294.19.2437

19. LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart JC, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med . (2005) 352(14):1425–35. doi: 10.1056/NEJMoa050461

20. Sampson M, Ling C, Sun Q, Harb R, Ashmaig M, Warnick R, et al. A new equation for calculation of low-density lipoprotein cholesterol in patients with normolipidemia and/or hypertriglyceridemia. JAMA Cardiol . (2020) 5(5):540–8. doi: 10.1001/jamacardio.2020.0013

21. Walldius G, Jungner I, Holme I, Aastveit AH, Kolar W, Steiner E. High apolipoprotein B, low apolipoprotein A-I, and improvement in the prediction of fatal myocardial infarction (AMORIS study): a prospective study. Lancet . (2001) 358(9298):2026–33. doi: 10.1016/S0140-6736(01)07098-2

22. Vallejo-Vaz AJ, Fayyad R, Boekholdt SM, Hovingh GK, Kastelein JJ, Melamed S, et al. Triglyceride-rich lipoprotein cholesterol and risk of cardiovascular events among patients receiving statin therapy in the TNT trial. Circulation . (2018) 138(8):770–81. doi: 10.1161/CIRCULATIONAHA.117.032318

23. Joshi PH, Khokhar AA, Massaro JM, Lirette ST, Griswold ME, Martin SS, et al. Remnant lipoprotein cholesterol and incident coronary heart disease: the Jackson heart and Framingham offspring cohort studies. J Am Heart Assoc . (2016) 5(5):e002765. doi: 10.1161/JAHA.115.002765

24. Ference BA, Kastelein JJP, Ray KK, Ginsberg HN, Chapman MJ, Packard CJ, et al. Association of triglyceride-lowering LPL variants and LDL-C–lowering LDLR variants with risk of coronary heart disease. JAMA . (2019) 321(4):364. doi: 10.1001/jama.2018.20045

25. Soran H, France MW, Kwok S, Dissanayake S, Charlton-Menys V, Younis NN, et al. Apolipoprotein B100 is a better treatment target than calculated LDL and non-HDL cholesterol in statin-treated patients. Ann Clin Biochem . (2011) 48(Pt 6):566–71. doi: 10.1258/acb.2011.010277

26. Quispe R, Martin SS, Michos ED, Lamba I, Blumenthal RS, Saeed A, et al. Remnant cholesterol predicts cardiovascular disease beyond LDL and ApoB: a primary prevention study. Eur Heart J . (2021) 42(42):4324–32. doi: 10.1093/eurheartj/ehab432

27. Björnson E, Adiels M, Taskinen MR, Burgess S, Rawshani A, Borén J, et al. Triglyceride-rich lipoprotein remnants, low-density lipoproteins, and risk of coronary heart disease: a UK biobank study. Eur Heart J . (2023) 44(39):4186–95. doi: 10.1093/eurheartj/ehad337

28. Bea AM, Cenarro A, Marco-Bened V, Laclaustra M, Martn C, Ibarretxe D, et al. Diagnosis of familial dysbetalipoproteinemia based on the lipid abnormalities driven by APOE2/E2 genotype. Clin Chem . (2023) 69(2):140–8. doi: 10.1093/clinchem/hvac213

29. de Graaf J, Hendriks JC, Demacker PN, Stalenhoef AF. Identification of multiple dense LDL subfractions with enhanced susceptibility to in vitro oxidation among hypertriglyceridemic subjects. Normalization after clofibrate treatment. Arterioscler Thromb . (1993) 13(5):712–9. doi: 10.1161/01.ATV.13.5.712

30. Durrington PN, Mackness MI, Bhatnagar D, Julier K, Prais H, Arrol S, et al. Effects of two different fibric acid derivatives on lipoproteins, cholesteryl ester transfer, fibrinogen, plasminogen activator inhibitor and paraoxonase activity in type IIb hyperlipoproteinaemia. Atherosclerosis . (1998) 138(1):217–25. doi: 10.1016/S0021-9150(98)00003-3

31. Charlton-Menys V, Durrington P. Apolipoproteins AI and B as therapeutic targets. J Intern Med . (2006) 259(5):462–72. doi: 10.1111/j.1365-2796.2006.01646.x

32. Durrington PN, Bhatnagar D, Mackness MI, Morgan J, Julier K, Khan MA, et al. An omega-3 polyunsaturated fatty acid concentrate administered for one year decreased triglycerides in simvastatin treated patients with coronary heart disease and persisting hypertriglyceridaemia. Heart . (2001) 85(5):544–8. doi: 10.1136/heart.85.5.544

33. Durrington PN. Triglycerides are more important in atherosclerosis than epidemiology has suggested. Atherosclerosis . (1998) 141 Suppl:S57–62. doi: 10.1016/S0021-9150(98)00219-6

Crossref Full Text | Google Scholar

34. Soran H, Adam S, Ho JH, Durrington PN. The Reaven syndrome: an historical perspective. Diab Vasc Dis Res . (2019) 16(2):116–7. doi: 10.1177/1479164119828899

35. Langlois MR, Sniderman AD. Non-HDL cholesterol or apoB: which to prefer as a target for the prevention of atherosclerotic cardiovascular disease? Curr Cardiol Rep . (2020) 22(8):67. doi: 10.1007/s11886-020-01323-z

36. Ballantyne CM, Pitt B, Loscalzo J, Cain VA, Raichlen JS. Alteration of relation of atherogenic lipoprotein cholesterol to apolipoprotein B by intensive statin therapy in patients with acute coronary syndrome [from the limiting UNdertreatment of lipids in ACS with rosuvastatin (LUNAR) trial]. Am J Cardiol . (2013) 111(4):506–9. doi: 10.1016/j.amjcard.2012.10.037

37. Patel RS, Pasea L, Soran H, Downie P, Jones R, Hingorani AD, et al. Elevated plasma triglyceride concentration and risk of adverse clinical outcomes in 1.5 million people: a CALIBER linked electronic health record study. Cardiovasc Diabetol . (2022) 21(1):102. doi: 10.1186/s12933-022-01525-5

38. Bashir B, Ho JH, Downie P, Hamilton P, Ferns G, Datta D, et al. Severe hypertriglyceridaemia and chylomicronaemia syndrome—causes, clinical presentation, and therapeutic options. Metabolites . (2023) 13(5):621. doi: 10.3390/metabo13050621

39. Langlois MR, Nordestgaard BG, Langsted A, Chapman MJ, Aakre KM, Baum H, et al. Quantifying atherogenic lipoproteins for lipid-lowering strategies: consensus-based recommendations from EAS and EFLM. Clin Chem Lab Med. (2020) 58(4):496–517. doi: 10.1515/cclm-2019-1253

40. Catapano AL, Graham I, De Backer G, Wiklund O, Chapman MJ, Drexel H, et al. 2016 ESC/EAS guidelines for the management of dyslipidaemias. Eur Heart J . (2016) 37(39):2999–3058. doi: 10.1093/eurheartj/ehw272

41. Virani SS, Morris PB, Agarwala A, Ballantyne CM, Birtcher KK, Kris-Etherton PM, et al. 2021 ACC expert consensus decision pathway on the management of ASCVD risk reduction in patients with persistent hypertriglyceridemia: a report of the American College of Cardiology solution set oversight committee. J Am Coll Cardiol . (2021) 78(9):960–93. doi: 10.1016/j.jacc.2021.06.011

42. Berglund L, Brunzell JD, Goldberg AC, Goldberg IJ, Sacks F, Murad MH, et al. Evaluation and treatment of hypertriglyceridemia: an endocrine society clinical practice guideline. J Clin Endocrinol Metab . (2012) 97(9):2969–89. doi: 10.1210/jc.2011-3213

43. Ginsberg HN, Packard CJ, Chapman MJ, Borén J, Aguilar-Salinas CA, Averna M, et al. Triglyceride-rich lipoproteins and their remnants: metabolic insights, role in atherosclerotic cardiovascular disease, and emerging therapeutic strategies-a consensus statement from the European Atherosclerosis Society. Eur Heart J. (2021) 42(47):4791–806. doi: 10.1093/eurheartj/ehab551

44. Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association task force on practice guidelines. J Am Coll Cardiol . (2014) 63(25 Pt B):2889–934. doi: 10.1016/j.jacc.2013.11.002

45. Bansal S, Buring JE, Rifai N, Mora S, Sacks FM, Ridker PM. Fasting compared with nonfasting triglycerides and risk of cardiovascular events in women. JAMA . (2007) 298(3):309–16. doi: 10.1001/jama.298.3.309

46. Langsted A, Nordestgaard BG. Nonfasting lipids, lipoproteins, and apolipoproteins in individuals with and without diabetes: 58,434 individuals from the Copenhagen general population study. Clin Chem . (2011) 57(3):482–9. doi: 10.1373/clinchem.2010.157164

47. Boquist S, Ruotolo G, Tang R, Björkegren J, Bond MG, de Faire U, et al. Alimentary lipemia, postprandial triglyceride-rich lipoproteins, and common carotid intima-media thickness in healthy, middle-aged men. Circulation . (1999) 100(7):723–8. doi: 10.1161/01.CIR.100.7.723

48. Teno S, Uto Y, Nagashima H, Endoh Y, Iwamoto Y, Omori Y, et al. Association of postprandial hypertriglyceridemia and carotid intima-media thickness in patients with type 2 diabetes. Diabetes Care . (2000) 23(9):1401–6. doi: 10.2337/diacare.23.9.1401

49. White KT, Moorthy MV, Akinkuolie AO, Demler O, Ridker PM, Cook NR, et al. Identifying an optimal cutpoint for the diagnosis of hypertriglyceridemia in the nonfasting state. Clin Chem . (2015) 61(9):1156–63. doi: 10.1373/clinchem.2015.241752

50. Mora S, Chang CL, Moorthy MV, Sever PS. Association of nonfasting vs fasting lipid levels with risk of Major coronary events in the anglo-scandinavian cardiac outcomes trial-lipid lowering arm. JAMA Intern Med . (2019) 179(7):898–905. doi: 10.1001/jamainternmed.2019.0392

51. Zilversmit DB. Atherogenesis: a postprandial phenomenon. Circulation . (1979) 60(3):473–85. doi: 10.1161/01.CIR.60.3.473

52. Groot PH, van Stiphout WA, Krauss XH, Jansen H, van Tol A, van Ramshorst E, et al. Postprandial lipoprotein metabolism in normolipidemic men with and without coronary artery disease. Arterioscler Thromb . (1991) 11(3):653–62. doi: 10.1161/01.ATV.11.3.653

53. Ginsberg HN, Jones J, Blaner WS, Thomas A, Karmally W, Fields L, et al. Association of postprandial triglyceride and retinyl palmitate responses with newly diagnosed exercise-induced myocardial ischemia in middle-aged men and women. Arterioscler Thromb Vasc Biol . (1995) 15(11):1829–38. doi: 10.1161/01.ATV.15.11.1829

54. Karpe F, de Faire U, Mercuri M, Gene Bond M, Hellénius ML, Hamsten A. Magnitude of alimentary lipemia is related to intima-media thickness of the common carotid artery in middle-aged men. Atherosclerosis . (1998) 141(2):307–14. doi: 10.1016/S0021-9150(98)00184-1

55. Peng J, Luo F, Ruan G, Peng R, Li X. Hypertriglyceridemia and atherosclerosis. Lipids Health Dis . (2017) 16(1):233. doi: 10.1186/s12944-017-0625-0

56. Toth PP. Triglycerides and atherosclerosis: bringing the association into sharper focus. J Am Coll Cardiol . (2021) 77:3042–5. doi: 10.1016/j.jacc.2021.04.058

57. Ghosh A, Gao L, Thakur A, Siu PM, Lai CWK. Role of free fatty acids in endothelial dysfunction. J Biomed Sci . (2017) 24(1):50. doi: 10.1186/s12929-017-0357-5

58. Kwaifa IK, Bahari H, Yong YK, Noor SM. Endothelial dysfunction in obesity-induced inflammation: molecular mechanisms and clinical implications. Biomolecules . (2020) 10(2). doi: 10.3390/biom10020291

59. Sena CM. Endothelial dysfunction in type 2 diabetes: targeting inflammation. In: Carrilho F, editor. Rijeka: IntechOpen (2018). p. 10.

60. Wilck N, Ludwig A. Targeting the ubiquitin-proteasome system in atherosclerosis: status quo, challenges, and perspectives. Antioxid Redox Signal . (2014) 21(17):2344–63. doi: 10.1089/ars.2013.5805

61. Basu D, Bornfeldt KE. Hypertriglyceridemia and atherosclerosis: using human research to guide mechanistic studies in animal models. Front Endocrinol (Lausanne) . (2020) 11:504. doi: 10.3389/fendo.2020.00504

62. Pal S, Semorine K, Watts GF, Mamo J. Identification of lipoproteins of intestinal origin in human atherosclerotic plaque. Clin Chem Lab Med . (2003) 41(6):792–5. doi: 10.1515/CCLM.2003.120

63. Nakano T, Nakajima K, Niimi M, Fujita MQ, Nakajima Y, Takeichi S, et al. Detection of apolipoproteins B-48 and B-100 carrying particles in lipoprotein fractions extracted from human aortic atherosclerotic plaques in sudden cardiac death cases. Clin Chim Acta . (2008) 390(1–2):38–43. doi: 10.1016/j.cca.2007.12.012

64. Nordestgaard BG, Benn M, Schnohr P, Tybjaerg-Hansen A. Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. JAMA . (2007) 298(3):299–308. doi: 10.1001/jama.298.3.299

65. Freiberg JJ, Tybjaerg-Hansen A, Jensen JS, Nordestgaard BG. Nonfasting triglycerides and risk of ischemic stroke in the general population. JAMA . (2008) 300(18):2142–52. doi: 10.1001/jama.2008.621

66. Hokanson JE, Austin MA. Plasma triglyceride level is a risk factor for cardiovascular disease independent of high-density lipoprotein cholesterol level: a meta-analysis of population-based prospective studies. J Cardiovasc Risk . (1996) 3(2):213–9. doi: 10.1097/00043798-199604000-00014

67. Patel A, Barzi F, Jamrozik K, Lam TH, Ueshima H, Whitlock G, et al. Serum triglycerides as a risk factor for cardiovascular diseases in the Asia-pacific region. Circulation . (2004) 110(17):2678–86. doi: 10.1161/01.CIR.0000145542.24347.18

68. Jónsdóttir LS, Sigfússon N, Gudnason V, Sigvaldason H, Thorgeirsson G. Do lipids, blood pressure, diabetes, and smoking confer equal risk of myocardial infarction in women as in men? The Reykjavik study. J Cardiovasc Risk . (2002) 9(2):67–76. doi: 10.1097/00043798-200204000-00001

69. Sarwar N, Danesh J, Eiriksdottir G, Sigurdsson G, Wareham N, Bingham S, et al. Triglycerides and the risk of coronary heart disease: 10,158 incident cases among 262,525 participants in 29 western prospective studies. Circulation . (2007) 115(4):450–8. doi: 10.1161/CIRCULATIONAHA.106.637793

70. Nichols GA, Philip S, Reynolds K, Granowitz CB, Fazio S. Increased residual cardiovascular risk in patients with diabetes and high versus normal triglycerides despite statin-controlled LDL cholesterol. Diabetes Obes Metab . (2019) 21(2):366–71. doi: 10.1111/dom.13537

71. Arca M, Veronesi C, D’Erasmo L, Borghi C, Colivicchi F, De Ferrari GM, et al. Association of hypertriglyceridemia with all-cause mortality and atherosclerotic cardiovascular events in a low-risk Italian population: the TG-REAL retrospective cohort analysis. J Am Heart Assoc . (2020) 9(19):e015801. doi: 10.1161/JAHA.119.015801

72. Lee H, Park JB, Hwang IC, Yoon YE, Park HE, Choi SY, et al. Association of four lipid components with mortality, myocardial infarction, and stroke in statin-naïve young adults: a nationwide cohort study. Eur J Prev Cardiol . (2020) 27(8):870–81. doi: 10.1177/2047487319898571

73. Després JP, Moorjani S, Tremblay A, Ferland M, Lupien PJ, Nadeau A, et al. Relation of high plasma triglyceride levels associated with obesity and regional adipose tissue distribution to plasma lipoprotein-lipid composition in premenopausal women. Clin Invest Med . (1989) 12(6):374–80. PMID: 2612090

PubMed Abstract | Google Scholar

74. Quispe R, Manalac RJ, Faridi KF, Blaha MJ, Toth PP, Kulkarni KR, et al. Relationship of the triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio to the remainder of the lipid profile: the very large database of lipids-4 (VLDL-4) study. Atherosclerosis . (2015) 242(1):243–50. doi: 10.1016/j.atherosclerosis.2015.06.057

75. Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L, et al. 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J . (2020) 41(1):111–88. doi: 10.1093/eurheartj/ehz455

76. Rana JS, Liu JY, Moffet HH, Solomon MD, Go AS, Jaffe MG, et al. Metabolic dyslipidemia and risk of coronary heart disease in 28,318 adults with diabetes Mellitus and low-density lipoprotein cholesterol <100 mg/dl. Am J Cardiol . (2015) 116(11):1700–4. doi: 10.1016/j.amjcard.2015.08.039

77. Varbo A, Benn M, Tybjærg-Hansen A, Jørgensen AB, Frikke-Schmidt R, Nordestgaard BG. Remnant cholesterol as a causal risk factor for ischemic heart disease. J Am Coll Cardiol . (2013) 61(4):427–36. doi: 10.1016/j.jacc.2012.08.1026

78. Do R, Willer CJ, Schmidt EM, Sengupta S, Gao C, Peloso GM, et al. Common variants associated with plasma triglycerides and risk for coronary artery disease. Nat Genet . (2013) 45(11):1345–52. doi: 10.1038/ng.2795

79. Sarwar N, Sandhu MS. Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies. Lancet . (2010) 375(9726):1634–9. doi: 10.1016/S0140-6736(10)60545-4

80. Rosenson RS, Davidson MH, Hirsh BJ, Kathiresan S, Gaudet D. Genetics and causality of triglyceride-rich lipoproteins in atherosclerotic cardiovascular disease. J Am Coll Cardiol . (2014) 64(23):2525–40. doi: 10.1016/j.jacc.2014.09.042 doi: 10.1126/science.1161524

81. Pollin TI, Damcott CM, Shen H, Ott SH, Shelton J, Horenstein RB, et al. A null mutation in human APOC3 confers a favorable plasma lipid profile and apparent cardioprotection. Science (1979) . (2008) 322(5908):1702–5. doi: 10.1126/science.1161524

82. Tada H, Kawashiri MA, Nomura A, Yoshimura K, Itoh H, Komuro I, et al. Serum triglycerides predict first cardiovascular events in diabetic patients with hypercholesterolemia and retinopathy. Eur J Prev Cardiol . (2018) 25(17):1852–60. doi: 10.1177/2047487318796989

83. Murphy SA, Pedersen TR, Gaciong ZA, Ceska R, Ezhov MV, Connolly DL, et al. Effect of the PCSK9 inhibitor evolocumab on total cardiovascular events in patients with cardiovascular disease: a prespecified analysis from the FOURIER trial. JAMA Cardiol . (2019) 4(7):613–9. doi: 10.1001/jamacardio.2019.0886

84. Giugliano RP, Pedersen TR, Park JG, de Ferrari GM, Gaciong ZA, Ceska R, et al. Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial. Lancet . (2017) 390(10106):1962–71. doi: 10.1016/S0140-6736(17)32290-0

85. Hagström E, Steg PG, Szarek M, Bhatt DL, Bittner VA, Danchin N, et al. Apolipoprotein B, residual cardiovascular risk after acute coronary syndrome, and effects of alirocumab. Circulation . (2022) 146(9):657–72. doi: 10.1161/CIRCULATIONAHA.121.057807

86. Nicholls SJ, Puri R, Anderson T, Ballantyne CM, Cho L, Kastelein JJP, et al. Effect of evolocumab on progression of coronary disease in statin-treated patients: the GLAGOV randomized clinical trial. JAMA . (2016) 316(22):2373–84. doi: 10.1001/jama.2016.16951

87. Puri R, Nissen SE, Shao M, Elshazly MB, Kataoka Y, Kapadia SR, et al. Non-HDL cholesterol and triglycerides. Arterioscler Thromb Vasc Biol . (2016) 36(11):2220–8. doi: 10.1161/ATVBAHA.116.307601

88. Pradhan AD, Aday AW, Rose LM, Ridker PM. Residual inflammatory risk on treatment with PCSK9 inhibition and statin therapy. Circulation . (2018) 138(2):141–9. doi: 10.1161/CIRCULATIONAHA.118.034645

89. Varbo A, Benn M, Tybjærg-Hansen A, Nordestgaard BG. Elevated remnant cholesterol causes both low-grade inflammation and ischemic heart disease, whereas elevated low-density lipoprotein cholesterol causes ischemic heart disease without inflammation. Circulation . (2013) 128(12):1298–309. doi: 10.1161/CIRCULATIONAHA.113.003008

90. The Coronory Drugy Project Research Group. Clofibrate and niacin in coronary heart disease. JAMA . (1975) 231(4):360–81. doi: 10.1001/jama.1975.03240160024021

91. Report from the Committee of Principal Investigators. A co-operative trial in the primary prevention of ischaemic heart disease using clofibrate. Heart . (1978) 40:1069–118. doi: 10.1136/hrt.40.10.1069

92. Frick MH, Elo O, Haapa K, Heinonen OP, Heinsalmi P, Helo P, et al. Helsinki heart study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. N Engl J Med . (1987) 317(20):1237–45. doi: 10.1056/NEJM198711123172001

93. Robins SJ, Collins D, Wittes JT, Papademetriou V, Deedwania PC, Schaefer EJ, et al. Relation of gemfibrozil treatment and lipid levels with major coronary events: VA-HIT: a randomized controlled trial. JAMA . (2001) 285(12):1585–91. doi: 10.1001/jama.285.12.1585

94. Bezafibrate Infarction Prevention (BIP) study. Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease. Circulation . (2000) 102(1):21–7. doi: 10.1161/01.CIR.102.1.21

95. Diabetes Atherosclerosis Intervention Study Investigators. Effect of fenofibrate on progression of coronary-artery disease in type 2 diabetes: the diabetes atherosclerosis intervention study, a randomised study. Lancet . (2001) 357(9260):905–10. doi: 10.1016/S0140-6736(00)04209-4

96. Meade T, Zuhrie R, Cook C, Cooper J. Bezafibrate in men with lower extremity arterial disease: randomised controlled trial. Br Med J . (2002) 325(7373):1139. doi: 10.1136/bmj.325.7373.1139

97. Keech A, Simes RJ, Barter P, Best J, Scott R, Taskinen MR, et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9,795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet . (2005) 366(9500):1849–61. doi: 10.1016/S0140-6736(05)67667-2

98. The ACCORD Study Group. Effects of combination lipid therapy in type 2 diabetes Mellitus. N Engl J Med . (2010) 362(17):1563–74. doi: 10.1056/NEJMoa1001282

99. Das Pradhan A, Glynn RJ, Fruchart JC, MacFadyen JG, Zaharris ES, Everett BM, et al. Triglyceride lowering with pemafibrate to reduce cardiovascular risk. N Engl J Med . (2022) 387(21):1923–34. doi: 10.1056/NEJMoa2210645

100. GISSI-Prevenzione Investigators. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-prevenzione trial. Lancet . (1999) 354(9177):447–55. doi: 10.1016/S0140-6736(99)07072-5

101. Yokoyama M, Origasa H, Matsuzaki M, Matsuzawa Y, Saito Y, Ishikawa Y, et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet . (2007) 369(9567):1090–8. doi: 10.1016/S0140-6736(07)60527-3

102. GISSI-HF Investigators. Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet . (2008) 372(9645):1223–30. doi: 10.1016/S0140-6736(08)61239-8

103. Kromhout D, Giltay EJ, Geleijnse JM. N–3 fatty acids and cardiovascular events after myocardial infarction. N Engl J Med . (2010) 363(21):2015–26. doi: 10.1056/NEJMoa1003603

104. Rauch B, Schiele R, Schneider S, Diller F, Victor N, Gohlke H, et al. OMEGA, a randomized, placebo-controlled trial to test the effect of highly purified Omega-3 fatty acids on top of modern guideline-adjusted therapy after myocardial infarction. Circulation . (2010) 122(21):2152–9. doi: 10.1161/CIRCULATIONAHA.110.948562

105. Galan P, Kesse-Guyot E, Czernichow S, Briancon S, Blacher J, Hercberg S. Effects of B vitamins and omega 3 fatty acids on cardiovascular diseases: a randomised placebo controlled trial. Br Med J . (2010) 341:c6273. doi: 10.1136/bmj.c6273

106. The ORIGIN Trial Investigators. N–3 fatty acids and cardiovascular outcomes in patients with dysglycemia. N Engl J Med . (2012) 367(4):309–18. doi: 10.1056/NEJMoa1203859

107. Writing Group for the AREDS2 Research Group. Effect of long-chain ω-3 fatty acids and lutein+zeaxanthin supplements on cardiovascular outcomes: results of the age-related eye disease study 2 (AREDS2) randomized clinical trial. JAMA Intern Med . (2014) 174(5):763–71. doi: 10.1001/jamainternmed.2014.328

108. The Risk and Prevention Study Collaborative Group. N–3 fatty acids in patients with multiple cardiovascular risk factors. N Engl J Med . (2013) 368(19):1800–8. doi: 10.1056/NEJMoa1205409

109. The ASCEND Study Collaborative Group. Effects of n−3 fatty acid supplements in diabetes mellitus. N Engl J Med . (2018) 379(16):1540–50. doi: 10.1056/NEJMoa1804989

110. Manson JE, Cook NR, Lee IM, Christen W, Bassuk SS, Mora S, et al. Marine n−3 fatty acids and prevention of cardiovascular disease and cancer. N Engl J Med . (2018) 380(1):23–32. doi: 10.1056/NEJMoa1811403

111. Bhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA, Ketchum SB, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med . (2018) 380(1):11–22. doi: 10.1056/NEJMoa1812792

112. Nicholls SJ, Lincoff AM, Garcia M, Bash D, Ballantyne CM, Barter PJ, et al. Effect of high-dose omega-3 fatty acids vs corn oil on major adverse cardiovascular events in patients at high cardiovascular risk: the STRENGTH randomized clinical trial. JAMA . (2020) 324(22):2268–80. doi: 10.1001/jama.2020.22258

113. Esposito K, Marfella R, Ciotola M, Di Palo C, Giugliano F, Giugliano G, et al. Effect of a Mediterranean-style diet on endothelial dysfunction and markers of vascular inflammation in the metabolic syndrome. JAMA . (2004) 292(12):1440. doi: 10.1001/jama.292.12.1440

114. Georgoulis M, Chrysohoou C, Georgousopoulou E, Damigou E, Skoumas I, Pitsavos C, et al. Long-term prognostic value of LDL-C, HDL-C, lp(a) and TG levels on cardiovascular disease incidence, by body weight status, dietary habits and lipid-lowering treatment: the ATTICA epidemiological cohort study (2002–2012). Lipids Health Dis . (2022) 21(1):141. doi: 10.1186/s12944-022-01747-2

115. Mateo-Gallego R, Marco-Benedí V, Perez-Calahorra S, Bea AM, Baila-Rueda L, Lamiquiz-Moneo I, et al. Energy-restricted, high-protein diets more effectively impact cardiometabolic profile in overweight and obese women than lower-protein diets. Clin Nutr . (2017) 36(2):371–9. doi: 10.1016/j.clnu.2016.01.018

116. Kaur G, Mason RP, Steg PG, Bhatt DL. Omega-3 fatty acids for cardiovascular event lowering. Eur J Prev Cardiol . (2024) 31(8):1005–14. doi: 10.1093/eurjpc/zwae003

117. Bashir B, Iqbal Z, Schofield J, Soran H. In: Krents AJ, Chilton RJ, editors. Cardiovascular Endocrinology & Metabolism Theory and Practice of Cardiometabolic Medicine . 1st ed. Stacy Masucci (2023). p. 97–135.

118. Alhassan A, Young J, Lean MEJ, Lara J. Consumption of fish and vascular risk factors: a systematic review and meta-analysis of intervention studies. Atherosclerosis . (2017) 266:87–94. doi: 10.1016/j.atherosclerosis.2017.09.028

119. Rumawas ME, Meigs JB, Dwyer JT, McKeown NM, Jacques PF. Mediterranean-style dietary pattern, reduced risk of metabolic syndrome traits, and incidence in the Framingham offspring cohort. Am J Clin Nutr . (2009) 90(6):1608–14. doi: 10.3945/ajcn.2009.27908

120. The AIM-HIGH Investigators. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med . (2011) 365(24):2255–67. doi: 10.1056/NEJMoa1107579

121. HPS2-THRIVE Collaborative Group. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med . (2014) 371(3):203–12. doi: 10.1056/NEJMoa1300955

122. D’Andrea E, Hey SP, Ramirez CL, Kesselheim AS. Assessment of the role of niacin in managing cardiovascular disease outcomes. JAMA Netw Open . (2019) 2(4):e192224. doi: 10.1001/jamanetworkopen.2019.2224

123. Schoonjans K, Staels B, Auwerx J. Role of the peroxisome proliferator-activated receptor (PPAR) in mediating the effects of fibrates and fatty acids on gene expression. J Lipid Res . (1996) 37(5):907–25. doi: 10.1016/S0022-2275(20)42003-6

124. Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines. Circulation . (2019) 139(25):e1082–143. doi: 10.1016/j.jacc.2018.11.003

125. Oliver M. The clofibrate saga: a retrospective commentary. Br J Clin Pharmacol . (2012) 74(6):907–10. doi: 10.1111/j.1365-2125.2012.04282.x

126. Cottet J, Mathivat A, Redel J. Therapeutic study of a synthetic hypocholesterolemic agent: phenyl-ethyl-acetic acid. Presse Med . (1954) 62(44):939–41. PMID: 13194567

127. Rubins HB, Robins SJ, Collins D, Fye CL, Anderson JW, Elam MB, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans affairs high-density lipoprotein cholesterol intervention trial study group. N Engl J Med . (1999) 341(6):410–8. doi: 10.1056/NEJM199908053410604

128. Manninen V, Tenkanen L, Koskinen P, Huttunen JK, Mänttäri M, Heinonen OP, et al. Joint effects of serum triglyceride and LDL cholesterol and HDL cholesterol concentrations on coronary heart disease risk in the Helsinki heart study. Implications for treatment. Circulation . (1992) 85(1):37–45. doi: 10.1161/01.CIR.85.1.37

129. Lee M, Saver JL, Towfighi A, Chow J, Ovbiagele B. Efficacy of fibrates for cardiovascular risk reduction in persons with atherogenic dyslipidemia: a meta-analysis. Atherosclerosis . (2011) 217(2):492–8. doi: 10.1016/j.atherosclerosis.2011.04.020

130. Bruckert E, Labreuche J, Deplanque D, Touboul PJ, Amarenco P. Fibrates effect on cardiovascular risk is greater in patients with high triglyceride levels or atherogenic dyslipidemia profile: a systematic review and meta-analysis. J Cardiovasc Pharmacol . (2011) 57(2):267–72. doi: 10.1097/FJC.0b013e318202709f

131. Keech AC, Mitchell P, Summanen PA, O’Day J, Davis TME, Moffitt MS, et al. Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial. Lancet . (2007) 370(9600):1687–97. doi: 10.1016/S0140-6736(07)61607-9

132. Emmerich KH, Poritis N, Stelmane I, Klindzane M, Erbler H, Goldsteine J, et al. Wirksamkeit und sicherheit von etofibrat bei patienten mit nicht proliferativer diabetischer retinopathie. Klin Monbl Augenheilkd . (2009) 226(07):561–7. doi: 10.1055/s-0028-1109516

133. Yamashita S, Masuda D, Matsuzawa Y. Pemafibrate, a new selective PPARα modulator: drug concept and its clinical applications for dyslipidemia and metabolic diseases. Curr Atheroscler Rep . (2020) 22(1):5. doi: 10.1007/s11883-020-0823-5

134. Humbert X, Dolladille C, Sassier M, Valnet-Rabier MB, Vial T, Guitton E, et al. Fibrates et risques thrombo-emboliques veineux: étude cas/non-cas dans la base nationale de pharmacovigilance. Therapies . (2017) 72(6):677–82. doi: 10.1016/j.therap.2017.07.002

135. Squizzato A, Galli M, Romualdi E, Dentali F, Kamphuisen PW, Guasti L, et al. Statins, fibrates, and venous thromboembolism: a meta-analysis. Eur Heart J . (2010) 31(10):1248–56. doi: 10.1093/eurheartj/ehp556

136. Delluc A, Tromeur C, le Moigne E, Nowak E, Mottier D, le Gal G, et al. Lipid lowering drugs and the risk of recurrent venous thromboembolism. Thromb Res . (2012) 130(6):859–63. doi: 10.1016/j.thromres.2012.08.296

137. Lacut K, le Gal G, Abalain JH, Mottier D, Oger E. Differential associations between lipid-lowering drugs, statins and fibrates, and venous thromboembolism: role of drug induced homocysteinemia? Thromb Res . (2008) 122(3):314–9. doi: 10.1016/j.thromres.2007.10.014

138. Kim KA, Kim NJ, Choo EH. The effect of fibrates on lowering low-density lipoprotein cholesterol and cardiovascular risk reduction: a systemic review and meta-analysis. Eur J Prev Cardiol . (2024) 31(3):291–301. doi: 10.1093/eurjpc/zwad331

139. Abourbih S, Filion KB, Joseph L, Schiffrin EL, Rinfret S, Poirier P, et al. Effect of fibrates on lipid profiles and cardiovascular outcomes: a systematic review. Am J Med . (2009) 122(10):962.e1–e8. doi: 10.1016/j.amjmed.2009.03.030

140. Koh KK, Quon MJ, Han SH, Chung WJ, Ahn JY, Seo YH, et al. Additive beneficial effects of fenofibrate combined with atorvastatin in the treatment of combined hyperlipidemia. J Am Coll Cardiol . (2005) 45(10):1649–53. doi: 10.1016/j.jacc.2005.02.052

141. Yamashita S, Hirano T, Shimano H, Tsukamoto K, Yoshida M, Yoshida H. Managing hypertriglyceridemia for cardiovascular disease prevention: lessons from the PROMINENT trial. Eur J Clin Invest . (2024). doi: 10.1111/eci.14227. [Epub ahead of print]38662591

142. Hirano T, Ito Y. The influence of triglycerides on small dense low-density lipoprotein cholesterol levels is attenuated in low low-density lipoprotein-cholesterol range: implications for the negative results of the PROMINENT trial. J Diabetes Investig . (2023) 14(7):902–6. doi: 10.1111/jdi.14013

143. Bang HO, Dyerberg J, Nielsen AB. Plasma lipid and lipoprotein pattern in Greenlandic West-Coast Eskimos. Lancet . (1971) 297(7710):1143–6. doi: 10.1016/S0140-6736(71)91658-8

144. Borow KM, Nelson JR, Mason RP. Biologic plausibility, cellular effects, and molecular mechanisms of eicosapentaenoic acid (EPA) in atherosclerosis. Atherosclerosis . (2015) 242(1):357–66. doi: 10.1016/j.atherosclerosis.2015.07.035

145. Jacobs ML, Faizi HA, Peruzzi JA, Vlahovska PM, Kamat NP. EPA And DHA differentially modulate membrane elasticity in the presence of cholesterol. Biophys J . (2021) 120(11):2317–29. doi: 10.1016/j.bpj.2021.04.009

146. Mason RP, Sherratt SCR, Jacob RF. Eicosapentaenoic acid inhibits oxidation of ApoB-containing lipoprotein particles of different size in vitro when administered alone or in combination with atorvastatin active metabolite compared with other triglyceride-lowering agents. J Cardiovasc Pharmacol . (2016) 68(1):33–40. doi: 10.1097/FJC.0000000000000379

147. Sherratt SCR, Mason RP. Eicosapentaenoic acid and docosahexaenoic acid have distinct membrane locations and lipid interactions as determined by x-ray diffraction. Chem Phys Lipids . (2018) 212:73–9. doi: 10.1016/j.chemphyslip.2018.01.002

148. Le VT, Knight S, Watrous JD, Najhawan M, Dao K, Mccubrey RO, et al. Higher docosahexaenoic acid levels lower the protective impact of eicosapentaenoic acid on long-term major cardiovascular events. FrontCardiovasc Med . (2023) 10.

149. American College of Cardiology. RESPECT-EPA: Highly Purified EPA Appears to Reduce Risks of CV Events in Japanese CAD Patients on Statins [Internet]. (2022). [cited 2022 Dec 21]. Available online at: https://www.acc.org/Latest-in-Cardiology/Articles/2022/11/01/22/00/sun-7pm-respect-epa-aha-2022

150. Daida H. Randomized trial for evaluation in secondary prevention efficacy of combination therapy–statin and eicosapentaenoic acid—RESPECT-EPA. American Heart Association Scientific Sessions; November 6, 2022; Chicago, IL.

151. American College of Cardiology. REDUCE-IT EPA Trial Shows Association Between Higher EPA Levels, Reduced CV Events [Internet]. (2020). [cited 2022 Dec 21]. Available online at: https://www.acc.org/latest-in-cardiology/articles/2020/03/24/16/41/mon-1045-eicosapentaenoic-acid-levels-in-reduce-it-acc-2020

152. Chan DC, Watts GF, Ng TWK, Yamashita S, Barrett PHR. Effect of weight loss on markers of triglyceride-rich lipoprotein metabolism in the metabolic syndrome. Eur J Clin Invest . (2008) 38(10):743–51. doi: 10.1111/j.1365-2362.2008.02019.x

153. Wilding JPH, Batterham RL, Calanna S, Davies M, Van Gaal LF, Lingvay I, et al. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med . (2021) 384(11):989–1002. doi: 10.1056/NEJMoa2032183

154. Jastreboff AM, Aronne LJ, Ahmad NN, Wharton S, Connery L, Alves B, et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med . (2022) 387(3):205–16. doi: 10.1056/NEJMoa2206038

155. Bashir B, Adam S, Ho JH, Linn Z, Durrington PN, Soran H. Established and potential cardiovascular risk factors in metabolic syndrome: effect of bariatric surgery. Curr Opin Lipidol . (2023) 34(5):221–33. doi: 10.1097/MOL.0000000000000889

156. Sjöström CD, Lissner L, Wedel H, Sjöström L. Reduction in incidence of diabetes, hypertension and lipid disturbances after intentional weight loss induced by bariatric surgery: the SOS intervention study. Obes Res . (1999) 7(5):477–84. doi: 10.1002/j.1550-8528.1999.tb00436.x

157. Sjöström L, Narbro K, Sjöström CD, Karason K, Larsson B, Wedel H, et al. Effects of bariatric surgery on mortality in Swedish obese subjects. N Engl J Med . (2007) 357(8):741–52. doi: 10.1056/NEJMoa066254

158. Heffron SP, Parikh A, Volodarskiy A, Ren-Fielding C, Schwartzbard A, Nicholson J, et al. Changes in lipid profile of obese patients following contemporary bariatric surgery: a meta-analysis. Am J Med . (2016) 129(9):952–9. doi: 10.1016/j.amjmed.2016.02.004

159. Adam S, Liu Y, Siahmansur T, Ho JH, Dhage SS, Yadav R, et al. Bariatric surgery as a model to explore the basis and consequences of the Reaven hypothesis: small, dense low-density lipoprotein and interleukin-6. Diab Vasc Dis Res . (2019) 16(2):144–52. doi: 10.1177/1479164119826479

160. Azmi S, Ferdousi M, Liu Y, Adam S, Iqbal Z, Dhage S, et al. Bariatric surgery leads to an improvement in small nerve fibre damage in subjects with obesity. Int J Obes (Lond) . (2021) 45(3):631–8. doi: 10.1038/s41366-020-00727-9

161. Adam S, Ho JH, Liu Y, Siahmansur T, Siddals K, Iqbal Z, et al. Bariatric surgery-induced high-density lipoprotein functionality enhancement is associated with reduced inflammation. J Clin Endocrinol Metab . (2022) 107(8):2182–94. doi: 10.1210/clinem/dgac244

162. Yadav R, Hama S, Liu Y, Siahmansur T, Schofield J, Syed AA, et al. Effect of roux-en-Y bariatric surgery on lipoproteins, insulin resistance, and systemic and vascular inflammation in obesity and diabetes. Front Immunol . (2017) 8:1512. doi: 10.3389/fimmu.2017.01512

163. Brownrigg JRW, Hughes CO, Burleigh D, Karthikesalingam A, Patterson BO, Holt PJ, et al. Microvascular disease and risk of cardiovascular events among individuals with type 2 diabetes: a population-level cohort study. Lancet Diabetes Endocrinol . (2016) 4(7):588–97. doi: 10.1016/S2213-8587(16)30057-2

164. Azmi S, Ferdousi M, Liu Y, Adam S, Siahmansur T, Ponirakis G, et al. The role of abnormalities of lipoproteins and HDL functionality in small fibre dysfunction in people with severe obesity. Sci Rep . (2021) 11(1):12573. doi: 10.1038/s41598-021-90346-9

165. Iqbal Z, Bashir B, Ferdousi M, Kalteniece A, Alam U, Malik RA, et al. Lipids and peripheral neuropathy. Curr Opin Lipidol . (2021) 32(4):249–57. doi: 10.1097/MOL.0000000000000770

166. Adam S, Azmi S, Ho JH, Liu Y, Ferdousi M, Siahmansur T, et al. Improvements in diabetic neuropathy and nephropathy after bariatric surgery: a prospective cohort study. Obes Surg . (2021) 31(2):554–63. doi: 10.1007/s11695-020-05052-8

167. Reynolds EL, Watanabe M, Banerjee M, Chant E, Villegas-Umana E, Elafros MA, et al. The effect of surgical weight loss on diabetes complications in individuals with class II/III obesity. Diabetologia . (2023) 66(7):1192–207. doi: 10.1007/s00125-023-05899-3

168. The STABILITY Investigators. Darapladib for preventing ischemic events in stable coronary heart disease. N Engl J Med . (2014) 370(18):1702–11. doi: 10.1056/NEJMoa1315878

169. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med . (2017) 377(12):1119–31. doi: 10.1056/NEJMoa1707914

170. Ridker PM, Everett BM, Pradhan A, MacFadyen JG, Solomon DH, Zaharris E, et al. Low-dose methotrexate for the prevention of atherosclerotic events. N Engl J Med . (2018) 380(8):752–62. doi: 10.1056/NEJMoa1809798

171. Tardif JC, Kouz S, Waters DD, Bertrand OF, Diaz R, Maggioni AP, et al. Efficacy and safety of low-dose colchicine after myocardial infarction. N Engl J Med . (2019) 381(26):2497–505. doi: 10.1056/NEJMoa1912388

172. Nidorf SM, Fiolet ATL, Eikelboom JW, Schut A, Opstal TSJ, Bax WA, et al. The effect of low-dose colchicine in patients with stable coronary artery disease: the LoDoCo2 trial rationale, design, and baseline characteristics. Am Heart J. (2019) 218:46–56. doi: 10.1016/j.ahj.2019.09.011

173. Mega JL, Braunwald E, Wiviott SD, Bassand JP, Bhatt DL, Bode C, et al. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med . (2011) 366(1):9–19. doi: 10.1056/NEJMoa1112277

174. Eikelboom JW, Connolly SJ, Bosch J, Dagenais GR, Hart RG, Shestakovska O, et al. Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med . (2017) 377(14):1319–30. doi: 10.1056/NEJMoa1709118

175. Bonaca MP, Bhatt DL, Cohen M, Steg PG, Storey RF, Jensen EC, et al. Long-Term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med . (2015) 372(19):1791–800. doi: 10.1056/NEJMoa1500857

176. Steg PG, Bhatt DL, Simon T, Fox K, Mehta SR, Harrington RA, et al. Ticagrelor in patients with stable coronary disease and diabetes. N Engl J Med . (2019) 381(14):1309–20. doi: 10.1056/NEJMoa1908077

177. Clinicaltrial.gov. Assessing the Impact of Lipoprotein (a) Lowering With Pelacarsen (TQJ230) on Major Cardiovascular Events in Patients With CVD (Lp(a)HORIZON) [Internet]. (2022). [cited 2022 Dec 21]. Available online at: https://clinicaltrials.gov/ct2/show/NCT04023552

178. Clinicaltrials.gov. Effect of Lipoprotein(a) Elimination by Lipoprotein Apheresis on Cardiovascular Outcomes (MultiSELECt) [Internet]. (2022). [cited 2022 Dec 21]. Available online at: https://clinicaltrials.gov/ct2/show/NCT02791802

179. Clinicaltrials.gov. A Study of LY3473329 in Adult Participants With Elevated Lipoprotein(a) at High Risk for Cardiovascular Events (KRAKEN) [Internet]. (2022). [cited 2022 Dec 21]. Available online at: https://clinicaltrials.gov/ct2/show/NCT05563246

180. ClinicalTrials.gov. Olpasiran Trials of Cardiovascular Events and Lipoprotein(a) Reduction (OCEAN(a))—Outcomes Trial [Internet]. (2024). [cited 2024 Feb 8]. Available online at: https://clinicaltrials.gov/study/NCT05581303

181. The HPS3/TIMI55–REVEAL Collaborative Group. Effects of anacetrapib in patients with atherosclerotic vascular disease. N Engl J Med . (2017) 377(13):1217–27. doi: 10.1056/NEJMoa1706444

182. Clinicaltrials.gov. Study to Investigate CSL112 in Subjects With Acute Coronary Syndrome (AEGIS-II) [Internet]. (2022). [cited 2022 Dec 21]. Available online at: https://clinicaltrials.gov/ct2/show/NCT03473223

183. ClinicalTrials.gov. Cardiovascular Outcome Study to Evaluate the Effect of Obicetrapib in Patients With Cardiovascular Disease (PREVAIL) [Internet]. (2024). [cited 2024 Feb 8]. Available online at: https://clinicaltrials.gov/study/NCT05202509

Keywords: hypertriglyceridaemia, cardiovascular risk, fibrates, omega-3 fatty acids, statins, atherosclerosis, residual risk

Citation: Bashir B, Schofield J, Downie P, France M, Ashcroft DM, Wright AK, Romeo S, Gouni-Berthold I, Maan A, Durrington PN and Soran H (2024) Beyond LDL-C: unravelling the residual atherosclerotic cardiovascular disease risk landscape—focus on hypertriglyceridaemia. Front. Cardiovasc. Med. 11 :1389106. doi: 10.3389/fcvm.2024.1389106

Received: 20 February 2024; Accepted: 8 July 2024; Published: 7 August 2024.

Reviewed by:

© 2024 Bashir, Schofield, Downie, France, Ashcroft, Wright, Romeo, Gouni-Berthold, Maan, Durrington and Soran. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Handrean Soran, [email protected] ; [email protected]

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

• Store finder

Heart Matters

More than a magazine: information, inspiration and support

• Heart Matters magazine
• Information and support
• Behind the headlines
• Cholesterol levels and statins

Flawed cholesterol study makes headlines

A controversial study has argued that if you have a high LDL (bad) cholesterol level when you are aged over 60, you will live longer, there is no increased risk of cardiovascular disease and that statins will have little effect. But can we trust these bold claims?

The researchers, led by Dr Uffe Ravnskov at the University of Lund, Sweden, looked at 19 existing studies which considered the association between ‘bad’ LDL cholesterol levels and the overall risk of death in people aged over 60. They concluded that 92 percent of people with a high cholesterol level lived longer, and called for a re-evaluation of the guidelines for cardiovascular prevention , “in particular because the benefits from statin treatment have been exaggerated.”

Cholesterol is essential for your body to work, although too much ‘bad cholesterol’ (called low-density lipoprotein or LDL) can lead to fatty deposits building up in your arteries. These fatty deposits can increase your risk of developing conditions such as  coronary heart disease ,  heart attack   and  stroke .

Statins are drugs that lower your body’s cholesterol level. They work by reducing the production of cholesterol in the liver and therefore reduce your risk of heart disease. 

Reliable research?

The total number of people involved in the study was nearly 70,000, but only 9 of the 19 studies actually included deaths from heart and circulatory disease.

Moreover, two-thirds of the total number of participants in this new analysis are from one study ( Bathum et al 2013 ). This study found that higher cholesterol (total, HDL, or LDL) in people aged 50+ was associated with a lower all-cause mortality.   That study also showed that taking a statin prescription provided a significant survival benefit, regardless of age, whereas the researchers in this new analysis are using it to argue against statins.

They relied on limited, aggregated and inconsistent information …an approach liable to bias John Danesh BHF Professor of Epidemiology

Furthermore,  the research , published in the BMJ Open journal, has been deemed unbalanced due to what John Danesh, BHF Professor of Epidemiology said was “crude study methods”. This is because their analysis "relied on limited, aggregated and inconsistent information from published sources, an approach liable to bias.”

Similarly Co lin Baigent, of the University of Oxford, has described the study as reaching “completely the wrong conclusion. In fact, we know that cholesterol is just as important as a cause of heart disease in older people as it is in the young. We know this because of the evidence from all the randomized trials of statin therapy, which collectively have studied substantial numbers of older people.”

Want to get fit and healthy?

Sign up to our fortnightly Heart Matters newsletter to receive healthy recipes, new activity ideas, and expert tips for managing your health. Joining is free and takes two minutes.

The authors themselves said that “We may have overlooked relevant studies as we only searched PubMed” (an online search for medical publications), and they may have excluded studies that evaluated LDL-C as a risk factor for death, if the study did not mention it in the title or abstract. “We may have overlooked a small number of relevant studies because we only searched papers in English,” they added.

Dr Tim Chico, a consultant cardiologist at Northern General Hospital in Sheffield, said there are several studies that has shown lowering cholesterol using a drug does reduce the risk of heart disease in the elderly. He said: “I am surprised the authors of this study do not refer to such trials, which tends to make their own paper disappointingly unbalanced.”

Evidence from large clinical trials demonstrates very clearly that lowering LDL cholesterol reduces our risk of death overall Professor Jeremy Pearson BHF Associate Medical Director

Some of the participants in the study with high cholesterol may have started statins during the study, and therefore their high life expectancy could be due to them being on statins. Similarly, some of them may have started a healthy diet  during the study, and this could have increased their life expectancy.

At least five of the study authors have previously written books questioning the links between cholesterol and heart disease. The lead author Dr Uffe Ravnskov, has written a book called ‘The Cholesterol Myths: Exposing the Fallacy that Saturated Fat and Cholesterol Cause Heart Disease’. Another of the authors, London cardiologist Dr Aseem Malhotra, is a prominent campaigner against statins.

The BHF View

Professor Jeremy Pearson, Associate Medical Director at the British Heart Foundation, said: “As we get older, many more factors determine our overall health, making the impact of high cholesterol levels less easy to detect.

"The evidence from large clinical trials demonstrates very clearly that lowering LDL cholesterol reduces our risk of death overall and from heart attacks and strokes, regardless of age. There is nothing in the current paper to support the authors’ suggestions that the studies they reviewed cast doubt on the idea that LDL cholesterol is a major cause of heart disease or that guidelines on LDL reduction in the elderly need re-evaluating.”

The media coverage

The story was covered by the Daily Mail , Guardian , Independent , Telegraph , BBC Radio Four and others. The Daily Mail headline ‘Statins 'may be a waste of time': Controversial report claims there's NO link between 'bad cholesterol' and heart disease’ did at least include the word ‘controversial’, rather than present the evidence as fact, while The Times’ headline Bad cholesterol ‘helps you live longer’ was arguably less balanced.

Much of the news coverage did show the controversy that the report has caused, although in some cases this was not mentioned till most of the way through the article.

It is important that people at high risk of a heart attack or stroke take their prescribed medication. Individuals can assess their cardiovascular risk and find information about how to reduce it using th e  Heart Age Tool , developed by the BHF, Public Health England, NHS Choices and Joint British Societies.

If someone is unsure about their heart medicines, they can speak with their GP or  contact our Heart Helpline .

What to read next...

Statins - your questions answered.

Read the article

Related Links

• Reducing your cholesterol
• 7 natural alternatives to statins that claim to lower cholesterol
• Could anyone be offered statins to lower their risk of heart attack and stroke?
• Subscribe to Heart Matters

More useful information

• U.S. Department of Health & Human Services

• Virtual Tour
• Staff Directory
• En Español

You are here

News releases.

News Release

Monday, November 21, 2022

Study challenges “good” cholesterol’s role in universally predicting heart disease risk

Lower levels of HDL cholesterol were associated with increased risks for heart attacks in white but not Black adults, and higher levels were not protective for either group.

A National Institutes of Health-supported study found that high-density lipoprotein (HDL) cholesterol, often called the “good cholesterol,” may not be as effective as scientists once believed in uniformly predicting cardiovascular disease risk among adults of different racial and ethnic backgrounds. 

The research, which published in the Journal of the American College of Cardiology , found that while low levels of HDL cholesterol predicted an increased risk of heart attacks or related deaths for white adults – a long-accepted association – the same was not true for Black adults.  Additionally, higher HDL cholesterol levels were not associated with reduced cardiovascular disease risk for either group.  

“The goal was to understand this long-established link that labels HDL as the beneficial cholesterol, and if that’s true for all ethnicities,” said Nathalie Pamir, Ph.D., a senior author of the study and an associate professor of medicine within the Knight Cardiovascular Institute at Oregon Health & Science University, Portland. “It’s been well accepted that low HDL cholesterol levels are detrimental, regardless of race. Our research tested those assumptions.”

To do that, Pamir and her colleagues reviewed data from 23,901 United States adults who participated in the Reasons for Geographic and Racial Differences in Stroke Study (REGARDS). Previous studies that shaped perceptions about “good” cholesterol levels and heart health were conducted in the 1970s through research with a majority of white adult study participants. For the current study, researchers were able to look at how cholesterol levels from Black and white middle-aged adults without heart disease who lived throughout the country overlapped with future cardiovascular events.  

Study participants enrolled in REGARDS between 2003-2007 and researchers analyzed information collected throughout a 10- to 11-year period. Black and white study participants shared similar characteristics, such as age, cholesterol levels, and underlying risk factors for heart disease, including having diabetes, high blood pressure, or smoking. During this time, 664 Black adults and 951 white adults experienced a heart attack or heart attack-related death. Adults with increased levels of LDL cholesterol and triglycerides had modestly increased risks for cardiovascular disease, which aligned with findings from previous research.  

However, the study was the first to find that lower HDL cholesterol levels only predicted increased cardiovascular disease risk for white adults. It also expands on findings from other studies showing that high HDL cholesterol levels are not always associated with reduced cardiovascular events. The REGARDS analysis was the largest U.S. study to show that this was true for both Black and white adults, suggesting that higher than optimal amounts of “good” cholesterol may not provide cardiovascular benefits for either group.  

“What I hope this type of research establishes is the need to revisit the risk-predicting algorithm for cardiovascular disease,” Pamir said. “It could mean that in the future we don’t get a pat on the back by our doctors for having higher HDL cholesterol levels.”  

Pamir explained that as researchers study HDL cholesterol’s role in supporting heart health, they are exploring different theories. One is quality over quantity. That is, instead of having more HDL, the quality of HDL’s function – in picking up and transporting excess cholesterol from the body – may be more important for supporting cardiovascular health .       They are also taking a microscopic look at properties of HDL cholesterol, including analyzing hundreds of proteins associated with transporting cholesterol and how varying associations, based on one protein or groups of proteins, may improve cardiovascular health predictions.   

“HDL cholesterol has long been an enigmatic risk factor for cardiovascular disease,” explained Sean Coady, a deputy branch chief of epidemiology within the National Heart, Lung, and Blood Institute (NHLBI)’s Division of Cardiovascular Sciences. “The findings suggest that a deeper dive into the epidemiology of lipid metabolism is warranted, especially in terms of how race may modify or mediate these relationships.”      The authors conclude that in addition to supporting ongoing and future research with diverse populations to explore these connections, the findings suggest that cardiovascular disease risk calculators using HDL cholesterol could lead to inaccurate predictions for Black adults.    

“When it comes to risk factors for heart disease, they cannot be limited to one race or ethnicity,” said Pamir. “They need to apply to everyone.”  

The REGARDS study is co-funded by the National Institute of Neurological Disorders and Stroke and the National Institute of Aging and received additional support from NHLBI.     To learn more about cholesterol and heart health, visit https://www.nhlbi.nih.gov/health/blood-cholesterol .     To learn about heart-healthy living, visit https://www.nhlbi.nih.gov/health/heart-healthy-living .                  About the National Heart, Lung, and Blood Institute (NHLBI): NHLBI is the global leader in conducting and supporting research in heart, lung, and blood diseases and sleep disorders that advances scientific knowledge, improves public health, and saves lives. For more information, visit https://www.nhlbi.nih.gov/ . 

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov .

NIH…Turning Discovery Into Health ®

Zakai NA, Minnier J, Safford MM, et al. Race-dependent association of high-density lipoprotein cholesterol levels with incident coronary artery disease.  J Am Coll  Cardiol .  2022; doi: 10.1016/j.jacc.2022.09.027.  

Connect with Us

• More Social Media from NIH

ApoB test may be more accurate measure of heart disease risk

U.s. guidelines may miss vulnerable patients whose cholesterol levels appear within healthy range, utsw researchers find.

Senior author Ann Marie Navar, M.D., Ph.D., is Associate Professor of Internal Medicine in the Division of Cardiology and in the Peter O'Donnell Jr. School of Public Health at UT Southwestern.

Newswise — DALLAS – Aug. 13, 2024 – The traditional lipid panel may not give the full picture of cholesterol-related heart disease risk for many Americans, according to a study led by UT Southwestern Medical Center researchers and published in  JAMA  Cardiology .

There are different types of cholesterol particles that can cause heart disease, including low-density lipoproteins (LDL), very low-density lipoproteins (VLDL), and intermediate-density lipoproteins (IDL). LDL-C is a measure of the weight of cholesterol in LDL particles and is one of the most common tests people use to measure cholesterol risk. Every LDL, VLDL, and IDL particle has a single protein on its surface called apolipoprotein B (apoB).

Prior research has shown that the number of “bad” cholesterol particles, measured by a blood test for apoB, is the most accurate marker for cholesterol risk. However, current guidelines do not recommend testing for apoB in all people. Instead, most only have their LDL-C measured, but that does not test for the total number of LDL particles. Measuring LDL-C alone may not be adequate to find people with high apoB levels, UTSW researchers and colleagues said.

“For most patients, the LDL-C measurement is usually ‘good enough’ because people with high LDL-C also usually have high apoB and vice versa, but that’s not true for everyone,” said senior author  Ann Marie Navar, M.D., Ph.D. , Associate Professor of  Internal Medicine  in the  Division of Cardiology  and in the  Peter O’Donnell Jr. School of Public Health  at UT Southwestern. “Some people have high apoB but a relatively low LDL-C, so their heart disease risk is underestimated by not measuring apoB. Others may have a high LDL-C but a low or normal apoB, and they aren’t at risk.”

Because the weight of cholesterol particles can vary from person to person, LDL-C and apoB measurements don’t always line up. When apoB levels vary from estimated values, they’re called “discordant.” In the case of patients with low or normal-appearing LDL-C and a high apoB level, LDL-C measurements may offer a false sense of security. This happens more commonly in people with metabolic risk factors such as obesity, diabetes, or high triglycerides. But even people without these conditions can have discordance.

The research team used data from the National Health and Nutrition Examination Survey (NHANES) to assess apoB discordance in the U.S. population. The NHANES database included apoB, LDL-C, high-density lipoprotein cholesterol (HDL-C, or “good” cholesterol), total cholesterol, and triglyceride levels for 12,688 adults measured between 2005 and 2016. To determine the discordance level for each individual, Dr. Navar and her colleagues calculated the difference between observed and expected apoB levels based on LDL-C.

As expected, apoB levels for patients in the study with metabolic risks were higher than predicted values. However, some metabolically healthy patients also had apoB levels that varied significantly from expected measures. Physicians following U.S. guidelines may overlook people who are at higher risk of developing atherosclerosis despite normal metabolic health markers. 

“I believe that our results, combined with a lot of other data showing the value of measuring apoB levels, support a revision of the guidelines to recommend apoB testing for everybody, not just those with certain clinical risk factors,” Dr. Navar said.

The study includes an  online calculator  for the public to estimate apoB levels based on the LDL-C level. As Dr. Navar explained, a higher-than-expected apoB level indicates a risk of heart disease that is greater than can be calculated by LDL-C alone.

Eric Peterson, M.D., M.P.H., Vice Provost and Senior Associate Dean for Clinical Research at UT Southwestern, contributed to this study. Dr. Peterson, who is also Professor of Internal Medicine and Vice President for Health System Research, holds the Adelyn and Edmund M. Hoffman Distinguished Chair in Medical Science. 

Information on author financial disclosures can be found in the manuscript.

About UT Southwestern Medical Center

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 21 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,200 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 120,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5 million outpatient visits a year.

Journal Link: JAMA Cardiology

MEDIA CONTACT

JAMA Cardiology

TYPE OF ARTICLE

• Experts keyboard_arrow_right Expert Pitch Expert Query Expert Directory
• Journalists
• About keyboard_arrow_right Member Services Accessibility Statement Newswise Live Invoice Lookup Services for Journalists Archived Wires Participating Institutions Media Subscribers Sample Effectiveness Reports Terms of Service Privacy Policy Our Staff Contact Newswise
• Blog FAQ Help