What is ApoA1 and how is it different from ApoB?

ApoA1 is the key protein characterizing HDL, made in the intestine and liver. Unlike ApoB, which stays with its particle throughout its life, ApoA1 doesn't stay with a single HDL particle; it can exchange onto other HDL particles and is present in multiple copies per HDL particle.

How do HDL particles initially form?

HDL formation begins when newly secreted ApoA1 engages with the ABC A1 transport protein. ABC A1 exports phospholipids and cholesterol from cells to ApoA1, forming early or nascent HDL particles.

What role does LCAT play in HDL maturation?

LCAT (lecithin-cholesterol acyltransferase) is a crucial enzyme that attaches a fatty acid to free cholesterol, creating cholesterol esters. These esters move to the center of the HDL particle, forming its core and leading to the mature HDL particles typically measured clinically.

Why did CETP inhibitors, designed to raise HDL cholesterol, fail in clinical trials?

CETP inhibitors strongly raise HDL cholesterol, but trials showed no cardiovascular benefit, and early drugs even increased mortality due to off-target effects. This suggested that merely increasing HDL cholesterol levels does not equate to improved HDL function or protection against atherosclerosis.

What is the role of the SR-B1 receptor in HDL metabolism?

SR-B1 (Scavenger Receptor Class B Type 1) is the major HDL receptor, primarily on the liver. It binds HDL, extracts cholesterol esters, and releases cholesterol-depleted HDL back into circulation. Defective SR-B1 can lead to very high HDL but paradoxically increases heart disease risk because cholesterol isn't efficiently cleared.

Why is high HDL cholesterol not always protective against cardiovascular disease?

High HDL cholesterol is not causally linked to protection against atherosclerosis. Genetic studies (Mendelian randomization) show that genetically high HDL cholesterol does not reduce cardiovascular risk. The mere quantity of cholesterol in HDL doesn't reflect its functional efficiency in removing cholesterol.

How does HDL cholesterol serve as an 'integrator' of cardiovascular risk factors?

HDL cholesterol levels can reflect the efficiency of 24-hour triglyceride metabolism and insulin resistance. Low HDL is often a marker of dysregulated triglyceride processing and insulin sensitivity, similar to how HbA1c integrates glucose levels over time, providing insight beyond a single fasting measurement.

What is reverse cholesterol transport and why is it important?

Reverse cholesterol transport (RCT) is the process where HDL picks up excess cholesterol from peripheral cells, especially macrophages in artery walls, and transports it back to the liver for excretion. This process is thought to be crucial for protecting against and potentially regressing atherosclerotic plaques.

How can HDL function be measured beyond just cholesterol levels?

A cholesterol efflux capacity assay measures how effectively HDL from an individual's plasma can extract cholesterol from cells in a lab setting. Studies show this functional measurement is a better predictor of cardiovascular risk than just HDL cholesterol levels.

What is the potential role of HDL and ApoA1 in neurodegenerative diseases like Alzheimer's?

ApoE, a brain-made lipid transport protein, is a major genetic risk factor for Alzheimer's (ApoE4 isoform), while ApoE2 is protective. Observational data suggests ApoA1, which crosses the blood-brain barrier, may also be protective against neurodegenerative diseases, potentially by interacting with lipid transporters like ABC A1 in the brain.

Key Moments

240 ‒ The confusion around HDL and its link to cardiovascular disease | Dan Rader, M.D.

Peter Attia MD

Science & Technology3 min read115 min video

Jan 30, 2023|94,818 views|1,102|165

Save to Pod

Key Moments

TL;DR

HDL cholesterol's role in cardiovascular disease is complex and not fully understood, with function, not just levels, being key.

Key Insights

HDL is a complex lipoprotein family crucial for lipid transport, distinct from the ApoB family.

Measuring HDL cholesterol alone is insufficient; HDL function, particularly cholesterol efflux capacity, is a more accurate predictor of cardiovascular risk.

Pharmacological attempts to raise HDL via CETP inhibitors have largely failed to demonstrate cardiovascular benefit.

The role of HDL in neurodegenerative diseases, especially Alzheimer's, is an emerging and promising area of research.

Understanding lipid metabolism in the brain is a significant frontier with potential therapeutic implications.

While HDL levels alone aren't causal for protection, low HDL can be a marker for other metabolic issues like insulin resistance.

THE BASICS: LIPIDS AND LIPOPROTEINS

Lipoproteins are essential for transporting lipids, which are water-insoluble, within the bloodstream. They consist of a lipid core surrounded by proteins. The ApoB family, including LDL, primarily transports triglycerides for energy. HDL, the focus of this discussion, is the other major lipoprotein family, characterized by ApoA1 protein and also involved in lipid transport, but with a far more complex biology and less understood function compared to ApoB.

HDL BIOGENESIS AND MATURATION

HDL production begins with ApoA1, secreted by the liver and intestine. A key transport protein, ABCA1, then facilitates the transfer of cholesterol and phospholipids from cells to ApoA1, forming nascent HDL. The enzyme LCAT esterifies cholesterol, creating cholesterol esters that form HDL's core, leading to a mature HDL particle. Genetic deficiencies in ABCA1 or LCAT highlight their critical roles, resulting in very low HDL levels and associated health issues like Tangier disease.

THE CHALLENGES OF PHARMACOLOGICAL INTERVENTION

Despite the historical view of HDL as 'good cholesterol,' attempts to pharmacologically raise HDL levels to reduce cardiovascular disease have largely been unsuccessful. Inhibiting CETP, an enzyme that transfers cholesterol esters, significantly raises HDL cholesterol but has failed to show consistent cardiovascular benefits in large trials, suggesting that simply increasing HDL cholesterol doesn't equate to improved function or reduced risk.

HDL FUNCTION AND REVERSE CHOLESTEROL TRANSPORT

A more nuanced understanding of HDL involves its role in reverse cholesterol transport (RCT), the process of removing cholesterol from peripheral tissues and returning it to the liver. Macrophages, in particular, are key players, utilizing transporters like ABCA1 to efflux cholesterol to HDL. This efflux capacity, rather than just HDL cholesterol levels, is now considered a more accurate predictor of cardiovascular risk, with impaired function paradoxically linked to higher HDL and increased disease.

HDL'S EMERGING ROLE IN NEURODEGENERATION

Recent research suggests HDL may play a protective role in neurodegenerative diseases, like Alzheimer's. ApoA1 has been found in the brain and CSF, and its presence is associated with reduced risk. Genetic factors like ABC A1 and ABC A7, involved in cholesterol transport, also link to Alzheimer's risk, supporting the hypothesis that HDL-related mechanisms in the brain are crucial for neuronal health and could be therapeutic targets.

MEASURING HDL FUNCTION AND FUTURE DIRECTIONS

Current clinical metrics for HDL, such as HDL cholesterol levels, are considered static and insufficient for assessing true cardiovascular risk. Developing reliable and accessible assays to measure HDL function, specifically cholesterol efflux capacity, is a key area of research. While challenges remain in translating these functional measurements into widespread clinical practice, advancements in assay development hold promise for better risk prediction and more targeted therapeutic interventions in the future.

Mentioned in This Episode

●Supplements

●Companies

●Organizations

●Studies Cited

●Concepts

●People Referenced

Common Questions

Lipoproteins are complex particles that transport lipids, like cholesterol and triglycerides, within the bloodstream. Since lipids don't mix with water, lipoproteins evolved as sophisticated vehicles to enable their transport and metabolism.

Topics

Reverse Cholesterol Transport Health & Longevity Cardiovascular Disease Prevention Medicine & Clinical Neurodegenerative Disease Lipoprotein Metabolism Cholesterol Efflux HDL Function Neuroscience & the Brain Insulin Resistance

Mentioned in this video

Studies & Research

Eric Norfolk Study

A large prospective study in the UK and Europe where samples were used to show that cholesterol efflux capacity was predictive of incident cardiovascular events over 10+ years.

University of Pennsylvania

Academic institution affiliated with Dan Rader's research and professorship.

Concepts

APO A5

An apolipoprotein that plays a very important role in stimulating lipoprotein lipase and the metabolism of triglyceride-rich lipoproteins. People lacking APO A5 have very high triglycerides.

SR-B1

A major HDL receptor, primarily on the liver, that binds to HDL particles, extracts cholesterol esters, and releases depleted HDL back into circulation. Deficiency leads to very high HDL but increased heart disease risk due to impaired cholesterol clearance.

Cholesterol Ester Transfer Protein

A protein that transfers cholesterol esters between ApoB-containing lipoproteins and HDL, modifying HDL particle size and composition. Inhibition of CETP significantly raises HDL cholesterol levels.

APOE

A lipid-binding protein primarily made in the brain (by microglia) that transports lipids. It exists in isoforms (E2, E3, E4), with ApoE4 being a major genetic risk factor for Alzheimer's and ApoE2 being protective against Alzheimer's but associated with hyperlipidemia.

Tangier disease

A rare human genetic disorder caused by a lack of ABC A1, resulting in virtually undetectable HDL and accumulation of cholesterol in macrophages throughout the body, leading to enlarged tonsils, spleen, and neurological issues.

ABC A1

A key transport protein whose role is to export lipids, particularly cholesterol and phospholipids, from the cell to newly secreted ApoA1, crucial for nascent HDL formation. Humans lacking this protein have virtually undetectable HDL.

Organizations

NIH

National Institutes of Health, where Dan Rader serves on the advisory board for clinical research.

Association of American Physicians

Prestigious association to which Dan Rader has been elected.

Perelman School of Medicine

Medical school at the University of Pennsylvania where Dan Rader is a professor.

National Heart, Lung, and Blood Institute

Institute where Dan Rader serves on the board of external experts.

International Society of Atherosclerosis

Organization where Dan Rader serves on the board of directors.

American Society of Clinical Investigation

Prestigious society to which Dan Rader has been elected.

Drugs & Medications

Dalceptropip

One of the CETP inhibitors that failed in clinical trials, but a post-hoc genetic study suggested a specific genotype might benefit, leading to a follow-up negative trial.

Clomiphene

A hormone used off-label for testosterone replacement in men. It stimulates LH and FSH production but can significantly raise desmosterol levels, posing a potential long-term risk similar to triparanol.

Torsatropin

The first CETP inhibitor developed by Pfizer, which not only failed to show benefit in reducing cardiovascular disease but also led to increased mortality due to off-target effects.

CSL 112

A recombinant HDL particle containing ApoA1, currently in clinical development. It's designed to promote cholesterol efflux and is being tested in acute coronary syndrome settings to see if it can reduce cardiovascular events.

Lipitor

A statin drug (atorvastatin) that was about to go off patent when initial CETP inhibitor trials were conducted, suggesting a commercial motivation for combination therapy trials.

Companies

National Academy of Medicine

Prestigious academy to which Dan Rader has been elected.

Vassar Strategies

A company co-founded by Dan Rader that measures cholesterol efflux capacity, primarily for biomedical and biopharma research, with interest in bringing it to clinical use.

Boston Heart Labs

A commercial laboratory that offers advanced blood tests, including HDL fractionation metrics which the host states they stopped paying attention to in clinical practice.

Merck

A pharmaceutical company that conducted a large, well-powered clinical trial of a niacin derivative, which ultimately showed minimal benefit for cardiovascular events.

Pfizer

The pharmaceutical company that developed the first CETP inhibitor, Torsatropin.

Supplements

Statin

A class of drugs used to lower LDL cholesterol, mentioned as a primary preventive therapy that should not be overlooked even with high HDL levels.

Triparanol

An early lipid-lowering drug introduced around 1950 that lowered total cholesterol but was later pulled off the market due to increased cardiovascular mortality, likely linked to increased desmosterol levels.

Niacin

A drug that effectively raises HDL cholesterol and modestly lowers ApoB, triglycerides, LDL, and Lp(a). Historically used, but large clinical trials showed minimal cardiovascular benefit, leading to its diminished use.

People

Peter Libby

A researcher noted for eloquently writing about how ApoB concentrations increase with aging, even in the absence of lifestyle factors.

Tom Dayspring

A lipid expert who highly recommended Dan Rader as a podcast guest.

Dan Rader

Professor of Molecular Medicine at the Perelman School of Medicine at the University of Pennsylvania, specializing in lipoprotein metabolism and atherosclerosis, particularly HDL function.

Phil Charlotte

An investigator in Dallas who has shown that HDL can promote nitric oxide production in cells and mice, which would be beneficial for blood pressure and atherosclerosis protection.