Podcast Summary
Understanding HDL's complex role in the body: HDLs, known as 'good cholesterol', have a crucial role in the body, but their biology, genesis, metabolism, and function are complex and challenging to manipulate pharmacologically for atherosclerosis treatment.
High-density lipoproteins (HDLs), often referred to as "good cholesterol," are much more complex than the simplistic label suggests. HDLs play a crucial role in the body, and understanding their biology, genesis, metabolism, and function is essential. Despite their importance, pharmacologically manipulating HDLs to impact atherosclerosis has been challenging, while our ability to manage the ApoB side of the equation has led to significant successes in cardiovascular disease treatment. Dan Rader, a professor of molecular medicine at the University of Pennsylvania, shares his expertise on HDLs in this episode, shedding light on the complexities and potential of this intriguing area of lipidology.
Understanding Lipoproteins: Complex Structures for Lipid Transport: Lipoproteins, made of lipids and proteins, transport triglycerides (ApoB-100) and cholesterol (HDL with Apo A1). HDL's complex metabolism sets it apart from ApoB lipoproteins.
Lipoproteins are complex structures in the blood that enable the transportation of lipids, primarily triglycerides and cholesterol. They are composed of lipids in the core and proteins on the surface, allowing for intricate metabolism and interaction with various receptors. ApoB lipoproteins, specifically ApoB-100, are responsible for transporting triglycerides and are linked to atherosclerotic cardiovascular disease. HDL, another lipoprotein, does not contain ApoB and instead carries cholesterol and other complex lipids, primarily through the protein POI1. The intricacies of HDL metabolism and its differences from ApoB lipoproteins make it a complex and fascinating area of study. Remember, Apo A1, specifically, is the most important protein associated with HDL. The lipid community's nomenclature can be confusing, so it's essential to distinguish between different proteins and their respective roles. HDL's genesis involves the formation and evolution of Apo A1, which is a key component of HDL and distinguishes it from other lipoproteins. The metabolism of HDL is more complex than that of ApoB lipoproteins, making it a captivating area of research.
Distinct Roles and Behaviors of ApoB and ApoA1 in Lipoprotein Metabolism: ApoB remains constant on LDL and VLDL particles, while ApoA1 can exchange between HDL and LDL, and is involved in HDL formation through ABCA1.
While both ApoB and ApoA1 are involved in lipoprotein metabolism, they have distinct roles and behaviors. ApoB, which is associated with LDL and VLDL, remains constant on its lipoprotein particle throughout its lifetime, primarily getting taken up by the liver. In contrast, ApoA1, a core protein of HDL, can have multiple copies on a single particle and can exchange between different HDL and even LDL particles. The formation of HDL begins with the secretion of ApoA1 from the liver or intestine, which then engages with the transport protein ABCA1 to acquire lipids. The absence of ABCA1 results in undetectable HDL levels, as the protein cannot protect the lipids once secreted. HDL particles are smaller than LDL particles due to their lower lipid content, and the names "high" and "low" density refer to their respective lipid content and buoyancy in density gradients. HDL particles have a shorter lifespan due to their lipid exchange properties.
The role of LCAT in maturing HDL particles: LCAT plays a crucial role in esterifying free cholesterol on HDL, forming mature HDL particles and preventing conditions like Tangier disease and Alcat deficiency.
The maturation of HDL particles from their nascent form to the mature form, which is what is typically measured as HDL cholesterol, is a critical process that involves the enzyme LCAT. LCAT plays a key role in esterifying free cholesterol on the HDL particle, making it more hydrophobic and forming the core of the mature HDL particle. People with deficiencies in LCAT have very low levels of HDL cholesterol and can't form mature HDL particles, leading to conditions like Tangier disease and Alcat deficiency. These conditions are characterized by low HDL cholesterol levels and, in the case of Alcat deficiency, progressive chronic kidney disease. ApoA1, the protein component of HDL, is highly conserved among mammals, and HDL is the primary lipoprotein in many lower mammals. The evolution of the LDL-centric lipid metabolism in humans is still a subject of debate among scientists.
Distinct Roles of ApoB and HDL in Lipid Metabolism: While HDL, carried by ApoA1 and ApoA2, protects against atherosclerosis and enhances energy metabolism, ApoB in LDL and VLDL transports triglycerides. Humans are less efficient at clearing ApoB, increasing risk. Other proteins like ApoA4 and ApoA5 impact lipid metabolism and offer therapeutic potential.
ApoB and HDL, two types of lipoproteins, have distinct roles in our bodies. While HDL, carried by proteins ApoA1 and ApoA2, is known for its protective role in reverse cholesterol transport and energy metabolism, ApoB, found in LDL and VLDL, is involved in transporting triglycerides to tissues for energy and storage. However, humans are less efficient than other animals in clearing ApoB-containing lipoproteins from our circulation, leading to higher concentrations and increased risk for atherosclerosis. It's not that we don't need ApoB, but we could be clearing it more efficiently. Additionally, there are other proteins, like ApoA4 and ApoA5, that play important roles in lipoprotein metabolism and are associated with HDL. ApoA5, for instance, stimulates lipoprotein lipase and metabolism of triglyceride-rich lipoproteins. Understanding these complex relationships can provide insights into potential therapeutic targets for managing lipid disorders and reducing the risk of cardiovascular diseases.
Understanding the Complexity of HDL: HDL is a dynamic system involved in transporting various substances within the blood, undergoing complex metabolism through lipases like hepatic lipase and endothelial lipase.
HDL, or High-Density Lipoproteins, are a complex system involved in transporting various substances within the blood, beyond just lipids. Unlike ApoB, which forms a monogamous relationship in the liver, HDL is dynamic and involves swapping, carrying, and loaning out substances. The nomenclature of HDL particles, such as HDL1, HDL2, and HDL3, is independent of the Apolipoproteins (APO A1, APO A2, etc.). These different HDL subclasses have varying sizes and densities and can be further fractionated using various methodologies. While understanding HDL biology and metabolism through fractionation is fascinating, it is relatively unimportant from a clinical relevance standpoint. Instead, the smaller, denser LDL particles, which contain ApoB, are more clinically significant in predicting cardiovascular risk. HDL undergoes complex metabolism once it's formed and mature, with lipases like hepatic lipase and endothelial lipase acting on its phospholipids. These lipases play essential roles in energy metabolism and HDL maturation.
Light paces and CETP influence HDL metabolism: Light paces contribute to HDL size and composition, while CETP modifies HDL by transferring cholesterol esters. High HDL cholesterol from CETP deficiency or CTAP inhibitors may improve cardiovascular outcomes.
Light paces and the cholesterol ester transfer protein (CETP) play crucial roles in high-density lipoprotein (HDL) metabolism. Light paces are essential for HDL metabolism and contribute to the distribution of different HDL sizes and protein compositions. CETP transfers cholesterol esters between apolipoprotein B-containing lipoproteins and HDL, significantly modifying the size and composition of HDL particles. People who lack CETP have hugely elevated HDL cholesterol levels due to the absence of this protein. The observation that high HDL cholesterol levels are associated with better cardiovascular outcomes led pharmaceutical companies to develop CTAP inhibitors to raise HDL cholesterol levels. Pfizer was the first to develop a CTAP inhibitor, Torcetrapib, which was shown to be effective in raising HDL cholesterol levels in clinical trials. However, the story goes beyond just raising HDL cholesterol, and it's important to understand the complex interplay between these proteins and their roles in overall lipid metabolism.
The complicated journey of CTP inhibitors to raise HDL and reduce atherosclerotic cardiovascular disease risk: Despite early promising results, trials using CTP inhibitors to raise HDL and reduce atherosclerotic cardiovascular disease risk have not been successful. Importance of conducting hard outcome trials to fully understand efficacy and safety of new treatments.
The excitement surrounding the use of CTP inhibitors to raise HDL cholesterol levels as a means to reduce atherosclerotic cardiovascular disease risk has been a long and complicated journey. Early trials using CTP inhibitors showed promising results in raising HDL levels, but the first trial in 2006 did not meet expectations as it not only failed to show a benefit but also had adverse effects. Subsequent trials with other CTP inhibitors also did not yield positive results, with some being stopped early. The failure of these trials led to the realization that HDL cholesterol itself is not directly and causally protective against atherosclerotic cardiovascular disease. Despite the setbacks, research continues in the development of a CTP inhibitor, but none are currently on the market. This experience underscores the importance of conducting hard outcome trials in cardiovascular medicine to fully understand the efficacy and safety of new treatments. The history of try paranoral, an early lipid-lowering drug, serves as a reminder of the importance of rigorous testing and the potential risks of approving drugs based on surrogate endpoints rather than hard outcomes.
Monitoring drug effectiveness over time: While some treatments may seem beneficial in the short term, their long-term effects should be carefully considered. Continuous monitoring of drug impact on health is crucial.
The effectiveness of a drug or treatment can change over time, and it's important to continually monitor its impact on health. The example given was the drug triparanol, which was initially thought to lower cholesterol but was later found to increase mortality due to a desmosterol spike. Another point discussed was the use of clomaphine for testosterone replacement therapy, which can lead to high desmosterol levels and potential long-term health concerns. The takeaway here is that while some treatments may seem beneficial in the short term, their long-term effects should also be carefully considered. Additionally, there is still ongoing research into CTP inhibitors as a potential treatment for lowering LDL cholesterol, despite previous failures of this class of drugs. Overall, the importance of careful monitoring and consideration of the potential risks and benefits of treatments cannot be overstated.
Understanding the paradox of high HDL and heart disease risk: High HDL levels aren't always protective, and a deficiency in the liver's major HDL receptor, SRB1, can lead to high HDL and increased heart disease risk despite the 'good cholesterol's' role in removing excess cholesterol from cells.
While HDL, often referred to as "good cholesterol," plays a crucial role in removing excess cholesterol from cells and transporting it back to the liver, issues can arise when the liver's major HDL receptor, SRB1, is deficient. This deficiency can lead to high HDL levels, but paradoxically, increased risk of heart disease due to the inability to efficiently unload the HDL and recycle it for further use. This concept is referred to as "constipation of the system." The absence of SRB1 is rare, but understanding this relationship between HDL, SRB1, and heart disease is essential for clinicians and researchers. High HDL levels are not always protective, and identifying the underlying cause of high HDL is crucial for appropriate interventions. The heritability of HDL levels is complex, involving multiple genes, including SRB1, but no single "smoking gun" gene has been identified for most cases of extreme high HDL. The clinical implications of high HDL are still being studied, and current evidence suggests that high HDL may not offer the same level of protection in all populations, especially in individuals of African ancestry.
HDL levels don't determine cardiovascular risk: Mendelian randomization studies show genetically high HDL doesn't protect against ASCVD, while low HDL doesn't increase risk. Low HDL may indicate insulin resistance and inefficiency in metabolizing triglycerides.
High HDL levels do not serve as a reason to withhold preventive therapies, such as statins, in patients at risk for cardiovascular disease (ASCVD). This is based on evidence from Mendelian randomization studies, which demonstrate that genetically high HDL levels do not offer protection against ASCVD, while low HDL levels do not increase risk. High HDL acts as an integrator of information related to insulin resistance, triglycerides, and inflammation. Low HDL levels may be used as a relative indicator to consider more aggressive treatment, especially when considering the overall risk profile. However, it's important to note that this does not apply to individuals of African ancestry due to the unreliability of HDL as a predictor in this population. Additionally, low HDL levels may indicate insulin resistance, as evidenced by the triglyceride-to-HDL ratio. The lower the HDL and the higher the triglycerides, the less efficient the body is at metabolizing triglycerides, leading to lower HDL levels.
HDL as an integrator of triglyceride metabolism: HDL cholesterol reflects 24-hour triglyceride metabolism better than a single overnight fasting measurement, and the relationship between HDL and triglycerides is strong, with repeated high-fat meals impacting HDL levels over time.
HDL cholesterol acts as an integrator of triglyceride metabolism, much like HBA1C does with glucose. During a high-fat milkshake challenge, people's responses vary greatly, and the higher the triglyceride response, the lower the HDL levels. This relationship is very strong. HDL cholesterol reflects 24-hour triglyceride metabolism better than a single overnight fasting measurement. HDL is not just an acute integrator during a meal but also has a substantial chronic effect due to repeated high-fat meals and their impact on postprandial triglyceride metabolism. While HDL cholesterol may only dip slightly during a single meal, the repeated dips from multiple high-fat meals can significantly impact HDL levels over time. This is why HDL is considered an integrator of triglyceride metabolism. Additionally, fasting triglycerides also affect HDL metabolism, and the postprandial component is a crucial part of the relationship. The lagging nature of HDL cholesterol through HDL biology further emphasizes the importance of considering both acute and chronic effects on lipid partitioning.
HDL levels reflect body's metabolic state and insulin resistance: HDL levels indicate 24-hour metabolic state, with insulin resistance impacting triglyceride levels and fat storage in the liver. Adiponectin, an adipokine, may influence HDL metabolism and serve as a potential biomarker for clinical care.
HDL levels, which are often referred to as the "good cholesterol," reflect the body's metabolic state over a 24-hour period, particularly in relation to insulin resistance. Insulin resistance, a condition that affects how the body uses insulin, can lead to differences in triglyceride levels and fat storage in the liver between insulin-sensitive and insulin-resistant individuals. HDL may also be integrating and reflecting other components of metabolism beyond triglycerides, including the adipokine adiponectin, which has an inverse relationship to insulin resistance and may affect HDL metabolism. While niacin, a drug that raises HDL levels, was once thought to be beneficial due to its broad lipid-lowering effects, recent clinical trials have failed to show significant cardiovascular event reduction, leading to its decline in use. The role of adiponectin and other potential biomarkers in guiding clinical care is an area of ongoing investigation.
HDL's Role in Cholesterol Metabolism for Macrophages: HDL facilitates the removal of excess cholesterol from macrophages, preventing their transformation into foam cells and atherosclerotic plaques.
HDL plays a crucial role in the body's cholesterol metabolism, particularly for macrophages. Macrophages, which are scavenger cells, pick up cholesterol from various sources, including dead cells and LDLs. To get rid of the excess cholesterol, macrophages use transporters like ABCA1 to push the cholesterol out of the cell and into HDL particles. This process is called efflux or delipidation. HDL then transports the cholesterol back to the liver for metabolism or excretion. However, when macrophages are unable to effectively rid themselves of cholesterol, they become foam cells, which are a hallmark of atherosclerotic plaques. Understanding the mechanisms of HDL delipidation and reverse cholesterol transport is essential for preventing and treating cardiovascular diseases.
Understanding Cholesterol Efflux from Macrophages for Better Atherosclerosis Protection: Effective cholesterol efflux from macrophages is crucial for atherosclerosis protection through reverse cholesterol transport. Current clinical measurements are insufficient to assess this function, leading to research on promoting the first step of the process for potential new therapies.
The process of cholesterol efflux from macrophages and other cells, particularly in the blood vessel wall, is a crucial step in the broader physiologic process called reverse cholesterol transport (RCT). RCT is the mechanism by which the body returns cholesterol from tissues back to the liver for excretion. The more effective this process is, the better protected one is against atherosclerosis. However, current clinical measurements, such as HDL cholesterol levels or HDL particle size, are crude and do not accurately reflect the function of HDL in promoting cholesterol efflux. Therefore, efforts have focused on finding ways to promote the first step of this process, which is the driving of efflux from macrophages and other cells. This could potentially lead to new therapies for reducing the risk of atherosclerotic cardiovascular disease. Additionally, it is important to note the distinction between static biomarkers, such as HDL cholesterol, and dynamic biomarkers, which reflect the function or process over time. The former allows us to miss important information about the velocity and effectiveness of the process.
Understanding HDL's role in reverse cholesterol transport goes beyond just cholesterol transfer: HDL's role in reverse cholesterol transport is more about promoting cholesterol efflux from cells than just transferring it between lipoproteins, and measuring its efflux capacity is a better predictor of cardiovascular disease risk
The function of HDL (High-Density Lipoprotein) in reverse cholesterol transport is more complex than just transferring cholesterol between lipoproteins. While LDL (Low-Density Lipoprotein) also plays a role in transporting cholesterol back to the liver, HDL's role is more about promoting efflux of cholesterol from cells. The future of commercial assays to measure HDL function lies in measuring its cholesterol efflux capacity, which is a better predictor of cardiovascular disease risk than just measuring HDL cholesterol levels. An ex vivo cholesterol leaflux assay has been developed to measure HDL functionality in humans, and there is ongoing research to bring this assay clinically.
Measuring HDL's ability to remove cholesterol from cells could predict cardiovascular events more accurately: New clinical assay measures HDL's efflux capacity using macrophages, correlating directly with risk, predicting hard events, and potentially scalable with AI.
Researchers are developing a new clinical assay to measure the efflux capacity of HDL, which could potentially predict cardiovascular events more accurately than current methods like HDL cholesterol levels. The assay uses macrophages to measure the ability of HDL to remove cholesterol from cells, and early studies have shown that the rank order of effectiveness correlates directly with risk, not just proxies like insulin resistance or other measurements. The predictive power of this measurement has been demonstrated in large prospective studies, showing that it is predictive of hard events, not just associations. However, more research is needed to determine if this is causal or just a better associative measure. Additionally, there is potential to use AI to find markers that predict efflux capacity, which could make the measurement more accessible and scalable. The overall number of HDL particles, which is a different measure from HDL cholesterol, has also been shown to be a better predictor of risk, but it is still a static measure and not as predictive as the functional measurement of efflux capacity.
The role of APOA1, HDL cholesterol, and ApoE in preventing cardiovascular diseases and neurodegenerative conditions: APOA1 and HDL cholesterol play a crucial role in preventing cardiovascular diseases and neurodegenerative conditions through the cholesterol efflux hypothesis. ApoE, a protein linked to lipoprotein metabolism, also influences risk for these conditions, with different isoforms impacting risk differently.
The role of APOA1 and HDL cholesterol in preventing cardiovascular diseases and neurodegenerative conditions is an active area of research. The cholesterol efflux hypothesis, which suggests that promoting the efflux of cholesterol from cells to HDL particles can reduce risk, is being tested through an intervention called CSL 112. Meanwhile, ApoE, a protein associated with lipoprotein metabolism and remnant particle uptake, is also linked to both cardiovascular diseases and neurodegenerative conditions. The ApoE gene produces different isoforms, and the combination of these isoforms can impact an individual's risk for various diseases. For instance, having two copies of the ApoE4 isoform increases the risk of Alzheimer's disease, while having two copies of the ApoE2 isoform, which is less effective in binding to LDL receptors, can lead to higher triglycerides and cholesterol levels but offers a 20% reduction in Alzheimer's disease risk. The exact mechanisms of how APOE interacts with these diseases, particularly through its role in lipid transport, are still being investigated.
APOA1 and Alzheimer's: Potential Protective Role: APOA1, a component of HDL, may protect against Alzheimer's through interactions with ABCA1, ABCA7, and APOE1. However, the relationship between APOE genotype and APOA1's protective effect is unclear. More research is needed to understand how to promote APOA1 transport into the brain and develop clinical applications.
APOA1, a component of HDL, may have a protective role against neurodegenerative diseases, particularly Alzheimer's. This is based on observational data suggesting that APOE1, which interacts with APOA1, is a protective factor against Alzheimer's risk. ABCA1 and ABCA7, lipid transporters that APOA1 interacts with, are also implicated in neuroprotection. However, the relationship between APOE genotype and the protective effect of APOA1 is not well understood. The processes that transport APOA1 across the blood-brain barrier are not fully understood and could differ from person to person. If we could figure out how to promote more APOA1 transport into the brain, it may offer an opportunity to reduce Alzheimer's risk. Additionally, HDL, which contains APOA1, may promote nitric oxide production and insulin sensitivity, potentially contributing to overall health and disease prevention. However, translating these observations to human relevance is challenging. Commercial assays for measuring APOE concentration in the CSF, which would be necessary for clinical applications, do not yet exist.
Understanding HDL's role beyond cardiovascular disease: HDL's potential benefits in muscle function, insulin sensitivity, and the brain are intriguing but not yet clearly defined. Ongoing research aims to measure HDL function effectively, leading to improved risk prediction and potential new therapeutic interventions.
While High-Density Lipoprotein (HDL) particles have been shown to have potential health benefits, their clinical relevance to human disease and physiology is still unclear. The utility of HDL in areas like muscle function, insulin sensitivity, and the brain is intriguing but removed from the clear-cut benefits we see in cardiovascular disease (CVD). The challenge lies in measuring HDL function effectively and applying that knowledge in clinical practice. There is ongoing research into developing reliable assays to measure HDL function, which could lead to better risk prediction and potentially new therapeutic interventions. However, the success of these efforts remains to be seen. In the meantime, the majority of our tools for treating diseases like cancer and neurodegenerative disorders are ineffective, highlighting the need for continued exploration of HDL's role in health and disease.
Exploring lipid metabolism in the brain for neurodegenerative diseases: Peter Attia, a lipidologist, discusses the potential of investigating lipid metabolism in the brain for significant findings in neurodegenerative diseases, extending beyond just these conditions.
Understanding lipid metabolism in the brain is an important and exciting area of research for neurodegenerative diseases. Peter Attia, a long-term lipidologist, believes that this under-investigated area has the potential to uncover significant findings that could lead to therapeutic interventions. He acknowledges his biases as a lipidologist but is confident that the implications of this research will extend beyond just neurodegenerative diseases. The complexity of the subject matter was simplified eloquently by Peter during the discussion, making it accessible to regular listeners. For those interested in diving deeper into the topic, Attia's membership program offers exclusive content, including comprehensive podcast show notes, monthly AMA episodes, access to a private podcast feed, and discounts on recommended products.
