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🔑 Key Takeaways

  1. Understanding Reverse Cholesterol Transport (RCT) is essential for maintaining a healthy cholesterol balance and preventing complications, as LDL and HDL cholesterol levels alone do not provide a complete picture.
  2. High levels of HDL cholesterol do not necessarily indicate efficient reverse cholesterol transport, as there are multiple pathways for cholesterol to be transported back to the liver, including the use of receptors and free diffusion. Further research is needed to understand the implications for conditions like familial hypercholesterolemia.
  3. The theory of forward cholesterol transport is an oversimplification as multiple particles, including VLDL and chylomicrons, play a role in this process, emphasizing the need for further exploration and understanding.
  4. APOE enhances clearance of LDL particles, reducing the risk of heart disease, while APOC3 increases atherogenicity. Measuring APOC3 levels could identify remnant lipoproteins and inform cardiovascular management.
  5. Insulin resistance leads to an increase in LDL particle numbers and VLDL levels, emphasizing the importance of evaluating absolute changes in lipid markers for insulin-resistant patients.
  6. Particle numbers, specifically APOB or LDL particle number, are crucial in accurately assessing and making clinical decisions regarding cholesterol levels. Understanding the role of different particles in lipid transportation is also important.
  7. The terms "good" and "bad" cholesterol can be misleading, as it is the actions of lipoproteins that determine whether cholesterol is beneficial or detrimental to the body.
  8. LDL cholesterol alone is not enough to accurately assess cardiovascular risk; other factors like HDL cholesterol, triglycerides, and APOB should also be considered for a comprehensive assessment.
  9. Cholesterol levels alone may not accurately predict the risk of atherosclerosis, as demonstrated in a case where a woman had elevated atherosclerosis despite normal LDL levels. Other cardiovascular risk factors should be considered for a comprehensive assessment. CTP inhibitors show potential in addressing HDL dysfunction.
  10. HDL cholesterol levels alone do not provide a complete understanding of its function. More specific biomarkers are needed to accurately assess HDL function and improve treatment and nutrition therapies.
  11. Understanding HDL functionality is still limited and attempts to increase HDL levels through drugs have been unsuccessful. High HDL cholesterol levels may not provide protection against coronary atherosclerosis.
  12. Raising HDL cholesterol alone does not provide cardiovascular benefits, highlighting the importance of comprehensive research and a nuanced approach to addressing cardiovascular risk factors.
  13. Drug development can be unpredictable and expensive, with unexpected toxicities leading to the termination of trials. Despite setbacks, companies continue research to find safer and more effective alternatives in lowering APO B levels.
  14. The pharmaceutical industry must carefully consider the potential risks and benefits of new drugs, prioritizing patient safety and adhering to strict regulations to avoid harm and legal repercussions.

📝 Podcast Summary

The Complex Process of Reverse Cholesterol Transport (RCT)

Understanding cholesterol homeostasis is more complex than just looking at LDL and HDL cholesterol levels. Reverse cholesterol transport (RCT) plays a crucial role in removing excess cholesterol from the body. It involves the process of cells effluxing cholesterol, which can then be transported by HDL particles back to the liver. The liver can utilize the cholesterol or excrete it through bile. However, the reabsorption of bile salts by the ileum can limit the effectiveness of RCT. It is important to recognize that LDL and HDL cholesterol measurements do not provide a complete picture of the intricate movement and trafficking of cholesterol. A deeper understanding of RCT is necessary to maintain proper cholesterol balance and prevent complications.

The Complexities of Cholesterol Transport in the Body

The understanding of cholesterol transport in the body is more complex than previously thought. It was commonly believed that high levels of HDL cholesterol indicated efficient reverse cholesterol transport, as HDL would take cholesterol back to the liver. However, further research has revealed multiple pathways for cholesterol to be transported back to the liver, including the use of receptors and free diffusion. Additionally, it has been found that red blood cells and albumin can also accept free cholesterol through diffusion, providing another pathway for LDL particles to acquire cholesterol. This newfound complexity challenges the traditional view of cholesterol transport and suggests the need for further investigation into its implications for conditions like familial hypercholesterolemia.

The Complexity of HDLs in Lipidology: A Challenging Task for Experts

Understanding the complexity of high-density lipoproteins (HDLs) in lipidology is a challenging task. Even experts like Peter Attia and Thomas Dayspring admit their limitations in comprehending HDLs fully. It is particularly crucial to note that the early theory of forward cholesterol transport, with APO B family carrying cholesterol to tissues and HDL family bringing it back, is an oversimplification. For instance, VLDL and chylomicrons released by the liver or intestine play a role in the forward cholesterol transportation system. But when these particles lose core triglycerides and phospholipids, they become remnants and are swiftly cleared by receptors primarily found in the liver. This process involves APOE receptors, which contribute to the rapid clearance of VLDLs, chylomicrons, and intermediate-density lipoproteins (IDLs). Ultimately, this conversation highlights the intricate mechanisms involved in lipoprotein transportation and emphasizes the need for further exploration and understanding.

APOE and APOC3: Key Factors in Cardiovascular Health

APOE is an important ligand that greatly affects the efficacy and clearance of LDL particles. If someone has the genetic gift of expressing APOE on their LDL particles, their clearance rate is enhanced, resulting in lower levels of APOB and LDL particles, which reduces the risk of heart disease. Additionally, APO lipoprotein C3 plays a role in increasing the atherogenicity of LDL particles. Therefore, measuring APOC3 levels through an assay or genetic testing could be a valuable tool in identifying remnant lipoproteins that may contribute to arterial wall issues. Furthermore, higher APOC3 levels indicate a higher risk, independent of lipid profiles, making it an important factor to consider. Pharmaceutical companies are even developing APOC3 inhibitors to address this concern. Overall, this conversation highlights the significance of APOE and APOC3 in understanding and potentially managing cardiovascular health.

The Role of Insulin Resistance in Lipoprotein Pathologies

Insulin resistance plays a significant role in the increase of LDL particle numbers and VLDL levels. Thomas Dayspring emphasizes that triglyceride-rich lipoprotein pathologies, which are commonly associated with insulin resistance, lead to higher levels of VLDL particles. These VLDL particles, with APOC 3, have a longer plasma residence time and are converted into LDL particles. As a result, LDL particle numbers skyrocket, while VLDL particles only double or triple in quantity. Peter Attia highlights that it's crucial to consider absolute changes rather than just relative changes when evaluating lipid markers. He also questions the accuracy of using VLDL cholesterol as a measurement for VLDL remnants, suggesting it is a crude estimation. Despite this, targeting a VLDL cholesterol level below 15 milligrams per episode is still recommended for insulin-resistant patients.

Understanding Lipid Transportation Systems and Particle Numbers in Clinical Assessments

The therapy used to reduce LDL particles also helps in getting rid of remnant lipoproteins. Normalizing APOB or LDL particle number is crucial in making clinical decisions. There is a significant discordance between APOB or LDL particle number and non HDL cholesterol, indicating the need to rely on particle numbers for accurate clinical assessments. Alan Snyderman, who is highly respected in this field, emphasizes the importance of using particle numbers to make appropriate clinical decisions. Furthermore, it is important to understand the role of chylomicrons and VLDLs in delivering triglycerides, not cholesterol, to specific cells in the body. Cholesterol in these particles serves a structural purpose, making them spherical and allowing them to carry more triglycerides. Overall, this conversation highlights the significance of understanding lipid transportation systems and the role of different particles in cholesterol delivery.

The Actions of Lipoproteins Determine the Classification of Cholesterol

Cholesterol molecules are not inherently good or bad. What determines their classification is what the lipoprotein carrying the cholesterol does with it. HDL, often referred to as "good cholesterol," acts as a cholesterol acceptor and helps cells get rid of excess cholesterol. When HDL acquires free cholesterol, it transforms it into cholesterol ester and transfers it to other lipoproteins like LDL, commonly known as "bad cholesterol." However, the cholesterol molecule itself remains the same throughout this process. It is the actions of the lipoproteins that determine whether the cholesterol is beneficial or detrimental. Therefore, using terms like "good" and "bad" cholesterol can be misleading and should be avoided when discussing cholesterol with patients.

The importance of considering multiple lipid metrics in cardiovascular risk assessment

LDL cholesterol alone is not the only important factor when assessing cardiovascular risk. Many people argue that LDL cholesterol is irrelevant because it is calculated and not directly measured, introducing variability. However, it is important to consider other factors such as HDL cholesterol, triglycerides, and APOB as they are proxies for APOB, which is a strong indicator of atherosclerotic disease. Adjusting for APOB would significantly impact the role of low HDL cholesterol as an independent risk factor. Studies like the multi-ethnic study of atherosclerosis (MESA) and the Framingham offspring study offer valuable insights into the relationship between lipid metrics and cardiovascular risk. It is important to consider a comprehensive assessment of lipid levels when making recommendations for patient risk assessment.

The Limitations of Cholesterol Levels in Assessing Atherosclerosis Risk

Cholesterol levels alone cannot accurately determine the risk of atherosclerosis. In the case discussed, a woman had elevated atherosclerosis despite having normal levels of LDL ("bad" cholesterol) and high levels of HDL ("good" cholesterol). This was due to a rare genetic condition where the cholesterol trafficking pattern was disrupted, resulting in dysfunctional HDL particles that could not effectively clear cholesterol. Lowering APOB was found to be the only treatment option. It is important to consider other cardiovascular risk factors and not solely rely on cholesterol levels. The CTP inhibitors were mentioned as potential drugs to address HDL dysfunction, pointing to an interesting area of research in the field of cardiovascular health.

The Intricacies of Cholesterol Transfer and the Importance of HDL and LDL Teamwork

The process of cholesterol transfer within the body is highly intricate and involves multiple lipoproteins. HDL is responsible for pulling cholesterol out of cells and can transfer it to LDL particles. Surprisingly, 30 to 60 percent of the cholesterol in LDL particles comes from HDL particles. This teamwork between HDL and LDL is essential for proper lipid transportation. However, the measurement of HDL cholesterol levels alone does not provide a complete understanding of its functional status. More specific biomarkers are needed to assess HDL function accurately. The complexity of the lipid transportation system suggests that the term "reverse cholesterol transport" is overly simplistic and lacking in true understanding. Therefore, it is crucial to delve deeper into the intricacies of cholesterol transfer for effective treatment and nutrition therapies.

The Role of HDL Subpopulations in Transporting Substances to Cells

HDL subpopulations, with their various proteins and phospholipids, play a vital role in transporting necessary substances to specific cells in the body. Similar to how fire departments dispatch different trucks to different types of fires, HDL subpopulations show up where they are needed based on the recognition of proteins or phospholipids on their surface by the cells that need them. However, there is still much we don't understand about HDLs and how to analyze them effectively. Attempts to raise HDL levels through drugs like niacin and CTEP inhibitors have not been successful due to limited knowledge and understanding of HDL functionality. Furthermore, individuals with high HDL cholesterol levels may not necessarily have protection against coronary atherosclerosis, suggesting that other factors like APOE may be involved in the clearance of cholesterol.

Reevaluating the Use of CETP Inhibitors for Raising HDL Cholesterol Levels

The use of CETP inhibitors to raise HDL cholesterol levels was a misguided approach in the past. It was believed that raising HDL cholesterol through CETP inhibition would provide cardiovascular benefits. However, subsequent research, such as Mendelian randomization studies, showed that high HDL cholesterol does not necessarily protect against heart disease. The lack of understanding about the complex interplay between different lipid markers and genes led to the development of ineffective drugs. This highlights the importance of comprehensive research before developing medications that target specific markers. Additionally, it emphasizes the need for a nuanced approach in addressing cardiovascular risk factors, rather than solely focusing on one biomarker like HDL cholesterol.

Unexpected Challenges and Costly Trials in Drug Development

The development of certain drugs can be unpredictable and costly. The trial for the drug Torsetropip was initially thought to be a sure success but was ultimately terminated due to unforeseen toxicities. Despite this setback, Pfizer and other companies continued their research and developed different CTEP inhibitors. One such inhibitor, Dalsetripib, showed promising results with minimal toxicity. However, due to the expense of conducting trials and the availability of more effective alternatives like PCSK9 inhibitors, further development of Dalsetripib was discontinued. Merck was the only company to successfully complete a trial for a potent CTEP inhibitor, but concerns about its long-term effects and lack of significant benefits led them to choose not to bring it to market. The focus shifted towards finding safer options that could effectively lower APO B levels.

Balancing Innovation and Safety in Pharmaceutical Development

The pharmaceutical industry faces the challenge of balancing the potential benefits and risks of new drugs. In particular, the discussion highlights the case of Merck, who decided not to commercialize a product despite successful trials. This decision was driven by concerns about the long-term consequences and potential harm to other biological systems, as well as the strict regulations imposed by the FDA. The conversation also references the example of Vioxx, a drug that was hailed as a breakthrough but later withdrawn due to safety concerns. These instances illustrate the delicate balance between bringing innovative treatments to market and ensuring patient safety. It underscores the importance of taking a cautious and responsible approach in pharmaceutical development to avoid legal consequences and harm to patients.