Lipids, Cholesterol, and Heart Disease Notes

Cardiovascular Disease (CVD)

• CVD encompasses several conditions, including:

  • Coronary Heart Disease (CHD): Accounts for approximately half of all CVD cases. It involves the reduction of blood flow to the heart muscle due to atherosclerosis.

  • Ischemic Stroke: Represents a quarter of CVD cases; caused by a fat-derived blockage (thromboembolism) reducing blood flow to the brain, leading to neuronal damage and potential long-term disability.

  • Angina: Chest pain or discomfort caused by reduced blood flow to the heart, often a symptom of coronary artery disease.

  • Myocardial Infarction (Heart Attack): Results from an acute lack of oxygen to the myocardium tissue, leading to tissue death. Often caused by a sudden blockage of a coronary artery.

  • Atherosclerosis: Blockage in arteries due to thromboembolism (clot-derived blockage), characterized by the buildup of plaque inside the arteries, narrowing them and reducing blood flow.

Factors Linked to Heart Disease

• High Blood Cholesterol Levels:

  • Sources of Cholesterol:

    • Dietary Intake:

      • Approximately $500$ mg absorbed per day in the intestine. Absorption efficiency is between $30-60\%$. Approximately the same amount is secreted in bile, which can be reabsorbed or excreted in feces. Factors such as dietary fiber can affect cholesterol absorption.

    • De Novo Synthesis (in the liver):

      • Produces $650-900$ mg per day, which is secreted into the blood. This synthesis is tightly regulated by the body's cholesterol levels. Medications like statins target this pathway to lower cholesterol.

      • Total cholesterol production: $1-1.5$ g per day in a 70 kg male.

  • Cholesterol is required for:

    • Membrane synthesis: An essential component of cell membranes, maintaining their structure and fluidity.

    • Steroid hormone synthesis: Precursor to vital hormones like cortisol, aldosterone, estrogen, and testosterone.

Cholesterol Balance

• De novo synthesis contributes $600-1000$ mg of cholesterol in the liver. This is influenced by dietary intake and hormonal regulation.

• Diet contributes approximately $1$ g of cholesterol. This amount can vary widely based on dietary habits.

• About $750-1250$ mg is processed as bile acids and secreted into the intestine to aid in fat digestion.

• Approximately 50% of bile acids are reabsorbed in the ileum and returned to the liver via enterohepatic circulation.

• The remaining 50% (approximately $500$ mg) is excreted in feces, representing a major route of cholesterol elimination from the body.

• The cholesterol is taken up into the liver from the systemic circulation and gastrointestinal (GI) tract via various lipoprotein receptors.

High Blood Levels of Triacylglycerides

• Dietary intake: $60-130$ g of fat per day, with 90\%$ being absorbed mainly in the small intestine. Factors affecting absorption include pancreatic lipase activity and bile acid availability.

• Major energy source in some developed countries, constituting 40-45\%$ of the diet. High intake can lead to elevated blood triacylglyceride levels.

Biosynthesis of Fats and Cholesterol

• Fatty acids are converted to triacylglycerols (TAGs) via fatty acid synthase (FAS) in the cytoplasm. This process is influenced by diet and hormonal signals.

• Cholesterol is synthesized via the mevalonate pathway, a complex series of enzymatic reactions occurring in the endoplasmic reticulum. This pathway is a key target for cholesterol-lowering drugs.

Lipid Transport in Blood

• Fats are hydrophobic, posing a challenge for transport in the aqueous environment of the blood. They require transport mechanisms to reach different tissues.

• Delivery to peripheral cells is necessary for:

  • Energy needs (triacylglycerides - TAGs): TAGs are broken down to provide energy for cellular functions.

  • Membrane synthesis: Lipids are used to build and repair cell membranes.

  • Bile production: Cholesterol is converted into bile acids in the liver, aiding in the digestion and absorption of fats.

• Lipids associate non-covalently with proteins in plasma or serum, forming lipoproteins or chylomicrons. These structures allow lipids to be transported throughout the body.

• Lipoproteins are classified by density:

  • Density = Protein : Lipid. The ratio of protein to lipid determines the density of the lipoprotein particle.

  • Higher lipid content results in lower density. Lipoproteins with more triacylglycerides are less dense than those with more protein.

  • Isolation is achieved by ultracentrifugation, a technique that separates particles based on their density.

Cholesterol Transport

• Besides de novo biosynthesis, cholesterol and fatty acids are also obtained from the diet, contributing to the total pool of lipids.

• Cholesterol Transport Pathways:

  • Forward Transport: From the GI tract to the liver and peripheral tissues. This involves the absorption of dietary cholesterol and its distribution throughout the body.

  • Reverse Transport: From peripheral tissues back to the liver, a crucial process for removing excess cholesterol from cells and reducing the risk of atherosclerosis.

• Cholesterol can be converted into bile in the liver, which is then secreted into the intestine to aid in fat digestion and absorption.

Lipoprotein Structure

• Outer Section:

  • Polar proteins (apolipoproteins) that interact with the aqueous environment of the blood.

  • Phospholipid head groups, forming a hydrophilic surface that stabilizes the lipoprotein particle.

  • Apoproteins, which have structural and functional roles, including activating enzymes and binding to receptors.

• Inner Section:

  • Hydrophobic lipid components, sequestered away from the aqueous environment.

  • Fatty acids (FA), lipids, cholesterol (free/esterified), which constitute the core of the lipoprotein particle.

• Classes of lipoproteins: HDL, IDL, LDL, VLDL. Each class has distinct functions and compositions.

• HDL is further split into two classes, HDL2 and a little VHDL, based on density and apolipoprotein content.

Lipoprotein Composition

• Different lipoproteins have varying compositions of protein, phospholipids, cholesterol, cholesteryl esters, and triacylglycerols. These differences influence their function and metabolism.

• Chylomicrons have a very high triacylglycerol content (85%) and low protein content (2%). They are responsible for transporting dietary fats from the intestine.

• VLDL has a high triacylglycerol content (50%) and a moderate protein content (10%). VLDL transports endogenously synthesized triacylglycerides from the liver to peripheral tissues.

• LDL is rich in cholesteryl esters (37%) and has a protein content of 23%. LDL is the primary carrier of cholesterol in the blood and delivers cholesterol to cells.

• HDL has the highest protein content (55%) and a relatively lower triacylglycerol content (4%). HDL is involved in reverse cholesterol transport, removing cholesterol from cells and transporting it to the liver.

Apolipoproteins

• Apolipoproteins play critical roles in lipoprotein metabolism, including structural support, enzyme activation, and receptor binding.

• Examples Include:

  • ApoA-I: Activates LCAT (lecithin-cholesterol acyltransferase) and interacts with the ABC transporter; found in HDL. ApoA-I is crucial for HDL's role in reverse cholesterol transport.

  • ApoA-II: Inhibits LCAT; found in HDL. ApoA-II modulates HDL metabolism and may have anti-atherogenic effects.

  • ApoB-48: Involved in cholesterol transport/clearance; found in chylomicrons. ApoB-48 is essential for the assembly and secretion of chylomicrons from the intestine.

  • ApoB-100: Binds to the LDL receptor; found in VLDL and LDL. ApoB-100 mediates the uptake of LDL into cells via receptor-mediated endocytosis.

  • ApoC-II: Activates lipoprotein lipase; found in chylomicrons, VLDL, and HDL. ApoC-II is required for the hydrolysis of triacylglycerides in chylomicrons and VLDL.

  • ApoE: Triggers clearance of VLDL and chylomicron remnants; found in chylomicrons, VLDL, and HDL. ApoE mediates the binding of these remnant particles to hepatic receptors, facilitating their uptake by the liver.

Lipoprotein Overview

• VLDL: Secreted from the liver (free cholesterol : esterified cholesterol ≈ 1:1). VLDL transports endogenously synthesized triacylglycerides to peripheral tissues.

• IDL: Possible intermediate between VLDL and LDL. IDL is formed during the breakdown of VLDL and can be further metabolized to LDL.

• LDL: Major carrier of cholesterol (60\%); 90% apoprotein = Apo B-100. LDL delivers cholesterol to cells via receptor-mediated endocytosis.

• HDL: Highest ratio of protein to lipid (1:1); strong inverse relationship with cardiovascular disorders. HDL participates in reverse cholesterol transport, removing excess cholesterol from cells and transporting it to the liver for excretion.

• Chylomicrons: Deliver TAG and cholesterol esters from the gut to the liver. Chylomicrons are formed in the intestine and transport dietary fats to the liver and peripheral tissues.

Chylomicrons

• Water-insoluble spherical globules, ranging in size from 75 to 1200 nm.

• Core: 95% TAG and 5% cholesterol esters, compared to LDL and HDL (20% TAG and 80% cholesterol esters). The core contains the majority of the dietary fats.

• Outer shell: phospholipids, cholesterol, apoproteins C (66%), B (22%), and A (12%). The outer shell stabilizes the particle and allows it to interact with the aqueous environment of the blood.

• Involved in forward transport of cholesterol from the intestine to the liver and peripheral tissues.

Chylomicron Formation

• Chylomicrons are formed in the intestine (specifically, within the enterocytes) possibly via the Golgi apparatus.

• Secreted during the absorption of dietary fat (TAG), typically within 30 minutes of fat ingestion.

• Size is related to the amount of fat intake; higher fat intake leads to larger chylomicrons.

• Production continues post-absorptive state, although at a reduced rate.

Cholesterol Uptake from Diet

• Intestinal cell uptake of cholesterol involves transport proteins like NPC1L1.

• Cholesterol is converted to cholesterol ester by ACYL: COENZYME A-O-ACYLTRANSFERASE (ACAT), facilitating its incorporation into chylomicrons.

Cholesterol Esterification

• Acyl-CoA-cholesterol acyl transferase (ACAT) esterifies cholesterol with a fatty acyl-CoA to form cholesteryl ester, a more hydrophobic form of cholesterol that can be efficiently packaged into lipoproteins.

Fat-Soluble Vitamin Uptake

• Vitamins are also transported by chylomicrons, ensuring their delivery to various tissues.

• Examples: carotenoids, retinyl esters (Vitamin A), and tocopherol esters (Vitamin E).

Apoproteins in Chylomicrons

• Synthesized in the intestinal mucosal cells and are essential for normal function, including lipoprotein assembly and metabolism.

• Initially have Apo B48, A3, and A4. These apoproteins play various roles in chylomicron structure and function.

• Apo B100 is post-transcriptionally modified to generate ApoB48. This modification is unique to the intestine.

• To generate ApoB48, CAA becomes UAA (2153 glu becomes a termination codon), generating a truncated 2152 amino acid protein. This process involves RNA editing.

Chylomicrons in Plasma

• Chylomicrons in the plasma contain Apo B48, C, and E, which they acquire from HDL.

Mature Chylomicrons

• Apo CII is essential for binding to endothelial cells via lipoprotein lipase (bound to the cell surface via a proteoglycan). This binding triggers the hydrolysis of triacylglycerides.

• The rate of hydrolysis depends on the number of Apo CII (up to 12). More Apo CII molecules result in faster hydrolysis.

• Chylomicrons have a half-life of 10-15 minutes in circulation, reflecting their rapid metabolism.

• Lipoprotein lipase hydrolyzes a TAG in the chylomicron to remove a fatty acid, releasing fatty acids and glycerol into the tissues.

Lipoprotein Lipase

• Highly regulated by hormones, nutritional status, and tissue-specific factors.

• Synthesized initially by parenchymal cells of tissue and then secreted and relocates to capillary endothelium. This ensures that lipolysis occurs at the site of uptake.

• Bound by polysaccharide chains to the endothelial cells. These chains help to anchor the enzyme to the capillary surface.

• Rapid turnover: half-life of a few hours, allowing for quick adjustments in response to changing metabolic needs.

• Insulin promotes the synthesis of lipoprotein lipase in adipose tissue, facilitating the storage of fat after a meal.

Chylomicron Binding

• After hydrolysis of TAG, ApoC leaves the chylomicrons and returns to HDL, modulating the activity of other lipoproteins.

Chylomicron Remnants

• Still contain 20% of initial TAG and 100% of cholesterol esters. These remnants are enriched in cholesterol.

• Transported to the liver, where they are taken up and further processed.

• Hepatic lipoprotein receptors recognize B48 and take up the chylomicron remnant (similar uptake to LDL). This process clears the remnants from circulation.

Chylomicron System

• Up to 300 g of TAG can be hydrolyzed daily, highlighting the efficiency of this system.

• Very rapid: less than 1% detected in blood at any one time, indicating efficient clearance.

• Half-life: <10 minutes, even shorter for remnant chylomicrons, ensuring rapid removal of dietary fats from circulation.

Clinical Disorders: Abetalipoproteinemia

• Genetic disorder (autosomal recessive): inability to synthesize Apo B (B48 or B100), therefore affecting chylomicron (or LDL) production. This leads to impaired fat absorption and lipoprotein metabolism.

• Steatorrhea: frothy, foul-smelling, and floating stool due to high fat content. This is a result of unabsorbed fats in the intestine.

• Fats and fat-soluble vitamins are not absorbed in the diet, leading to deficiencies in essential nutrients.

Clinical Disorders: Hyperlipoproteinemia

• Often due to lipoprotein lipase deficiency or defects in ApoC-II, leading to impaired triacylglyceride hydrolysis.

• Massive hyperchylomicronemia occurs when the patient is on a normal diet and disappears completely in a few days on fat-free feeding. This indicates that dietary fat is the primary source of the elevated chylomicrons.

  • Deficiency of LPL (Type 1): Lack of functional lipoprotein lipase.

  • Production of abnormal LPL (Type 2): Production of a defective enzyme with reduced activity.

  • ApoC-II deficiency: Lack of the essential activator for lipoprotein lipase.

Clinical Disorders: Diabetes Mellitus (Type 1)

• Autoimmune destruction of insulin-producing cells, leading to insulin deficiency.

• Decreased insulin affects LPL synthesis as a side effect, resulting in hyperlipoproteinemia. Insulin is crucial for the synthesis of LPL in adipose tissue.

Summary / Learning Outcomes

• Introduction to cholesterol uptake from the diet and its esterification within intestinal cells.

• Difference between different lipoproteins in terms of content (Chylomicrons/LDL/HDL), including their apolipoprotein composition and function.

• Different Apoproteins for different lipoproteins, including their roles in lipoprotein metabolism and receptor binding.

• The specific production and processing of chylomicrons, from their assembly in the intestine to their clearance from the circulation.