7. Cholesterol & Lipid Metabolism

Cholesterol & Lipoprotein Metabolism

Overview

• Presenter: Dr. Declan McKernan, University of Galway

• Course: PM309 Cardiovascular Drugs

Learning Outcomes

• Understand the processes of:

  • Absorption of lipoproteins

  • Metabolism and transport of lipoproteins

• Recognize factors contributing to atherosclerosis

Fat Digestion

• Sources of Fat:

  1. Dietary intake of fat

  2. Liver synthesis of fat

• Digestion Process:

  1. Dietary fats emulsified by bile salts in the small intestine.

  2. Intestinal lipases break down triacylglycerols (TGs).

  3. Fatty acids absorbed and converted back into TGs.

  4. TGs incorporated into chylomicrons.

  5. Chylomicrons circulate through the bloodstream.

  6. Lipoprotein lipase (LPL) releases glycerol and fatty acids from TGs.

  7. Fatty acids enter cells for energy or storage.

• Role of Lipoproteins:

  • Transport triglycerides and organize cholesterol movement.

Lipids & Plasma Lipoproteins

• Functions of Fats:

  • Energy source, cell membrane integrity, bile production, steroid hormones, intercellular signaling (e.g., prostaglandins).

• Lipoproteins:

  • Transport triglycerides and cholesterol in blood, differentiated by density, size, and protein content (larger, less dense lipoproteins contain more lipids).

Lipoproteins Structure & Function

• Structure:

  • Surface: Monolayer of phospholipid and unesterified cholesterol.

  • Core: Hydrophobic triglycerides and cholesteryl esters.

  • Amphipathic apolipoproteins provide stability.

• Functions:

  • Transport hydrophobic molecules (cholesterol, triglycerides, fat-soluble vitamins).

  • Serve as ligands for receptors or co-factors in enzymatic reactions.

  • ApoB-containing lipoproteins: Deliver TGs to muscle and fat tissues (includes chylomicrons and VLDL).

  • HDL and apoB remnants primarily involved in cholesterol transport.

Lipoprotein Metabolism

• Key Components:

  • Hepatic and peripheral interactions (e.g., LDL, HDL, VLDL).

• LDL Function:

  • Internalized via receptors and influence cellular cholesterol levels.

Assembly of ApoB-Containing Lipoproteins

• Purpose: Deliver fatty acids as TGs to muscle and adipose tissue.

• Types:

  • Chylomicrons (dietary TG transport) and VLDL (endogenous TG transport).

• Assembly Regulation:

  • Availability of apolipoprotein B and triglycerides, microsomal triglyceride transfer protein (MTP), and tissue-specific editing of mRNA.

Absorption of Cholesterol & Triglycerides

• Mechanism:

  • Micelles facilitate absorption in enterocytes (duodenum, jejunum).

  • Long-chain fatty acids and monoglycerides enter via carrier-mediated transport and are re-esterified into TGs.

  • Cholesterol absorbed via Niemann-Pick C1-like 1 (NPC1L1) from micelles.

  • Remaining cholesterol esterified and packaged with apoB48 for transport.

Intravascular Metabolism

• Interaction of ApoCII:

  • Acquired by chylomicrons and VLDL from HDL, facilitating LPL binding.

• Function of LPL: Hydrolyzes TGs, promoting uptake of fatty acids in muscle or adipose cells.

Receptor-Mediated Clearance of ApoB Lipoproteins

• Process:

  • Hydrolyzed lipoprotein remnants bind to liver receptors, leading to uptake by hepatocytes.

  • LDL and LRP play crucial roles in clearance of lipoproteins.

Formation & Clearance of LDL Particles

• Chylomicrons vs. VLDL: Only 50% of VLDL are cleared from plasma.

• IDL & LDL Formation: Through interactions with hepatic lipase and loss of apolipoproteins.

• LDL Internalization: Triggered by binding between apoB100 and LDL receptors, influencing cholesterol metabolism.

Cholesterol Synthesis

• Pathways:

  • De novo biosynthesis from acetyl-CoA through several steps yielding cholesterol.

  • Uptake and export mechanisms also involved, regulated by various proteins (NPC1L1, ABCA1).

HDL Formation

• Function of HDL:

  • Primarily produced by liver to remove excess cholesterol from cells (reverse cholesterol transport).

  • Formation involves interaction with several proteins (e.g., apoAI, LCAT).

• Process:

  1. Initial formation of pre-β-HDL.

  2. Maturation into α-HDL and cholesterol uptake.

Biliary Lipid Secretion

• Liver Functions:

  • Secretes unesterified cholesterol or converts it to bile acids, promoting fat digestion.

• Biliary Lipids: Stored in gallbladder, released during fatty meals.

• Enterohepatic Circulation: Biliary acids re-enter the liver after fat digestion.

Risk Factors for Atherosclerosis

• Lipid Levels:

  • Various combinations of LDL, HDL, total cholesterol and triglyceride levels indicate different risk levels for atherosclerosis.

LDL & Atherosclerosis

• Mechanism:

  • LDL receptors crucial for LDL clearance; elevated LDL can complicate atherosclerosis.

• Atherosclerosis Development:

  • Involves LDL oxidation, foam cell formation, inflammation, and plaque development.

Summary

• Key Lipoproteins: Chylomicron, VLDL, LDL, IDL, HDL are vital for fat and cholesterol transport.

• Core Functions: Serve as energy sources and biomolecular structures.

• Regulation: Lipoprotein metabolism impacts atherosclerosis risk; dysfunctional processes can lead to diseases.