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Lipoprotein Structures, Function and Metabolism

Lipoprotein Structures, Function and Metabolism (2). Lipoproteins in plasma. Density Mobility Component CM CM TG rich

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Lipoprotein Structures, Function and Metabolism

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  1. Lipoprotein Structures, Function and Metabolism (2)

  2. Lipoproteins in plasma Density Mobility Component CM CM TG rich VLDL Pre-b-lipoprotein TG rich LDL b-lipoprotein Cholesterol rich HDL a-lipoprotein Cholesterol/protein rich

  3. Chylomicron Transport dietary lipids from the intestine to the peripheral tissues

  4. VLDL – IDL - LDL • VLDL function: Deliver TG from liver to peripheral tissue cells • LDL function: Deliver Cholesterol from live to peripheral tissue cells

  5. Metabolism of VLDL and LDL

  6. LDL • Cholesterol rich • Can be taken up either by the peripheral tissues or by the liver • LDL is taken up by LDL receptor through apoB100/LDL receptor interaction. • After internazation, the LDL is digested by lysosomal enzymes. The cholesterol is released and the receptor recycles back to the membrane. • LDL function: Deliver cholesterol from liver to peripheral tissue cells.

  7. LDL receptor (839 aa) extracellular domain is responsible for apoB100/apoE binding intracellular domain is responsible for clustering of LDL receptors into clathrin- coated pit region of plasma membrane LDL receptors exist in most peripheral tissues and in the liver.

  8. Michael S. Brown and Joseph L. Goldstein discovered LDL-receptor. 1985 Nobel prize in Medicine

  9. LDL cholesterol levels are positively related to risk of cardiovascular disease • Therefore, cholesterol in LDL has been called “bad cholesterol” • Defects in the LDL receptor leads to familial hypercholesterolemia

  10. Familial Hypercholesterolemia • LDL-receptor deficiency • 420 different mutations identified • LDL-receptor activity: 0-25% of normal • Classes of LDL-receptor mutations • 1 – no receptors • 2 – blockage of receptor from ER to Golgi Apparatus • 3 – receptor does not bind LDL normally • 4 – receptor does not accumulate in clathrin-coated pit • 5 – receptor fails to release LDL after internalization and does not recycle to cell surface

  11. Metabolism of HDL

  12. HDL • HDL are synthesized in the liver and intestine as a small disc-like particle. • Proteins on the surface of HDL: apoAs, apoCs, apoE, CETP，LCAT. • Nascent HDL acquires cholesterol in peripheral tissues.

  13. HDL • The cholesterol is esterificated by LCAT (lecithin cholesterol • acyltransferase)associated with the particle. This reaction is • activated by apoA-I • The cholesterol ester move to the hydrophobic core of the • particle and particle becomes spherical.

  14. HDL • HDL particles bind to SRB1 receptors (scavenger receptor type B1) on the liver and are taken into the cells. • HDL particles are also a reservoir for apolipoproteins (especially apoE & apoCII） • Some of the CE in HDL is transferred from HDL to other lipoproteins by cholesterol ester transfer protein （CETP）

  15. HDL • HDL salvage excess cholesterol from cells and reverse-transport cholesterol from peripheral cells to the liver for excretion • HDL cholesterol levels are inversely related to risk of cardiovascular disease • Therefore, cholesterol in HDL has been called “good cholesterol”

  16. Main Functions of Lipoproteins • CM: transfer exogenous lipids (dietary fat) from intestine to peripheral tissues. • VLDL-LDL: transfer endogenous lipids from liver to peripheral tissues. • HDL: reverse cholesterol transport from peripheral tissues to liver.

  17. Lipoproteins (a) • Another kind of atherogenic lipoprotein. • Consist of LDL and a protein designated as apo(a) • The apo(a) is covalently linked to apoB-100 by a disulfide linkage • High risk association with premature coronary artery disease and stroke.

  18. Hyperlipoproteinemia

  19. Fredrickson classification of hyperlipoproteinemia Type I (hyperchylomironemia): Increased CM Type II-A (hyper-b-lipoproteinemia): Increased LDL Receptor deficiency or polygenic disorder. Type II-B: Increased VLDL + LDL Increased production of VLDL and impaired LDL catabolism Type III: (broad-b-lipoproteinemia) Increased IDL, elevated cholesterol and triglycerides

  20. Fredrickson classification Type IV: (hyper-pre-b-lipoproteinemia) Increased VLDL Impaired VLDL catabolism Type V: Increased CM + VLDL Reduced lipoprotein lipase

  21. Where do we get cholesterol? • Our bodies make all the cholesterol we need. • We also get cholesterol from foods we eat.

  22. Blood cholesterol levels increase by eating these products Beef poultry, fish milk, eggs, cheese, yogurt, etc.

  23. Why worry about cholesterol? Blood cholesterol can stick to the sides of arteries. Blockages can form. It can lead to serious medical problems: Heart attack and Stroke.

  24. What does my total cholesterol mean? • 200-239 mg/dL

  25. HDL Cholesterol

  26. LDL Cholesterol

  27. Triglycerides

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