Lipoprotein Structures, Function and Metabolism

1. Lipoprotein Structures, Function and Metabolism (4)

2. Cholesterol synthesis • About 1g of cholesterol is synthesized per day in adults, liver: 50%; intestine 15%; other tissues: 35%. • All C-atoms of cholesterol come from acetyl CoA; reducing equivalents come from NADPH • Energy to drive synthesis comes from ATP hydrolysis • Key enzyme (rate limiting enzyme) in cholesterol synthesis is HMG CoA reductase

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4. Function of bile acids • Aid in digestion and absorption of dietary fat: emulsify fats due to detergent activity • Stimulate the action of pancreatic lipase • Stimulate intestinal motility • Keep cholesterol in solution (as micelles)

5. Bile acids are efficiently recycled Enterohepatic circulation: • Bile acids are efficiently reabsorbed in the intestine and returned via the portal vein to the liver for reuse (enterohepatic circulation) • Of 15-30 g of bile acids secreted/day, only 0.5 g are lost in feces (i.e., 0.5 g of cholesterol is excreted)

6. Cholelithiasis If more cholesterol enters the bile than can be excreted, cholesterol may precipitate/ crystallize in the gallbladder leading to gallstone disease • Causes: • obstruction of the bile duct • severe hepatic dysfunction • excessive suppression of bile acid synthesis

7. Lipoproteins and Atherosclerosis LDL: Risk factor for atherosclerosis HDL: Protective factor for atherosclerosis

8. Atherosclerosis • a condition in which an artery wall thickens as the result of a build-up of fatty materials such as cholesterol. • a syndrome affecting arterial blood vessels. • a chronic inflammatory response in the walls of arteries, mainly due to the accumulation of macrophage white blood cells and promoted by low-density lipoproteins • thickening and loss of elasticity of arterial walls • hardening of the arteries

9. Coronary Heart Disease (CHD) • CHD is one of the most common and serious effects of atherosclerosis. Cholesterol deposits build up in blood vessel walls and narrow the passageway for the movement of blood. The resulting condition often leads to eventual blockage of the coronary arteries and a “heart attack”.

10. Risk Factors Controllable Uncontrollable • Sex • Men more prone than women • Hereditary • Genetic differences • Age • Atherosclerosis begins in the young, but does not precipitate organ injury until later in life • High blood pressure • High blood cholesterol • Smoking • Lack of physical activity • Obesity • Diabetes • Stress and anger

11. Cholesterol and CHD

12. Normal Artery

13. Lipoproteins and atherosclerosis • The endothelium in the arterial wall becomes more permeable to lipoprotein and allows migration of cells to the underlying layer (intima). • LDL penetrate the vascular wall and deposit in the intima, where they undergoing oxidation to become oxidized LDL (OxLDL). • Oxidized LDL stimulate endothelial expression of some adhesion molecules. • Adhesion molecules attract monocytes, which enter the wall and transform into macrophages.

14. Vessel Lumen Monocyte LDL Endothelium MCP-1 LDL oxidized LDL Intima . Role of LDL in Atherosclerosis MCP-1: monocyte chemotactic protein-1

15. Vessel Lumen Monocyte LDL Endothelium MCP-1 LDL Intima Oxidized LDL OX-LDL PromoteDifferentiation ofMonocytes intoMacrophages Macrophage Role of LDL in Atherosclerosis

16. Vessel Lumen Monocyte LDL AdhesionMolecules Endothelium MCP-1 LDL Cytokines Ox-LDL Intima Macrophage Role of LDL in Atherosclerosis

17. Vessel Lumen Monocyte LDL AdhesionMolecules Endothelium MCP-1 LDL OX-LDL Taken up by Macrophage Intima Macrophage Foam Cell Steinberg D et al. N Engl J Med 1989;320:915-924. Role of LDL in Atherosclerosis

18. LDL must be oxidized to be pathogenic (atherogenic) • In macrophage: • High affinity receptor specific for LDL (LDL receptor) become down- • regulated when the cell has sufficient cholesterol; • Non-specific scavenger receptors take up OX-LDL cholesterol and are not • down-regulated by cholesterol in the cells.

19. Macrophage take up oxidized LDL, when overload with lipid, become “foam cells”. • Conglomerate of foam cells form fatty streaks or yellow patches visible in the arterial wall. • Dying foam cells release lipid that form lipid pool within the arterial wall. Foam cells

20. Surrounding smooth muscle start to secrete a range of small peptides, which stimulate smooth muscle cells to proliferate and to migrate toward the lumen side of the arterial wall. • In the same time, smooth muscle cells start synthesizing extracellular matrix, such as collagen. • Relocated smooth muscle cells, collagen-rich fibrous tissue, macrophages all together form a “Cap” that cover the lipid pool. This is a matured atherosclerotic plaque.

21. Fibrous cap Thrombus Lipid core • The plaque protrudes into the arterial lumen, grows slowly over years, and finally obstruct the artery. This decreases blood flow in the affected vessel. • Rupture or ulceration of fibrous cap rapidly leads to thrombosis and obstruct the artery.

22. HDL is Protective • HDL prevent foam cell formation • HDL inhibits oxidative modification of LDL • HDL inhibits expression of adhesion molecules

23. Vessel Lumen Monocyte LDL Endothelium AdhesionMolecules MCP-1 LDL OX-LDL Cytokines Foam Cell Macrophage Intima HDL Promote Cholesterol Efflux Miyazaki A et al. Biochim Biophys Acta 1992;1126:73-80. HDL Prevent Foam Cell Formation Lipids Online

24. Vessel Lumen Monocyte LDL Endothelium AdhesionMolecules MCP-1 LDL HDL InhibitOxidationof LDL OX-LDL Cytokines Foam Cell Macrophage Intima HDL Promote Cholesterol Efflux . HDL Inhibits Oxidative Modificationof LDL

25. HDL Inhibit Adhesion Molecule Expression Monocyte Vessel Lumen LDL Endothelium AdhesionMolecules MCP-1 LDL HDL InhibitOxidationof LDL OX-LDL Cytokines Foam Cell Macrophage Intima HDL Promote Cholesterol Efflux HDL Inhibits Expression ofAdhesion Molecules Lipids Online

26. Get regular medical checkups. • Control your blood pressure. • Check your cholesterol. • Don’t smoke. • Exercise regularly. • Maintain a healthy weight. • Eat a heart-healthy diet. • Manage stress. Prevention

27. Cholesterol Drugs? Talk to your doctor, and follow his/her advice.