Lipoprotein Structures, Function and Metabolism (4)

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

acid

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)

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 g of bile acids secreted/day, only 0.5 g are lost in feces (i.e., 0.5 g of cholesterol is excreted)

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

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

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

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”.

Risk Factors 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 Controllable High blood pressure High blood cholesterol Smoking Lack of physical activity Obesity Diabetes Stress and anger

Cholesterol and CHD

Normal Artery

Lipoproteins and atherosclerosis 1.The endothelium in the arterial wall becomes more permeable to lipoprotein and allows migration of cells to the underlying layer (intima). 2.LDL penetrate the vascular wall and deposit in the intima, where they undergoing oxidation to become oxidized LDL (OxLDL). 3.Oxidized LDL stimulate endothelial expression of some adhesion molecules. 4.Adhesion molecules attract monocytes, which enter the wall and transform into macrophages.

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

Role of LDL in Atherosclerosis LDL LDL Endothelium Vessel Lumen Intima Monocyte Oxidized LDL OX-LDL Promote Differentiation of Monocytes into Macrophages MCP-1 Macrophage

Role of LDL in Atherosclerosis LDL LDL Endothelium Vessel Lumen Monocyte Ox-LDL Macrophage MCP-1 Adhesion Molecules Cytokines Intima

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

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.

5.Macrophage take up oxidized LDL, when overload with lipid, become “foam cells”. 6.Conglomerate of foam cells form fatty streaks or yellow patches visible in the arterial wall. 7.Dying foam cells release lipid that form lipid pool within the arterial wall. Foam cells

8.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. 9.In the same time, smooth muscle cells start synthesizing extracellular matrix, such as collagen. 10. 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.

11. The plaque protrudes into the arterial lumen, grows slowly over years, and finally obstruct the artery. This decreases blood flow in the affected vessel. 12. Rupture or ulceration of fibrous cap rapidly leads to thrombosis and obstruct the artery. Thrombus Fibrous cap Lipid core

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

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

HDL Inhibits Oxidative Modification of LDL LDL LDL. Endothelium Vessel Lumen Monocyte LDL OX- LDL Macrophage MCP-1 Adhesion Molecules Cytokines Foam Cell HDL Promote Cholesterol Efflux Intima HDL Inhibit Oxidation of LDL

HDL Inhibits Expression of Adhesion Molecules LDL LDL Endothelium Vessel Lumen Monocyte OX-LDL Macrophage MCP-1 Adhesion Molecules Cytokines Intima HDL Inhibit Oxidation of LDL HDL Inhibit Adhesion Molecule Expression Foam Cell HDL Promote Cholesterol Efflux Lipids Online

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.

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