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 synthe

sis 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 recycledEnterohepatic 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)

Cholelithiasis If more cholesterol enters the bile than can be excreted, cho

lesterol 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 FactorsUncontrollable

• Sex

Men more prone than womenMen more prone than women

• HereditaryGenetic differencesGenetic differences

• AgeAtherosclerosis begins in the Atherosclerosis begins in the young, but does not precipitate young, but does not precipitate organ injury until later in lifeorgan injury until later in life

Controllable

• High blood pressure• High blood cholesterol• Smoking• Lack of physical activity• Obesity• Diabetes• Stress and anger

Cholesterol and CHDCholesterol 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

LDLLDL

LDL

.

Endothelium

Vessel LumenVessel Lumen

IntimaIntima

MonocyteMonocyte

oxidized LDL

MCP-1

MCP-1: monocyte chemotactic protein-1

Role of LDL in Atherosclerosis

LDLLDL

LDLLDLEndothelium

Vessel LumenVessel Lumen

IntimaIntima

MonocyteMonocyte

Oxidized LDLOxidized LDLOX-LDL PromoteDifferentiation ofMonocytes intoMacrophages

MCP-1MCP-1

Macrophage

Role of LDL in Atherosclerosis

LDLLDL

LDLLDLEndothelium

Vessel LumenVessel LumenMonocyte

Ox-LDL

MacrophageMacrophage

MCP-1MCP-1

AdhesionMolecules

Cytokines

IntimaIntima

Role of LDL in Atherosclerosis

LDLLDL

LDLLDLEndothelium

Vessel LumenVessel LumenMonocyteMonocyte

Macrophage

MCP-1

AdhesionAdhesionMoleculesMolecules

Steinberg D et al. N Engl J Med 1989;320:915-924.Foam Cell

OX-LDL Taken up by

Macrophage

IntimaIntima

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

LDLLDL

LDL

Miyazaki A et al. Biochim Biophys Acta 1992;1126:73-80.

Endothelium

Vessel LumenVessel LumenMonocyte

OX-LDL

Macrophage

MCP-1AdhesionMolecules

Cytokines

IntimaIntimaHDL Promote Promote Cholesterol Efflux Efflux

Foam Cell

Lipids Online

HDL Inhibits Oxidative Modificationof LDL

LDLLDL

LDL

.

Endothelium

Vessel LumenVessel LumenMonocyte

OX-LDLLDL

Macrophage

MCP-1AdhesionMolecules

Cytokines

Foam Cell

HDL Promote Cholesterol EffluxIntimaIntima

HDL InhibitOxidation

of LDL

HDL Inhibits Expression ofAdhesion Molecules

LDLLDL

LDLEndothelium

Vessel LumenVessel LumenMonocyte

OX-LDL

Macrophage

MCP-1MCP-1AdhesionMolecules

Cytokines

IntimaIntima

HDL InhibitOxidation

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.