ChylomicronTransport dietary lipids from the intestine to the peripheral tissues

VLDL – IDL - LDL

• VLDL function: Deliver TG from liver to peripheral tissue cells• LDL function: Deliver Cholesterol from live to peripheral tissue cells

HDL function:

Reverse-transport cholesterol from peripheral cells to the liver for excretion

Cholesterol metabolism

Exclusively found in animal: animal sterol

2g/kg for health person

Role of cholesterol1. An essential component of cell membranes, has a vital role f

or membrane functions.

2. Used to synthesize bile acids in the liver.

3. Used to synthesize steroid hormones. glucocorticoids

mineralocorticoids androgens estrogens progestins

4. Used to synthesize Vitamin D.

Liver is most important organ for cholesterol metabolism

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; reduc

ing 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

Cholesterol synthesis

• First three acetyl CoA forms HMG CoA

• HMG CoA reductase catalyzes the rate limiting (regulated) step of the pathway, formation of mevalonic acid from HMG CoA and 2 NADPH

• Decarboxylation of mevalonic acid forms isopentyl-pyrophosphate (IPP, 5-C unit).

• Condensation of two IPP forms geranyl PP (GPP, 10-C)

• Condensation of GPP and IPP forms farnesyl PP (FPP, 15-C).

• Condensation of two FPP forms squalene (30-C).

• Squalene becomes cyclized lanosterol, and then cholesterol

Regulation of cholesterol synthesis

• Regulation of cholesterol synthesis via :– feedback inhibition of HMG CoA reductase by cholesterol

– cholesterol inhibits transcription of HMG CoA reductase gene

– Inhibit by drugs, such as Compactin and Lovastatin.

R= H: compactin

R= CH3: lovastatin

-- hormonal regulation of HMG-CoA reductase glucagon leads to phosphorylation: inactivate the enzyme insulin favors dephosphorylation: activate the enzyme

Metabolism of Bile acids

• Formed from cholesterol in the liver

• Rate limiting step is the conversion of cholesterol to 7-alpha cholesterol by 7--hydroxylase

• Utilized during digestion of fats (act as detergents)

Bile acids & salts• Before leaving the liver, bile acids are conjugated in amide

linkage to glycine (glycocholic acid) or taurine (e.g. taurochenodeoxycholic acid)

• These compounds are more fully ionized at neutral pH (carboxylate and sulfate, with low pKa) and are better detergents

HO HO OH7a-hydroxylase

NADPH + H + NADP

cholesterol 7a-hydroxycholesterol

HO OH

OH

C S

O

CoA

H

HO OH

C S

O

CoA

H

chenodeoxycholyl- CoA

cholyl-CoA

12a-hydroxylaseO2; NADPH + H +

2 CoA-SHO2NADPH + H +

2 CoA-SH

Synthesis of Bile Acids

HO

C S

O

CoA

Hcholyl-CoA

HO

C

O

H

N CH2 COOH

glycineCoA-SH

Conversion of cholyl-CoA to glycocholic acid

Glycocholic acid

Glycochenodeoxycholic acid

Conversion of cholyl CoA to taurocholic acid

Taurocholic acid Taurochenodeoxycholic acid

Taurine

Secondary bile acids

• Bacteria in the intestine can remove glycine and taurine• They can also modify bile acids to form secondary bile acid

s (minus one -OH group, e.g., deoxycholic acid, lithochoic acid)

acid

Glycocholic acid

Deoxycholic acid

Taurocholic acid

Glycochenodeoxycholic acid

Taurochenodeoxycholic acid

Lithocholic acid

About bile acids

• Cholic acid is the bile acid found in the largest amount in bile

• Cholic acid and chenodeoxycholic acid are referred to as primary bile acids

• Bile acids are converted to either glycine or taurine conjugates (in humans the ratio of glycine to taurine conjugates is 3:1)

• Bacteria in the intestine can remove glycine and taurine. They can also modify bile acids to form secondary bile acids (minus one -OH group, e.g., deoxycholic acid, lithochoic 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)

Emulsification of Fat by Bile

• Mixed micelle formed by bile acids, triacylglycerols and pancreatic lipase

• Detergent character of bile salts is due to the hydrophobic-hydrophilic nature of the molecules

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 gall bladder leading to gallstone disease

• Causes:– severe ileal disease– 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• hardening of the arteries due to the deposition of ather

omas• caused by the deposition of cholesteryl esters on the wal

ls of arteries• atherosclerosis is correlated with high LDL and low H

DL

Author: Sukhinder C. Kaur

572 pages, Springer; $139.00

Cholesterol & risk of heart diseaseTotal Cholesterol CategoryLess than 200 mg/dL Desirable level

200-239 mg/dL Borderline high

240 mg/dL and above High blood cholesterol (more than doubles risk)

LDL Cholesterol Level CategoryLess than 100 mg/dL Optimal

100-129 mg/dL Near or above optimal

130-159 mg/dL Borderline high

160-189 mg/dL High

190 mg/dL and above Very high

HDL Cholesterol Level CategoryLess than 40 mg/dL A major risk factor for heart disease

40-59 mg/dL Moderate

60 mg/dL and above Protective against heart disease

•LDL must be oxidized to be pathogenic (atherogenic)

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.

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

Improving Your Levels

• Exercise• Improved diet• Maintain a healthy weight• Quit smoking• Possibly cholesterol drugs

Diet• Reduce your intake of

fats and cholesterols.• Increase your intake of

fruits and vegetables.• Add more fiber.• Eat low-fat or fat-free

dairy products.• Avoid eating too many

calories.

Exercise• 30 minutes a day• 4+ times a week

Cholesterol Drugs

• Talk to your doctor, and follow his/her advice.