Cholesterol and Bile Acid Metabolism

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Cholesterol and Bile Acid Metabolism

• Medical Biochemistry
• Lecture 52

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CHOLESTEROL SYNTHESIS, TRANSPORT, AND EXCRETION

• Cholesterol is present in tissues and in plasma
  lipoproteins either as free cholesterol or,
  combined with a long-chain free fatty acid, as
  cholesteryl ester.  
• It is synthesized in many tissues from acetyl-çoA
  and is eliminated from the body in the bile as
  cholesterol or bile salts. 
• Cholesterol is the precursor of all other
  steroids, such as sex hormones, bile acids, and
  vitamin D. 
• It occurs in foods of animal origin such as egg
  yolk, meat, liver, and brain. 

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CHOLESTEROL SYNTHESIS, TRANSPORT, AND EXCRETION
(cont)

• A little more than half the cholesterol of the
  body arises by synthesis (about 700 mg/d), and
  the remainder is provided by the average diet.
  The liver accounts for 10 of total synthesis in
  humans, the intestine for about another 10. 
• Microsomal (endoplasmic reticulum) and cytosol
  fraction of the cell is responsible for
  cholesterol synthesis.

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Acety-CoA is the source of all carbon atoms in
cholesterol

• It can be divided into five steps 
• Step 1. Acetyl-CoA forms HMG-CoA and
  mevalonate. 
• Step 2. Mevalonate forms active isoprenoid
  units. 
• Step 3. Six isoprenoid units form squalene. 
• Step 4. Squalene is converted to lanosterol. 
• Step 5. Lanosterol is converted to cholesterol.

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Cholesteryl ester transfer protein facilitates
transfer of cholesteryl ester from HDL to other
lipoproteins 

• This protein is present in the plasma of humans
  but not the rat, is associated with HDL. 
• It facilitates transfer of cholesteryl ester from
  HDL to VLDL, IDL, and LDL and allows
  triacylglycerol to transfer in the opposite
  direction.

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Bile acids are formed from cholesterol

• About 1 gram of cholesterol is eliminated from
  the body per day. Approximately half is excreted
  in the feces after conversion to bile acids. The
  remainder is excreted as cholesterol. 
• The primary bile acids are synthesized in the
  liver from cholesterol. These are cholic acid
  and chenodeoxycholic acid.

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CLINICAL ASPECTS

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• Serum cholesterol is correlated with the
  incidence of atherosclerosis and coronary heart
  disease.
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• Changes in diet play an important role in
  reducing serum cholesterol Substitution in the
  diet of polyunsaturated and monosaturated fatty
  acids for some of the saturated fatty acids is
  most beneficial. Sunflower, cottonseed, corn,
  olive, and soybean oil contain high concentration
  of monounsaturated fatty acids. On the other
  hand, butterfat, beef fat, and palm oil contain a
  high proportion of saturated fatty acids.
• Lifestyle affects the serum cholesterol level

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When diet changes fail, hypolipidemic drugs will
reduce serum cholesterol and triacylglycerol

• Cholestyramine resins Block reabsorption of
  bile acids. 
• Sitosterols acts by blocking the absorption of
  cholesterol from the gastrointestinal tract. 
• Mevocore or lovastatin inhibitors of HMG-CoA
  reductase 
• Clofibrate or gemfibrozil exert their effect by
  diverting esterification to oxidation of free
  fatty acids. 
• Probucol increase LDL catabolism via receptor
  independent pathway, prevents oxidation of LDL 
• Nicotinic acid reduces the flux of FFA by
  inhibiting adipose tissue lipolysis, thereby
  inhibiting VLDL production by the liver.

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