(Transcribed from Dr. Laville’s handout, 2 June 2000 by Brian Buschman)
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Cholesterol is a 27-carbon structure that is synthesized in the liver from acetyl-CoA by acyl transferase The acetyl-CoAs are joined to form HMG CoA (from 3 acetyl CoAs) which is a 6 carbon structure. From this point the HMG-CoA can either proceed to acetoacetate to form ketone bodies or to nevalonate to make cholesterol.
The reaction is catalyzed by HMG-CoA reductase is the key regulatory point. If cholesterol is high then HMG-CoA reductase is inhibited and HMG-CoA just waits around or is converted into ketone bodies. The feedback inhibition is regulated by the level of the circulating cholesterol, the amount of cholesterol taken up by the gut and by hormonal regulation. Insulin encourages it’s synthesis while glucagon inhibits it.
Cholesterol is the precursor for steroid hormones, as discussed by Dr. M last semester. It is also the precursor for bile salts. Bile salt formation is also regulated by 7-a-hydroxylase to form chenocholic acid and cholic acid. (If you see them on a mini you can recognize bile salts because their name sounds like colon so you can guess they are related to food.) These are the primary bile salts. In the gut they are dehydrozylated to form secondary bile salts. Some are reabsorbed, primarily in the terminal ileum and some are excreted in the feces.
Bile acids are essential for micelle formation. Cholesterol or bile acid deficiency will result in deficiencies of fat absorption, fatty stools and malabsorption of vitamins A, D, E and K. Cholesterol that precipitates in the gal bladder forms gal stones. Gal stones are most common in fat, fertile females.
In the blood it is common to find cholesterol, cholesterol esters, triglycerides, phospholipids and vitamins A, D, E and K all in insoluble fatty forms. To be transported they are bound in apolipoproteins.
The lipid part of the lipoprotein may be heterogeneous (mixed between lipids) and is found in the center of the lipoprotein. This is the part which controls the density of the lipoprotein. The protein part is homogenous and found outside. It controls the surface properties of the lipoproteins.
Lipoproteins are classified by their molecular size, electrophoretic mobility or hydrated densities. Based on density they are classified as chylomicrons, VLDL, IDL, LDL or HDL. Density decreases with triglycerides and increases with protein and phospholipid content.
Lipoproteins have three functional roles:
1) Transport hydrophobic material.
2) Serve as ligands for uptake of cellular lipids.
3) Serve as cofactors in lipoprotein metabolism.
Apo E is made in the liver and is distributed as VLDL, IDL and HDL. Apo E binds to the remnant receptor and to the B,E receptor. It has a higher affinity for the B, E receptor then B100.
There are three forms of Apo E which differ at only one AA.
n E3 is the common form.
n E2 is associated with high triglycerides and cholesterol levels.
n E4 is associated with high cholesterol levels.
Free cholesterol activated ACAT (acyl-CoA cholesterol acyltransferase). LDL receptors are only synthesized if the cell needs more LDL. If there is already plenty of cholesterol inside the cell then no new LDL receptors will be made. This is the only regulation of cholesterol levels at the cellular level. The primary regulation of intracellular cholesterol comes by regulating the circulating levels of cholesterol.
Cholestyramia is a bile acid exchange resin. It lowers the plasma cholesterol level by binding cholesterol.
Lovastatin is an HMG-CoA reductase inhibitor. It lowers plasma cholesterol by preventing the formation of cholesterol.
Bezafibrate is a lipoprotein lipase stimulant. Lowers cholesterol levels by triggering cholesterol degradation.
Probucol lowers triglycerides levels by an unknown mechanism.
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