Cholesterol I

Question 1

influx and efflux of liver cholesterol

Answer 1

• liver plays an essential role in maintaining human cholesterol homeostasis
• sources of the livers cholesterol pool include dietary cholesterol and that synthesized by liver de novo in and out of the liver
• cholesterol leaves the liver as unmodified free cholesterol in the bile, by conversion to bile salts secreted into intestine, or as VLDL secreted into circulation
• balance of influx and efflux is not perfect and can lead to deposition of cholesterol in endothelial linings of blood vessels

Question 2

cholesterol structure and its ester

Answer 2

• four planar hydrocarbon rings (A-D)-steroid nucleus
• 8C hydrocarbon attached to C17 of D ring, OH attached to C3 of A, and a DB b/n C5 and C6 of B ring
• most cholesterol in plasma is esterified to a FA at carbon 3
• cholesterol ester is even more hydrophobic

Question 3

component of cell membranes

Answer 3

• sterols evolved to fill the flickering spaces between the FA chains in membrane bilayers
• OH group gives amphipathic component
• steroid rings and hydrocarbon tail intercalate between FA chains, polar OH group in line with polar heads
• at physiologic conditions, cholesterol increases the packing within the hydrophobic core of the bilayer
• increases mechanical strength with decreasing permeability and fluidity

Question 4

sterols

Answer 4

• cholesterol is major form in animal tissues
• contain 4 fused hydrocarbon rings, 8-10 carbon atoms in the hydrocarbon tail attached to C17 and an OH at C3
• 40% of dietary cholesterol absorbed, only 5% of plant sterols

Question 5

beta-sitosterol

Answer 5

• plant sterol
• actively transported back into intestine along with other excess cholesterol
• ATP binding cassette family of transporters (ABCG5 or G8)
• when either transporter is defective- rare AR condition of sitosterolemia
• acummulated beta-sitosterol and excess cholesterol eventually enter blood stream
• explains increased cardiovascular morbidity in people with this disorder
• ezetimibe blocks cholesterol intestinal absorption through the enterocyte brush border

Question 6

basics of cholesterol synthesis

Answer 6

• synthesized by virtually all cells, except RBCs
• majority synthesized by the liver, intestines, adrenal cortex and repro tissues
• similar to FA synthesis, all carbons provided by acetyl coA and NADPH is reducing equivalent
• requires energy that is supplied by hydrolysis of the thioester bond of acetyl CoA and the terminal phosphate of ATP
• reactions on cytoplasmic surface of smoothER and require ER membrane and cytosolic enzymes

Question 7

regulatory step

Answer 7

• HMG-CoA to mevalonate

- CoA released means its irreversible

Question 8

degradation of cholesterol

Answer 8

• ring structure not metabolized to CO2 and water in humans
• sterol nucleus eliminated from body by conversion to bile acids and salts
• small percentage of cholesterol is eliminated in the feces or by secretion into the bile which carries it to the intestine for elimination.
• some of the cholesterol in the intestine is bodified by bacteria before excretion
• primary products made are isomers of coprostanol and cholestanol, reduced forms
• two compounds above and cholesterol make up a majority of neutral fecal sterols

Question 9

bile acid structure

Answer 9

• bile is a mixture of bile salts, phosphatidyl choline and other organic and inorganic molecules
• passes from the liver to duodenum through duct or stored
• acids contain steroid nucleus ring structure with two or three OH groups and a hydrocarbon side chain with a terminal carboxyl group
• COOH pka is 6, approx pH of duodenal lumen
• 50% H (acids) 50% no H (salts) in lumen
• OH groups below plane of sterol ring structure (alpha) and methyl groups above (beta)
• polar/nonpolar face
• act as emulsifying agent in the intestines
• prepare complex lipids for digestion by pancreatic enzymes
• cholic acid, chenodeoxycholic acid

Question 10

bile acid synthesis

Answer 10

• multi step process
• OH groups are added to sterol ring, DB in B ring reduced, hydrocarbon shortened by 3, adds COO
• rate limiting step is addition of OH at carbon 7- makes it a 7-alpha-hydroxycholestero
• catalyzed by cholesterol 7-alpha-hydroxylase
• requires O2 and NADPH
• expression of enzyme down regulated by bile acids

Question 11

conjugated bile salts

Answer 11

• conjugated to glycine or taurine before they leave (come from cys metabolism)
• an amide bond forms between the carboxyl group of the bile acid and the amino group of glycine or taurine
• glycholic and glycochenocolic acid and taurocholic and taurochenocolic acid
• glycine to taurine is 3:1
• addition of glycine (COOH) or sulfate (taurine) lower the pKa and the salts are ionized at alkaline pH of bile
• conjugated bile salts are better detergents than the bile acids because of their increased amphipathic nature
• only conjugated forms in bile

Question 12

intestinal flora

Answer 12

• bacteria in intestine can remove glycine and taurine from conjugated bile salts
• can also remove OH group from C7, produces secondary bile acids

Question 13

enteroheptatic circulation of bile salts

Answer 13

• 0.5 g lost per day (<3%) in the feces is compensated for by the 0.5 g/day synthesized from cholesterol in the liver
• liver secretes bile salts into bile, which enters duodenum
• reabsorbed in the terminal ileum of the intestine by Na/ bile salt cotransporter
• returned to blood by different transporter
• albumin binds and transports the bile salts in the blood
• hepatocytes take up bile salts from the blood using isoform of Na+/bile transporter

Question 14

cholelithiasis

Answer 14

• stored in gallbladder
• movement of cholesterol into bile must be accompanied by bile salt and phospholipid secretion
• if dual secretion is disrupted by a decrease of bile salt production or increased cholesterol secretion, imbalance where cholesterol can’t be solubilized by bile salts/ phospholipids
• results in precipitation of cholesterol and formation of gall stones
• laproscopic cholecystectomy