1
Q
influx and efflux of liver cholesterol
A
- 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
2
Q
cholesterol structure and its ester
A
- 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
3
Q
component of cell membranes
A
- 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
4
Q
sterols
A
- 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
5
Q
beta-sitosterol
A
- 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
6
Q
basics of cholesterol synthesis
A
- 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
7
Q
regulatory step
A
- HMG-CoA to mevalonate
- CoA released means its irreversible
8
Q
degradation of cholesterol
A
- 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
9
Q
bile acid structure
A
- 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
10
Q
bile acid synthesis
A
- 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
11
Q
conjugated bile salts
A
- 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
12
Q
intestinal flora
A
- bacteria in intestine can remove glycine and taurine from conjugated bile salts
- can also remove OH group from C7, produces secondary bile acids
13
Q
enteroheptatic circulation of bile salts
A
- 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
14
Q
cholelithiasis
A
- 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
