Cholesterol Metabolism 1 - CB Flashcards
What form does cholesterol leave the liver?
unmodified free cholesterol in bile, as VLDL, or conversion to bile acids/salts
What happens if the balance of cholesterol influx and efflux is off?
it deposits on endothelial linings
What is a steroid nucleus?
4 planar rings
What is cholesteryl ester?
cholesterol with a FA attached (The form found in blood plasma) it is more hydrophobic
What gives cholesterol its polar head?
-OH (hydroxyl) Carbon 3
How does cholesterol affect a membrane at physiologic conditions?
increases packing thus increasing rigidity and decreasing permeability and fluidity.
What gives cholesterol its hydrophobic part of its amphipacity (I think i made this word up, amphipathic properties)?
The 4 fused rings and the hydrocarbon tail on carbon 17 of ring D
Fact: plant sterols arent absorbed as well
I need a beer
What causes sitosterolemia?
defective ABCG5 or ABCG8 sterol transporter in enterocytes. This pumps excess sterols out into the lumen
What does ezetimibe do?
Blocks the intestinal absorption of cholesterol at the brush border
What cells synthesize cholesterol?
Nearly all except RBCs,
most is syn. in liver, intestines, adrenal cortex, reproductive tissues
Where do the carbons come from in cholesterol?
acetyl coa,
What does cholesterol Syn. use for reducing power?
NADPH
Where do the cholesterol syn rxns happen?
cytosolic surface of smooth ER
List the steps of cholesterol syn.?
2 acetyl coa___thiolase__> Acetoacetyl CoA___HMG-CoA Synthase_+acetylcoa__> HMG CoA___HMG CoA reductase__+ 2 NADPH____> Mevalonate
What step in cholesterol syn is rate limiting?
HMG CoA reducase (HMG CoA to Mevalonate)
enzyme expression inhibited by cholesterol
on the cytosolic surface of smooth ER membrane
irreversible reaction bc CoA is released
See “Mevalonate to cholesterol” the diagram on page 362 of the notes
this shit sucks
How many ATP does it take to make squalence?
18 (3 per isoprenoid)
What triggers the cyclization squalence resulting in lanosterol?
The hydroylation of squalence
What is Smith-lemil-optiz syndrome?
Autosomal recessive disorder of cholesterol syn. (7dehydrocholesterol-7reductase)
List the ways cholesterol syn is regulated?
sterole dependent transcriptional regulation, sterol accelerated enzyme degredation, sterol independent phosphorylation-dephosphorylation, and hormonal
Regulation of Cholesterol gene expression (HMG CoA reductase
when low cholesterol levels:
SREBP2 binds to SCAP and activates the complex, and moves to golgi and SCREB is cleaved. A piece goes into the nucleus and binds to SCRE and stimulates gene expression.
Cholesterol binds and inhibits SCAP
Regulation of cholesterol by enzyme degradation
in high levels of cholesterol, cholesterol binds to HMG coa reductase causing it to be degraded by ubiquintination and proteosomes
Does phosphorylation activate or inactivate HMG CoA reductase?
Phosphorylation inactivates
Dephosphorylation activates
What hormones up regulate HMG CoA reductase expression?
Insulin and thyroxine
What hormones down regulate HMG CoA reductase expression?
glucagon and glucocorticoids
What are statins analogues of?
HMG, they act as a competitive inhibitor for HMG CoA reductase
Is the ring structure of cholesterol metabolized?
No, it is turned into bile salts/acids (eliminated in feces). some is modified in intestines by bacteria to become copropstanol and cholestanol
What is in bile?
bile salts, phophatidyl choline
What percentage of bile is salts in the duodenum? acids? Why?
50-50 bc the pKa of the hydroxyl group is around 6, the pH in the intestine is 6
Why can bile salts act as emulsifying agents?
They have a polar face (hydroxyls point down) and a nonpolar face (methyls point up)
Two most common bile acids?
Cholic acid and chenodeoxycholic acid
How is cholesterol modified to make a bile salt/acid?
Hydroxyls are added, a double bond is reduced, the hydrocarbon tail is shortened by 3 carbons
What is the rate limiting step of bile acid syn?
the addition of the hydroxyl goup to the C7 of cholesterol making 7alpha-hydroxycholesterol (via cholesterol-7-alpha-hydroxylase
What does cholesterol-7-alpha-hydroxylase need for its reaction?
O2 and NADPH
What amino acids do bile salts conjugate with? Why do they conjugate?
Taurine and glycine, makes them better detergents
Only the conjugated forms are found in bile (then unconjugate in intestines)
How is a secondary bile salt produced?
The removal of the C7 hydroxyl
How is bile reabsobed? How much is reabsorbed?
intestines: enterocyte Na+-bile salt cotransporter isoform
Blood: albumin carries it to the liver and a hepatocyte Na+-bile salt cotransporter isoform
(95%reabsorbed)
What is enterohepatic circulation?
The synthesis, release and reabsoptions of bile salts
Why do gallstones form?
The precipitation of cholesterol due to an imbalance in cholesterol and bile salt secretion
