6.17 Cholesterol Metabolism I Flashcards
Cholelithiasis
Cause: Results when there is an imbalance between cholesterol secretion and bile salt production
Symptoms: precipitation of cholesterol and formation of gallstones
Treatment: laproscopic cholecystectomy
Sitosterolemia
defective ATP Binding Cassette transporter (takes excess cholesterol back into lumen of intestines). Since the body is unable to get rid of the cholesterol it has absorbed through pooping it leaks into the bloodstream. Results in increased cardiovascular morbidity
Major sources of liver cholesterol
Dietary cholesterol, Cholesterol from extrahepatic tissues, De novo synthesis
In what form does cholesterol leave the liver?
Free cholesterol secreted in the bile, secretion of VLDL, conversion to bile acids/salts
What is the structure of cholesterol?
4 planar hydrocarbon rings (steroid nucleus) + hydroxyl group + hydrocarbon tail (8 carbons)
At physiologic conditions, what does cholesterol do to the lipid bilayer membrane?
increases packing within the hydrophobic core of the bilayer, increasing mechanical strength, decreasing permeability and fluidity
What does the drug ezetimibe do?
Blocks cholesterol intestinal absorption through the enterocyte brush border
What are the inputs for cholesterol synthesis?
carbons are provided by acetyl CoA, reducing equivalents by NADPH, energy through hydrolysis of the thioester bond of acetyl CoA and ATP.
Steps of Cholesterol Synthesis
Acetyl CoA -> Acetoacetyl CoA -> HMG CoA -> Mevalonate -> 5-Pyrophosphomevalonate -> IPP -> Dimethylallyl pyrophosphate -> GPP -> FPP -> Squalene -> Lanosterol -> Cholesterol
How is HMG CoA Reductase regulated? (Remember that HMG CoA Reductase converts HMG CoA to Mevalonate as part of cholesterol synthesis)
Regulation of gene expression, enzyme degradation, Phsophorylation/Dephosphorylation, Hormones
What do statin drugs do?
Lower cholesterol levels in the blood by acting as competitive inhibitors of HMG CoA Reductase
How is structure of cholesterol degraded? What are the two products?
The sterol nucleus (4 planar hydrocarbon rings) is converted to bile acids and bile salts. Some choleterol can be reduced to coprostanol and cholestanol and pooped out!
What is the structure of bile acid?
steroid nucleus ring structure, 2 or 3 hydroxyl group, hydrocarbon side chain with a terminal carboxyl group
What is special about bile acids? What does this allow them to do?
They have a polar and nonpolar face. This allows them to act as emulsifying agents preparing complex lipids for digestion.
Rate limiting step of bile acid synthesis?
Addition of the hydroxyl group at carbon 7 of cholesterol. Catalyzed by enzyme cholesterol-7-a-hydroxylase. Inhibited by bile acids (feedback inhibition).
