Cholesterol Metabolism Lec 1 Flashcards
What are the 2 sources of livers cholesterol pool?
Dietary
de novo synthesis by extra hepatic tissues/liver itself
When influx and efflux of cholesterol does not match what occurs?
Deposition of cholesterol in the endothelial linings of blood vessels
Most cholesterol in the plasma is esterified to what?
Fatty acid at carbon 3
What does cholesterol do to the cell membrane?
increases mechanical strength
decreases permeability and fluidity
What role does the hydroxyl group play on the cholesterol molecule?
Hydroxyl sits on carbon 3 of the A ring and gives the hydrophobic molecule its amphiphilic character
OH is in line with polar head groups and in contact with the aqueous env.
What is a sterol composed of?
Four fused hydrocarbon rings
8-10 carbon atoms in the hydrocarbon tail attached to carbon 17 on the D ring
hydroxyl group at carbon 3 on ring A
What is Sitosterolemia and what causes it?
What is seen with this dz?
Inherited plant sterol storage dz
Mutation in ABCG5 and ABCG8 genes–which code ABC transporters sterolin-1 and 2
Increased Phytosterols found in blood and tissues
Coronary heart dz is the primary cause of illness and premature death
What provides all carbons in cholesterol synthesis and what provides the reducing equivalents?
Acetyl CoA and NADPH
What is required for cholesterol synthesis?
hydrolysis of the thirster bond of acetyl CoA and terminal phosphate of ATP
ER membrane and cytosolic enzymes
What are the steps from Acetyl CoA–> HMG CoA?
2 Acetyl CoA condense and lose 1 CoA–>Acetoacetyl CoA
Another Acetyl CoA comes in and is added by cytosolic HMG-CoA synthase–> HMG CoA
What is the key regulatory step in the conversion of HMG-CoA to Mevalonate and how is it regulated?
HMG CoA reductase–integral membrane protein of smooth ER with catalytic domain facing the cytoplasm
Expression is inhibited by cholesterol
What does the conversion of HMG-CoA to Mevalonate require and is this reaction reversible?
2 molecules of NADPH are required along with the HMG CoA reductase
Reaction is irreversible because the CoA is released
What are some Nonsterol isoprenoids?
Dolichol
coenzyme Q
Vit K
Is cholesterol a sterol isoprenoid or nonsterol isoprenoid?
sterol
What is prenylation?
Covalent attachment of farnesyl to proteins–anchoring proteins to plasma membrane
What is Smith-Lemli-Opitz syndrome (SLOS)?
Partial deficiency in 7-dehydrocholesterol-7-reductase—enzyme that reduces the double bond in 7-DHC–converting it to cholesterol
Therefore–pt has impaired cholesterol synthesis
How does SREBP-2 play a role in cholesterol synthesis?
When cholesterol levels are low SREBP-2-SCAP complex moves to the golgi where SREBP is cleaved
SREBP transcription factor enters the nucleus, binds SRE and stimulates the expression of HMG CoA reductase–increasing expression of enzyme and cholesterol synthesis
What occurs to the SREBP complex when cholesterol levels are high?
Binds to the sterol sensing domain of SCAP, which binds to additional ER proteins—anchoring the SREBP-2-SCAP complex to the ER membrane and slowing cholesterol synthesis
What happens to HMG CoA reductase when cholesterol levels are high?
Cholesterol binds the sterol-sensing domain of reductase itself–causing binding of reductase to ER membrane triggering ubiquitination and proteasomal degradation
When ATP is low and AMP is high what is the result of HMG CoA reductase and cholesterol synthesis? Why?
Enzyme is inactive and cholesterol synthesis is reduced
Reductase controlled by AMP-activated protein kinase and phosphoprotein phosphatase
Kinase- phosphorylates the reductase–inactive
phosphastase- dephosphorylates the reductase–active
What hormones play a key role in expression of HMG CoA?
Insulin and thyroxine–> upregulate expression
Glucagon and glucocorticoids–> down regulate expression
How do statin drugs work?
Statins–structural analogues to HMG—competitive inhibitors of HMG CoA reductase–lower plasma levels of cholesterol
What are the two most common primary bile acids?
Cholic acid
Chenodeoxycholic acid
How do bile acids/salts act as emulsifying agents in the intestines? and what does this do?
Both have a polar face and non polar face—preparing complex lids for digestion by pancreatic digestive enzymes
What enzyme is needed for bile salt synthesis and what does this enzyme do? What down regulates this enzyme?
Cholesterol 7-a-hydroxylase–rate limiting step which adds hydroxyl group at carbon 7 of cholesterol converting it to 7-a-hydroxycholesterol
Down regulated by bile acids–more bile acids=less bile acid synthesis
Are the conjugated ionized bile salts or bile acids better detergents?
Bile salts because of their increased amphipathic nature
–only the conjugated forms are found in bile
What is the role of intestinal flora?
removal of glycine and taurine from conjugated bile salts and removal of the hydroxyl group from carbon 7–producing secondary bile acids
How is cholelithiasis caused?
Movement of cholesterol into the bile must be accompanied by bile salt and phospholipid secretion
A decrease of bile salt production or increased cholesterol secretion will cause an imbalance where cholesterol cannot be sufficiently solubilized by the bile salts and phospholipids–causing precipitation of cholesterol and formation of gallstones
