Cholesterol Metabolism Lec 1

Question 1

What are the 2 sources of livers cholesterol pool?

Answer 1

Dietary

de novo synthesis by extra hepatic tissues/liver itself

Question 2

When influx and efflux of cholesterol does not match what occurs?

Answer 2

Deposition of cholesterol in the endothelial linings of blood vessels

Question 3

Most cholesterol in the plasma is esterified to what?

Answer 3

Fatty acid at carbon 3

Question 4

What does cholesterol do to the cell membrane?

Answer 4

increases mechanical strength

decreases permeability and fluidity

Question 5

What role does the hydroxyl group play on the cholesterol molecule?

Answer 5

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.

Question 6

What is a sterol composed of?

Answer 6

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

Question 7

What is Sitosterolemia and what causes it?

What is seen with this dz?

Answer 7

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

Question 8

What provides all carbons in cholesterol synthesis and what provides the reducing equivalents?

Answer 8

Acetyl CoA and NADPH

Question 9

What is required for cholesterol synthesis?

Answer 9

hydrolysis of the thirster bond of acetyl CoA and terminal phosphate of ATP

ER membrane and cytosolic enzymes

Question 10

What are the steps from Acetyl CoA–> HMG CoA?

Answer 10

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

Question 11

What is the key regulatory step in the conversion of HMG-CoA to Mevalonate and how is it regulated?

Answer 11

HMG CoA reductase–integral membrane protein of smooth ER with catalytic domain facing the cytoplasm

Expression is inhibited by cholesterol

Question 12

What does the conversion of HMG-CoA to Mevalonate require and is this reaction reversible?

Answer 12

2 molecules of NADPH are required along with the HMG CoA reductase

Reaction is irreversible because the CoA is released

Question 13

What are some Nonsterol isoprenoids?

Answer 13

Dolichol
coenzyme Q
Vit K

Question 14

Is cholesterol a sterol isoprenoid or nonsterol isoprenoid?

Answer 14

sterol

Question 15

What is prenylation?

Answer 15

Covalent attachment of farnesyl to proteins–anchoring proteins to plasma membrane

Question 16

What is Smith-Lemli-Opitz syndrome (SLOS)?

Answer 16

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

Question 17

How does SREBP-2 play a role in cholesterol synthesis?

Answer 17

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

Question 18

What occurs to the SREBP complex when cholesterol levels are high?

Answer 18

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

Question 19

What happens to HMG CoA reductase when cholesterol levels are high?

Answer 19

Cholesterol binds the sterol-sensing domain of reductase itself–causing binding of reductase to ER membrane triggering ubiquitination and proteasomal degradation

Question 20

When ATP is low and AMP is high what is the result of HMG CoA reductase and cholesterol synthesis? Why?

Answer 20

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

Question 21

What hormones play a key role in expression of HMG CoA?

Answer 21

Insulin and thyroxine–> upregulate expression

Glucagon and glucocorticoids–> down regulate expression

Question 22

How do statin drugs work?

Answer 22

Statins–structural analogues to HMG—competitive inhibitors of HMG CoA reductase–lower plasma levels of cholesterol

Question 23

What are the two most common primary bile acids?

Answer 23

Cholic acid

Chenodeoxycholic acid

Question 24

How do bile acids/salts act as emulsifying agents in the intestines? and what does this do?

Answer 24

Both have a polar face and non polar face—preparing complex lids for digestion by pancreatic digestive enzymes

Question 25

What enzyme is needed for bile salt synthesis and what does this enzyme do? What down regulates this enzyme?

Answer 25

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

Question 26

Are the conjugated ionized bile salts or bile acids better detergents?

Answer 26

Bile salts because of their increased amphipathic nature

–only the conjugated forms are found in bile

Question 27

What is the role of intestinal flora?

Answer 27

removal of glycine and taurine from conjugated bile salts and removal of the hydroxyl group from carbon 7–producing secondary bile acids

Question 28

How is cholelithiasis caused?

Answer 28

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