"Molecular & Cellular Princ Med Cholesterol Metabolism Steven Goodman" 3/16

Question 1

What are the major sources of cholesterol for the liver?

Answer 1

1. Dietary cholesterol which becomes chylomicron remnants
2. Cholesterol from extrahepatic tissues which becomes HDL
3. De novo synthesis of cholesterol by the liver

Question 2

What are the major ways that cholesterol leaves the liver?

Answer 2

1. Free cholesterol is secreted in the bile
2. Cholesterol is converted to bile acids/salts
3. Cholesterol is secreted by the liver as VLDL

Question 3

What are the effects of cholesterol in the lipid bilayer?

Answer 3

1. OH-group allows cholesterol to be amphipathic
2. Cholesterol increases packing within the hydrophibic core of the membrane
   - -this increases the strength of the membrane, and decreases the permeability/fluidity of the membrane

Question 4

What are the characteristics of sterols?

Answer 4

1. Four planar fused hydrocarbon rings
2. A hydrocarbon tail attached at C-17
3. OH group attached at C-3
   Cholesterol is a major sterol.

Question 5

What is sitosterolemia?

Answer 5

Rare, inherited, autosomal recessive disorder in which the body can’t deal with plant sterols, has faulty transporters for them. Increased phytosterols are found in tissues and blood. These patients have a tendency toward CAD, atherosclerosis, and tuberous xanthomas (skin lesion).

Question 6

Name one cell type that does not produce cholesterol.

Answer 6

RBCs do not produce cholesterol. The majority of cholesterol is made by the liver, adrenal cortex and reproductive tissues.

Question 7

The reactions of cholesterol synthesis require energy and enzymes. Where do these reactions occur? Where does the energy come from.

Answer 7

Cholesterol synthesis occurs on the cytoplasmic side of the smooth ER. ER membrane embedded and cytosolic enzymes are required. Energy comes from hydrolysis of the thioester bond of acetyl coA. Reducing equivalents from from NADPH.

Question 8

Acetyl CoA condenses to eventually form what molecule?

Answer 8

HMG CoA

This is the first few steps of cholesterol synthesis

Question 9

What is the rate limiting step in the synthesis of cholesterol?

Answer 9

HMG CoA –> Mevalonate is the key regulatory step in cholesterol synthesis. Its enzyme, HMG CoA reductase, is inhibited by excess cholesterol.

Question 10

What makes many of the steps in cholesterol synthesis irreversible?

Answer 10

Many of the steps in cholesterol synthesis are irreversible bc they involve a release of pyrophosphate, which is P-P.

Question 11

A partial deficiency in 7-dehydrocholesterol-7-reductase results in what multisystem embryonic malformation syndrome?

Answer 11

Smith-Lemli-Opitz syndrome, SLOS

Autosomal recessive disorder of cholesterol biosynthesis

Question 12

What are the effects of statin drugs?

Answer 12

Statins are structural analogs of HMG CoA reductase, and therefore can lower formation of cholesterol by serving as competitive inhibitors of HMG CoA reductase.
Pravastatin is one example.

Question 13

How is cholesterol degraded?

Answer 13

Cholesterol is mostly degraded through becoming bile acids/bile salts, and small portion is used by bacteria.
The primary products of cholesterol degradation are isomers of coprostanol and cholestanol (reduced forms of cholesterol).

Question 14

What are the components of bile?

Answer 14

Bile is a mixture of bile salts, phosphatidylcholine and other stuff. The two primary bile acids are: cholic acid and chenodeoxycholic acid.

Question 15

What is the rate limiting step in bile acid synthesis?

Answer 15

The rate limiting step in bile acid synthesis is the addition of the OH group at C-7 of cholesterol, converting it to 7-alpha-hydroxycholesterol.

This reaction is catalyzed by cholesterol-7-hydroxylase

Question 16

What happens to bile acids before they leave the liver that makes them better detergents in digestion of complex lipids?

Answer 16

Cholic acid is attached (conjugated) to a glycine.
Chenodeoxycholic acid is conjugated to taurine.
Only conjugated bile acids are found in bile. Addition of these amino acids lowers the pKa of the structures.

Question 17

What protein binds bile salts when they travel in the blood?

Answer 17

Albumin

Question 18

What causes cholelithiases to form?

Answer 18

The movement of cholesterol into the bile must be accompanied by bile salt and phospholipid secretion. Either a decrease in bile salt production, or an increase in cholesterol secretion, creates an imbalance where cholesterol cannot be solubilized enough by bile salts and phospholipids. This causes cholesterol to precipitate in the form of stones.