Lecture 67

Question 1

What is spur cell anemia?

Answer 1

In spur cell anemia, erythrocyte membranes accumulate an excess of cholesterol and take on a spiny shape. This leads to decreased fluidity and decreases the ability of the erythrocytes to pass through capillaries. Cells are destroyed prematurely in the spleen.

Question 2

All cells can synthesize cholesterol. But what is the major site of cholesterol synthesis?

Answer 2

Liver (20-50%)

Question 3

What is the recommended dietary intake of cholesterol?

Answer 3

< 300 mg/day

Question 4

What is ergosterol?

Answer 4

Ergosterol is produced by fungi. It cannot be used in human membranes, as a precursor for bile acids or as a precursor for steroid hormones. However, it can be used to produce Vitamin D2.

Question 5

What are cholesterol esters?

Answer 5

In cholesterol esters, the hydroxyl group of cholesterol is esterified with a fatty acid.

Question 6

What enzyme forms cholesterol esters? Where does this enzyme function and what does it do there?

Answer 6

ACAT (acyl CoA: cholesterol acyl-transferase).

1. Liver. Converts cholesterol to cholesterol esters for packaging into VLDL
2. Small intestine. Converts cholesterol to cholesterol esters for packaging into chylomicrons.

Question 7

Which fatty acid is most commonly esterified to cholesterol?

Answer 7

Oleic acid

Question 8

What percentage of bile acids and cholesterol are reabsorbed?

Answer 8

Cholesterol: 40-50%

Bile Acids: 90-95%

Question 9

Which drug lowers serum cholesterol levels by reducing the reabsorption of cholesterol in the ileum?

Answer 9

Ezetimibe

Question 10

How much energy is needed for cholesterol biosynthesis?

Answer 10

6 ATP

8 NADPH

Question 11

What is the branch point for the cholesterol biosynthesis and ketone body pathways?

Answer 11

HMG-CoA

Question 12

Where is HMG-CoA reductase located?

Answer 12

Endoplasmic Reticulum

Question 13

Describe the regulation of HMG-CoA Reductase via enzyme activity.

Answer 13

1. High levels of AMP result in the phosphorylation (activation) of AMP-activated protein kinase.
2. AMP-activated protein kinase phosphorylates (inactivation) HMG-CoA reductase, therefore decreasing cholesterol biosynthesis.
3. Insulin triggers a phosphatase to remove the phosphate, resulting in the activation of HMG-CoA reductase.

Question 14

What are the two targets of AMP-activated protein kinase?

Answer 14

HMG-CoA Reductase (Cholesterol Biosynthesis) and Acteyl-CoA Carboxylase (Fatty Acid Synthesis)

Question 15

Describe the regulation of HMG-CoA Reductase via protein degradation

Answer 15

1. HMG-CoA Reductase (in the ER membrane) interacts with Lanosterol.
2. This triggers recruitment of ubiquitin ligase. triggering proteasomal degradation
3. half life of HMG CoA Reductase is 12 h in the absence of sterols and <1 h under high sterol conditions

Question 16

Describe the regulation of HMG-CoA Reductase via transcription

Answer 16

1. SREBP and SCAP are located in the ER membrane.
2. When SCAP senses low levels of cholesterol, SREBP moves to the golgi, where it is cleaved by S1P and S2P, freeing SREBP to migrate to the nucleus
3. SREBP binds to an SRE and increases transcription of HMG-CoA Reductase (and also LDL receptor).

Question 17

How many ATPs are used in the conversion of mevalonate to farnesyl pyrophosphate?

Answer 17

3

Question 18

What are the two functions of geranyl pyrophosphate (10 C) and farnesyl pyrophosphate (15 C)?

Answer 18

1. Intermediates in cholesterol biosynthesis

2. They are used to covalently modify proteins (G proteins, Ras), allowing for association with membranes.

Question 19

What is formed by the condensation of 2 15C farnesyl pyrophosphates?

Answer 19

Squalene

Question 20

What is formed by cyclase activity on Squalene

Answer 20

Lanosterol

Question 21

What cholesterol levels define “high risk” for development of coronary heart disease?

Answer 21

Total Cholesterol: > 200 mg/dL

LDL: > 160 mg/dL

HDL: < 40 mg/dL

Question 22

Name 3 statins. What is their mechanism of function? Where is their primary site of action?

Answer 22

1. Lipitor, Zocor, Lovastatin
2. Competitive Inhibitors of HMG CoA Reductase
3. Liver

Question 23

What mutation is associated with Familial Hypercholesterolemia?

Answer 23

LDL receptor

Question 24

How do statins enhance cholesterol excretion?

Answer 24

1. Competitive inhibition of HMG CoA reductase decreases cholesterol levels.
2. SCAP senses low levels of cholesterol, leading to SREBP enhancing transcription of HMG CoA reductase and LDL receptor
3. LDL receptor increases uptake of cholesterol in the liver, increasing excretion.