Lecture 44: Cholesterol Synthesis and Elimination

Question 1

Where is cholesterol mainly found in the cells and what does it do there?

Answer 1

Cell membranes and it gives it a certain structure/ rigidity

Question 2

T/F: The amount of cholesterol from the inside of the cell to the outside decreases.

Answer 2

False. It increases as you go from inside to outside of the cell. Organelles with membranes (i.e. nucleus/ ER, etc) have less cholesterol in them than the plasma membrane.

Question 3

How many carbons are in cholesterol?

Answer 3

27 carbons

Question 4

Which are the most commonly modified carbons in cholesterol?

Answer 4

C3 (OH group) and C17 (side chain)

Question 5

Where is cholesterol synthesized?

Answer 5

liver and intestine so it is not required in the diet

Question 6

What are two common reasons for high cholesterol?

Answer 6

Too much cholesterol in the diet

Hyperactively producing cholesterol because of genetic predisposition

Question 7

How is cholesterol eliminated from the body?

Answer 7

Converted into bile acids/ salts in the liver

stored in gall bladder/ secreted into intestine

small percent is excreted in the feces

Question 8

What is the primary form in which cholesterol is transported in the plasma?

Answer 8

Cholesterol ester (esterification at C3 with fatty acid)

Packaged into lipoprotein particles

Question 9

How do you synthesize HMG CoA?

Answer 9

You use thiolase to make acetoacetyl CoA from acetyl CoA.

Then you use HMG CoA synthase on acetoacetyl CoA to make HMG CoA.

Question 10

What is the rate limiting enzyme for the synthesis of cholesterol?

Answer 10

HMG CoA reductase

Question 11

How much ATP/ NADPH is necessary to make cholesterol?

Answer 11

18 ATP
14 NADPH

cholesterol synthesis needs a lot of energy!

Question 12

Is cholesterol synthesis localized to one portion of the cell?

Answer 12

No! It occurs all over the cell (i.e. peroxisomes, ER, cytosol, mitochondria)

Question 13

What transcription factor regulates cholesterol synthesis genes?

Answer 13

SREBP (sterol responsive element binding protein)

Question 14

How does cholesterol regulated gene expression work when there is high intracellular cholesterol?

Answer 14

There is a decrease in transcription of nearly all genes encoding proteins in the cholesterol synthesis pathway

Question 15

How do you make mature proteolytically processed SREBP?

Answer 15

SREBP binds to SCAP (SREBP Cleavage Activating Protein)

When ER sterols are low (low cholesterol) complex moves to golgi where it is cleaved by Protease 1 and 2

Activated SREB moves to nucleus and activates expression of cholesterol synthesis genes

Question 16

What happens to HMGR when there is an increased level of intracellular cholesterol?

Answer 16

HMGR has a decreased stability and it becomes mis-folded and degraded

Question 17

T/F: Phosphorylated HMGR is active.

Answer 17

False. HMGR is inactivated by phosphorylation.

It is phosphorylated by AMP kinase.

Question 18

What does insulin and glucagon do to HMGR expression and activity?

Answer 18

Insulin stimulates HMGR expression and activity.

Glucagon inhibits HMGR expression and activity

Question 19

What are statins?

Answer 19

Statins competively inhibit HMGR. They mimic the transient intermediate mevadyl CoA.

Question 20

Why is there so many different statins?

Answer 20

Diversity of medication is important to treat variety of different people.

Question 21

What is the chemical name of Zetia?

Answer 21

ezetimibe

Question 22

What does zetia do?

Answer 22

It acts as a small intestine brush border.

It has no side effects because it does not enter the blood stream and inhibits the absorption of cholesterol but not triglycerides/ fat- soluble vitamins.

Question 23

What is Vytorin?

Answer 23

It is a combination drug of ezetimibe and simavastatin (i.e. a statin) that reduces cholesterol levels when compared to statin alone.

Question 24

Why is Vytorin useful?

Answer 24

It permits reduced doses of statins, which have side effects.

Question 25

What is the principal mechanism of eliminating cholesterol from the body?

Answer 25

Excretion of bile salts

Question 26

Cholesterol is a precursor to _________.

Answer 26

bile salts and bile acids

Question 27

Where are bile salts and acids synthesized, stored and secreted into?

Answer 27

Liver
gall bladder
intestine

Question 28

What do bile acids/salts do?

Answer 28

they emulsify dietary lipids making them accessible to pancreatic lipases

aid in the absorption of fat soluble vitamins (ADEK)

Question 29

What is the rate limiting enzyme for bile acid formation?

Answer 29

7- alpha- hydroxylase

Question 30

What inhibits/ promotes 7 alpha hydroxylase?

Answer 30

• cholic acid

+ cholesterol

Question 31

How do you make a bile acid?

Answer 31

You add OH group to the C7 of cholesterol

Question 32

Primary bile acids give rise to _______ which gives rise to ________ which are bile acids conjugated to glycine or taurine in the liver.

Answer 32

secondary bile acids

bile salts

Question 33

How do you treat hypercholesterolemia?

Answer 33

It is treated with compounds that sequester bile acids in the intestine.

These sequesterants:

1. prevent the reabsorption of bile acids
2. increase the conversion of cholesterol to bile acids
3. increase bile salt elimination in feces