Metabolism VIII: Cholesterol

Question 1

What are the key regulators of cholesterol synthesis?

Answer 1

• mevalonate
• HMG-CoA reductase
• 7-alpha-hydroxylase
• ACAT

Question 2

Cholesterol can be used to synthesize which 3 main things?

Answer 2

• steroid hormones (“-one” hormones, plus cortisol and estradiol)
• bile salts
• cholesterol esters (storage form)

Question 3

What happens to dietary cholesterol and TAGs in the intestines?

Answer 3

they are packaged into chylomicrons

Question 4

Does esterification make cholesterol more hydrophilic or hydrophobic?

Answer 4

hydrophobic, which is why cholesterol esters seem to be found on the inside of lipid structures

Question 5

What happens do synthesized cholesterol and TAGs (as opposed to dietary)?

Answer 5

they are packaged into VLDLs (vs. dietary sources, which are packaged into chylomicrons)

Question 6

What is the precursor of cholesterol and cholesterol esters?

Answer 6

acetyl-CoA

Question 7

Statins inhibit which enzyme?

Answer 7

HMG-CoA reductase (the rate-limiting enzyme in cholesterol synthesis)

Question 8

HMG CoA requires which reducing agent?

Answer 8

NADPH

Question 9

What is the significance of mevalonate (mevalonic acid)?

Answer 9

It is an important intermediate in cholesterol biosynthesis, and it is formed in a rxn catalyzed by HMG-CoA reductase.

Question 10

How does cholesterol affect HMG-CoA reductase?

Answer 10

It exerts a negative feedback effect on HMG-CoA reductase (when there is abundant cholesterol, there is no need to synthesize more).

Question 11

What is the first step in converting mevalonate (C6) to cholesterol?

Answer 11

converting it to a 5-carbon compound (isopentenylpyrophosphate) via a carboxylation rxn

Question 12

What happens after mevalonate is converted to a 5-carbon compound?

Answer 12

two 15-carbon molecules (farnesylpyrophosphate) are formed and join together in a reduction rxn to produce a 30-carbon compound, squalene; in a series of cyclization rxns, squalene is first converted to lanosterol (C30) and then cholesterol (C27 H45 OH) via reduction rxns

Question 13

A 30-carbon compound that is a natural and vital part of the synthesis of cholesterol, steroid hormones, and vitamin D in the human body.

Answer 13

squalene

Question 14

What is the rate-limiting enzyme in bile acid biosynthesis?

Answer 14

7-alpha-hydroxylase (completely oxidizes cholesterol at the 7th position)

Question 15

How does increased mevalonate affect HMG-CoA reductase, the enzyme involved in its formation?

Answer 15

• inhibits HMG-CoA reductase and increases degradation

- decreases translation of HMG-CoA reductase gene

Question 16

Does insulin activate or inhibit HMG-CoA reductase? Why?

Answer 16

It activates it because insulin=fed state=abundance of glucose=glycolysis leading to production of Ac-CoA=precursor of cholesterol synthesis

Question 17

What is HMG-CoA reductase inhibited by?

Answer 17

increased cholesterol, AMP, glucagon

Question 18

Describe the multiple levels of HMG-CoA reductase regulation.

Answer 18

• transcriptional level: inhibited by sterols, which bind to SRE and inhibit mRNA product. of enzyme
• translational/mRNA level: inhibited by non-sterol metabolites derived from mevalonate
• enzyme stability: degradation promoted by its products (mevalonate, cholesterol)
• phosphorylation: inhibition (AMP, glucagon)

Question 19

What catalyzes the conversion of cholesterol into its storage form, cholesterol esters?

Answer 19

ACAT (Acyl-CoA Cholesterol Acyl Transferase)

Question 20

Cholesterol excess leads to…

Answer 20

• inhibition of cholesterol synthesis
• promotion of cholesterol utilization within hepatocytes
• inhibition of HMG-CoA reductase
• activation of ACAT
• activation of 7-alpha-hydroxylase

Question 21

Cholesterol deprivation leads to…

Answer 21

• activation of cholesterol synthesis
• inhibition of cholesterol utilization within hepatocytes
• activation of HMG-CoA reductase
• inhibition of ACAT
• inhibition of 7-alpha-hydroxylase