Cholesterol Synthesis & Related Metabolites

Question 1

What are the hormone regulators of HMG-CoA Reductase?

cholesterol synthesis

Answer 1

• insulin: up-regulates transcription of the gene for HMG-CoA reductase
• glucagon: downregulates transcription of the gene for HMG-CoA reductase

fed-state (high insulin) increases synthesis of cholesterol (corisol inhibits insulin secretion) why would we want more cholesterol in a fed state? Because cholesterol is a component of lipoproteins which are the molecules that carry the fat absorbed from the diet
fasting state (glucagon): decreases synthesis of cholesterol (cortisol stimulates glucagon secretion) (glucagon triggers glycogenolysis)

Question 2

What are the major sources of liver cholesterol?

Answer 2

• dietary cholesterol –> chylomicron remnants –> liver cholesterol pool
• cholesterol synthesized in extrahepatic tissues –> HDL –> liver cholesterol pool
• de novo synthesis in teh liver

Question 3

What are the major routes by which cholesterol leaves the liver?

Answer 3

• free cholesterol secreted in the bile
• secretion of VLDL
• conversion to bile acids/salts

Question 4

What is the critical step for the regulation of cholesterol biosynthesis?

Answer 4

HMG-CoA Reductase Step

Question 5

Is HMG-CoA Reductase active when it is phophorylated or not?

Answer 5

HMG CoA Reductase is active when it is not phosphorylated.

cholesterol synthesis

Question 6

What is the rate limiting reaction of cholesterol synthesis?

Answer 6

HMG-CoA –> mevalonate
enzyme: HMG-CoA Reductase
utilizes 2 NADPH

Question 7

How is the HMG-CoA Reductase level influenced by intracellular cholesterol level?

Answer 7

sterol regulatory element-binding protein (SREBP) & SREBP cleavage-activating protein is an activator of the HMG-CoA Reductase gene when cellular sterol levels are decreased

Question 8

Which of the following does NOT affect hepatic HMG-CoA Reductase activity?
A. Cytosolic NADH level
B. Glucagon and cortisol level
C. Liver protein phosphatase activity
D. Serum cholesterol level
E. Steroid response element binding proteins

Answer 8

A. Cytosolic NADH level

Question 9

Your patient goes on a binge and eats 12 egg yoks. Which protein would you NOT expect to show reduced synthesis?
A. Acyl cholesterol acyl transferase
B. Glycerol kinase
C. HMG CoA reductase
D. LDL receptor
E. Squalene synthetase

Answer 9

A. Acyl cholesterol acyl transferase
Acyl CoA-cholesterol acyl transferase (ACAT) helps esterify cholesterol.
Cholesterol esters are chemically very stable and hydrophobic. Cholesterol ester is the preferred form for storage and transport.

• Glycerol kinase is involved in triglyceride and glycerophospholipid synthesis (Why is the synthesis of triglycerides reduced when cholesterol consumption is high?)
• HMG CoA reductase is a vital enzyme in de novo cholesterol synthesis
• LDL receptor: LDL uptake and processing increases cytosolic cholesterol levels which down-regulates LDL receptor synthesis to reduce cholesterol uptake into the cell
• Squalene synthetase: This is the enzyme that leads to formation of squalene, an intermediate in cholesterol synthesis