Cholesterol Metabolism

Question 1

De Novo synthesis of Cholesterol

State
Location
Steps

Answer 1

Fed state, High I/G

Location:

• all tissues, particularly liver, intestine, adrenal cortex, reproductive tissue
• Cytosol

Steps:

1. Synthesis of HMG CoA
2. Synthesis of Mevalonic Acid
3. Synthesis of cholesterol

Question 2

De Novo synthesis of Cholesterol Phase I

Pathway
Energy requirements
Enzyme

Answer 2

Acetyl CoA –> HMG CoA

Energy:
driven by excess of ACoA

Enzyme:
HMG-CoA Synthase (cyto)

NOTE: HMG-CoA Synthase (mito) catalyzes RL step of ketone body synthesis

Question 3

De Novo synthesis of Cholesterol Phase II

Pathway
Energy requirements
Enzyme

Answer 3

HMG-CoA –> Mevalonic Acid

Energy Carrier: NADPH

Enzyme:
HMG-CoA Reductase
-SER associated
-Rate Limiting Step

Question 4

De Novo synthesis of Cholesterol Phase III

Pathway
Energy requirements
Enzyme

Answer 4

Mevalonic Acid –> Cholesterol

Energy carrier: NADPH and ATP

Enzymes: 9 Enzymes

Question 5

Regulation of cholesterol synthesis

Answer 5

HMG CoA Reductase Regulation

1. Phosphorylation (follows rule of thumb)
   - Dephosphorylation increases HMG-CoA reductase activity
   - High I/G ratio favors dephosphorylation
   - Cholesterol synth active in fed state
2. Gene Expression
   - Low cytosolic cholesterol level = increased HMG-CoA reductase expression, vice versa

Question 6

Fates of Cholesterol

Answer 6

Synthesis of hepatic membranes

secretion as bile acids, biliary cholesterol, cholesterol esters

Question 7

Production of Cholesterol Esters

Answer 7

Produced by Acyl-CoA-Cholesterol acyltransferase (ACAT)

ACAT activated by increased [cholesterol] in cytosol

CE packaged in VLDLfor delivery

Excess stored as lipid droplets in liver

Question 8

3 Regulatory mechanisms of cholesterol in cells

Answer 8

1. De novo synthesis:
   - gene expression, synthesis of HMG CoA Reductase
2. LDL endocytosis: synthesis of LDL receptors
3. storage: ACAT activity

Question 9

Elimination of cholesterol

Answer 9

1g lost in two ways daily:

1. conversion to bile acid and bile salts
2. Cholesterol secretion into the bile and excretion in feces

Question 10

Dual critical role of bile salts

Answer 10

1. metabolic product of cholesterol

2. solubilizer of cholesterol in bile

Question 11

Synthesis of Bile Salts

Cholesterol 7 alpha hydroxylase

Answer 11

1. Cholesterol 7-alpha-hydroxylase
   - liver only
   - adds OH to position 7 of steroid ring
   - Inhibited by bile acids,
   - activated by cholesterol

Question 12

Fate of 7 alpha hydroxy cholesterol

Answer 12

converted to bile acids:

1. cholic acid
2. chenodeoxycholic acid

More hydrophilic than cholesterol due to extra OH and COO- groups

Question 13

Conversion of bile acids to bile salts

Answer 13

• bile acids in liver bound to glycine or taurine

- forms glycholic acid, glycochenodoxycholic acid, taurocholic acid or taurochenodeoxycholic acid

Question 14

Hydrophobicity scale

Answer 14

Bile salts, bile acid, C, CE

Question 15

Secondary bile acids/salts

Answer 15

dehydroxylated by intestinal bacteria

deoxycholic acid and lithocholic acid