cholesterol metabolism

1. M.Prasad Naidu
MSc Medical Biochemistry,
Ph.D.Research Scholar

2. Cholesterol Metabolism
Sources of cholesterol
Cholesterol synthesis
Long and short term regulation
SREBP-2
Lowering cholesterol
Calculating your risk for CHD

3. Roles of Cholesterol
Membrane component
Steroid synthesis
Bile acid/salt precursor
Vitamin D precursor

4. Sources of Cholesterol
Diet De novo synthesis
Cholesterol synthesized
in extrahepatic tissues
Liver cholesterol
pool
Free cholesterol
In bile
Conversion to bile salts/acidsSecretion of HDL
and VLDL

5. Cholesterol Structure
FA for esterification

6. Dietary Cholesterol
Animal products – eggs
Absorb about 50%
Increase intake = decreased absorption
Excrete – 1 g/day (bile acids)

7. Dietary Cholesterol
Assume 400 mg intake / day
200 mg is absorbed
1000 mg is excreted
800 mg from de novo synthesis
Lowering cholesterol in diet has very little effect on
blood cholesterol !!!

8. Cholesterol Synthesis
Similar to ketogenic pathway
Occurs in cytosol
Requires NADPH and ATP
Highly regulated
80 % in liver, ~10% intestine, ~5% skin

9. CHOLESTEROL SYNTHESIS

10. HMG CoA Reductase : Regulation
Short-term regulation
Inhibited by phosphorylation
 AMP-dependent protein kinase
 When AMP is high (or ATP low!), why waste energy on
cholesterol synthesis
Long-term regulation
Proteolysis
Degradation stimulated by cholesterol and cholesterol
metabolites
Sterol-sensing domain

11. HMG CoA reductase -
Phosphorylation
AMP-Activated
Protein Kinase (high activity)
AMP-Activated
Protein Kinase
(low activity)
phosphatase
insulin
(+)
kinase
Glucagon/epi
(+)
increase cAMP
AMP
(+)
HMG CoA reductase – OH
(active)
HMG CoA reductase – P
(inactive)

12. HMG CoA Reductase : Regulation
Transcriptional regulation
SREBP-2
Responds to cellular levels of sterols

13. SREBP cleavage
activating protein

14. Site 1 and site 2 protease -

16. Free Cholesterol Pool
synthesis
Negative
Feedback (-)
LDL
receptor
LP
Negative
Feedback (-)
acat
CE
HDL
Steroid synthesis
C

17. Lowering Cholesterol
Statins – decrease HMG CoA
reductase activity
Muscle weakness
Why?

18. Lowering Cholesterol
Bile sequestering agents
Bile
acids
liver
Bile acids
95 % reabsorbed
5% in feces
NH3+
NH3+
1. Bind bile acid
2. Utilize more cholesterol
to make bile acids
>10% in feces

19. Lowering Cholesterol
Oat bran
Soluble fiber
Bind bile acids?
Niacin
3-8 grams / day (need 60 mg)
Inhibits VLDL excretion ? (fatty liver)
Flushing and liver damage