about cholesterol

1. Amer GUL
Sending to Sir,
Bashir Ahmad karimi

2. CHOLESTEROL
METABOLISM
Sources of cholesterol
Cholesterol synthesis
Long and short termregulation
SREBP-2
Lowering cholesterol
Calculating your risk forCHD

3. ROLES OF CHOLESTEROL
Membrane component
Steroid synthesis
Bile acid/saltprecursor
Vitamin Dprecursor

5. 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

6. CHOLESTEROL
STRUCTURE

7. Dietary Cholesterol
Animal products –eggs
Absorb about50%
Increase intake = decreasedabsorption
Excrete – 1 g/day (bileacids)

8. DIETARY CHOLESTEROL
Assume 400 mg intake /day
 2 0 0 mg isabsorbed
1000 mg isexcreted
 8 0 0 mg from de novosynthesis
Lowering cholesterol in diet has very little effect on
blood cholesterol !!!

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

10. CHOLESTEROL SYNTHESIS

11. HMG CoA Reductase :
Regulation
Short-term regulation
Inhibited byphosphorylation
 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

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

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

14. SREBP cleavage
activating protein

15. Site 1 and site 2 protease -

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

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

19. LOWERING CHOLESTEROL
Bile
acids
Bile sequesteringagents
liver
Bile acids
95 % reabsorbed
NH3+
NH3+
1. Bind bile acid
2. Utilize more cholesterol
to make bile acids
>51%0%inifnecfecses

20. LOWERING A
CHOLESTEROL
 O a t bran
Soluble fiber
Bind bileacids?
Niacin
 3-8 grams / day (need 60mg)
Inhibits VLDL excretion ? (fattyliver)
Flushing and liverdamage