Cholesterol

1. CHOLESTEROL BIOSYNTHESIS
• Contains cyclopentano perhydro
phenanthrene ring.
• Contains 27 c atoms
• Contains one hydroxyl group at 3 – c atom
• OH group is hydrophilic in nature

3. Cholesterol synthesis
• Biosynthesis takes place in
• Liver makes 80% of endogenous cholesterol
• Adrenal cortex
• Testis
• Ovaries
• Intestine
• Enzymes are partly in ER and partly in
Cytoplasm
• Rate limiting enzyme is HMG COA reductase

4. Cholesterol synthesis
• Total daily cholesterol production is 1 g/d
• Recommendation is 300 mg/d intake
• Actual is 600 mg/d of which only 300
mg/d is absorbed
• synthesis is at least 2/3 of total

5. MITOCHONDRION
Fatty acids
(2) Acetyl CoA
β-oxidation
Acetoacetyl CoA
HMG CoA
HMG CoA synthase
Thiolase
Acetoacetate β-Hydroxybutyrate
Ketone bodies
(only synthesized in liver)
HMG CoA lyase
oxaloacetate
Citrate Citrate
Mevalonate
CHOLESTEROL
smooth
endoplasmic
reticulum
HMG CoA
reductase
Acetoacetyl CoA
HMG CoA
cytoplasm
HMG-CoA
synthase
Thiolase
Figure 1. Synthesis of HMG-CoA in mitochondria (ketone bodies) and cytoplasm (cholesterol)
Lyase (requires ATP)
OAAmalatepyruvate+NADPH
malic enzyme
(2) Acetyl CoA
Statins

6. Mevalonate
Active Isoprenoids (C5)
Squalene (C30)
3ATP
CO2
Several
Condensation Steps
3ADP
NADPH
NADP+
Stage 2
Squalene (C30)
Cyclization
Squalene
epoxidase/
cyclase
Lanosterol (C30)
(4-ring structure)
O2
NADPH
NADP+
Stage 3
Stage 4
Lanosterol (C30)
(19 steps)O2
NADPH
NADP+ 3 CH3
Cholesterol (C27)
Acetyl CoA (C2)
HMG-CoA
HMG-CoA
Reductase
Mevalonate (C6)
NADPH
NADP+
Stage 1
Figure 2. The four stages of cholesterol biosynthesis
rate-determining step
cholesterol activates proteolytic degradation
amount controlled by induction/repression
hormonally controlled via phosphorylation

7. Cholesterol synthesis
􀂄 26 steps
􀂄 3 stages
􀂄 3 mol of acetyl CoA are used to
synthesize
3-hydroxy-3-methylglutaryl CoA (HMG
CoA)
􀂄 HMG CoA to squalene
􀂄 Rate limiting step of HMG CoA to
mevalonic
acid by HMG CoA reductase
􀂄 Formation of cholesterol from squalene

8. Cholesterol homeostasis
Intestine
Diet Excretion
Liver Plasma Tissues
Normal cholesterol level in adults: < 200 mg/dL

9. cholesterol abundance in the
cell:
• Most excess cholesterol is converted to
cholesterol esters by ACAT (acyl-CoA:
cholesterol acyltransferase).
• Some excess cholesterol is transferred
to endoplasmic reticulum (ER)

10. Regulation of Cholesterol
biosynthesis
• Negative feedback of cholesterol on
activity of HMG CoA reductase
• The amount of dietary intake determines the cholesterol biosynthesis
• Short term regulation:
» Covalent modification - dephosphorlytated
HMG COA reductase is active
• Long term regulation:
suppression of transcription of the gene
Hormones:
Insulin activates HMG COA reductase
Glucagon inactivates HMG COA reductase

11. Degradation of HMG-CoA
reductase is regulated by
cholesterol levels
ER membrane
Low cholesterol
HMG-CoA Red stable
High cholesterol
HMG-CoA Red degraded

12. HMG-CoA reductase activity can be
regulated in response to AMP-
dependent protein kinase
P
Active
Less active

13. Cholesterol catabolism
• Cholesterol is NOT an energy-producing
nutrient
• Transported to liver and excreted as bile
• 55% as cholesterol, 45% as bile acids

14. FATES OF CHOLESTEROL
Membrane structure
Precursor of steroid hormones and vitamin D
Esterification for storage
Esterification for elimination
Precursor to bile salts

15. Figure 4. Cholesterol Metabolism - Bile Acid Synthesis and its Regulation
Cholesterol
(1st
ring only)
HO
Feed forward
induction
by cholesterol
via binding to
liver LXR
receptor

Feedback repression
by bile acids via
binding to liver FXR
receptor

O2 + NADPH
vitamin C (cofactor)
NADP+
7α-Hydroxycholesterol
Bile Acids:
Cholic acid
Chenodeoxycholic acidmultipl
e steps
7α-Hydroxylase
feedback repression broken by cholestyramine
SYNTHESIS OF BILE SALTS

16. SUMMARY OF FACTORS AFFECTING CHOLESTEROL BALANCE
Decrease in intracellular free cholesterol is the result of:
esterification of cholesterol by ACAT for storage
use of cholesterol as precursor to other steroids or bile acids
Increase in intracellular free cholesterol is the result of:
endocytotic uptake of cholesterol-containing lipoproteins
by the LDL receptor
cholesterol biosynthesis
cholesterol ester hydrolysis by cholesterol esterase

17. HMG-CoA reductase is the target of
“statins”, drugs commonly taken to
reduce cholesterol
Statins:
Lovastatin (Mevacor)
Simvastatin (Zocor)
Prevastatin (Pravachol)
Atorvastatin (Lipitor)

18. Hot off the press: a new
cholesterol lowering drug
Devlin Fig. 17.38
cholesterol
(C-esters)
Etezimibe (Zetia)
For use in
conjunction with
statins

19. REVIEW OF CHOLESTEROL
1.What is the name of the steroid ring present in cholesterol ?
2.What is the rate limiting enzyme?
3.Where the cholesterol biosynthesis takes place?
4.In which cellullar organelle the cholesterol biosynthesis takes place?
5.What are the products form from cholesterol?
6.What are bile salts?
7.What is the rate limiting enzyme in bile acid synthesis?
8.What are the functions of cholesterol?
9.Which vitamin is synthesised from cholesterol?
10.How statin drugs reduces cholesterol level?
11. What is the normal level of cholesterol?
SHORT NOTES:
1.Write the fate of cholesterol?
2.What are bile acids and mention its function?
ESSAY:
1.Describe in detail about the biosynthesis of cholesterol and its degradation products
Mention its clinical significance.