cholesterol synthesis

1. *

2. *
*Greek word – chole = bile
Steros = solid
Ol = alcohol
*All cells can synthesize cholesterol .
*In a 70 kg man , 140 g cholesterol is present
*It is a light yellow crystalline solid .
*It is soluble in chloroform & other fat solvents .

3. *
*More important animal steroid which form other
steroid compounds form .
*Widely distributed in animal tissues .
*Absent in prokaryotes .
*In plants , cholesterol is absent , but other
steroids are present .
*In bacteria & plants compounds have similar to
steroids , known as hopanoids.

4. *
*Level of cholesterol in blood is related to
atherosclerosis and myocardial infarction .
*Abnormally cholesterol metabolism lead to
cardiovascular accidents and heart attacks .

5. *
1) CELL MEMBRANE
2) NERVE CONDUCTION
3) BILE ACIDS AND BILE SALTS
4) VITAMIN D3
5) ESTERIFICATION
6) STEROID HORMONES

6. *
*CYCLOPENTANOPERHYDROPHENANTH
RENE
*3 CYCLOHEXONE RINGS
*27 CARBON ATOMS

7. *
*Cholesterol is first hydrolyzed by cholesterol
esterase .
*Free cholesterol is incorporated to bile salts
micelle & absorbed into mucosal cell .
*Absorption needs micelle formation .
*There is specific protein in mucosal cell
which facilitates transport of cholesterol .

8. *
*Inside mucosal cell cholesterol is re-esterified and form
chylomicrons .
*Chylomicrons reach blood stream through lymphatics ( lacteals ) .
*This dietary cholesterol reaches liver through chylomicrons
remnants .
*Plant sterols decrease absorption of cholesterol .
*NPCH-1 protein is involved in absorption of cholesterol .
*Therapeutic effect of esetimibe drug is by interfering with function of
protein .

9. *
*Major sites of cholesterol synthesis are liver
, adrenal cortex , testis , ovaries , intestine
.
*All nucleated cells can synthesize cholesterol
including arterial wall .
*Enzymes are partly located in endoplasmic
reticulum and partly in cytoplasm .

10. 2 * acetyl-CoA
Acetyl-CoA is provided by ATP-citrate lyase
reaction as in case of FA synthesis .
1)
condensation
CoA
Acetoacetyl-CoA
synthase
Acetoacetyl-CoA

11. Production of
HMG-CoA
Acetoacetyl-CoA +
Acetyl-CoA
HMG-CoA ( beta hydroxy beta methyl
glutaryl -CoA
Cytosolic HMG CoA in cholesterol synthesis
Mitochondrial HMG CoA in ketogenesis
Co-A
HMG CoA-
synthase

12. Committed
step
HMG - CoA
mevalonate
HMG-CoA
reductase
NADPH+H
NADP

13. Production of 5
carbon unit
mevalonate
5-phosphomevalonate
Isopentenyl
pyrophosphate
3-phospho 5-
pyrophosphomevalonate
5-pyrophosphomevalonate
kinase
decarboxylase
kinase
kinase
ATP
ATP
ATP
ATPCO2

14. condensation
Isopentenyl phosphate
Fernesyl pyrophosphate
squalene
Gernyl pyrophosphate
Isopentenyl
phosphate
Dimethyl allyl
pyrophosphate
Isopentenyl
phosphate
isomerase
transferase
transferase PPi
PPi
Fernesyl
pyrophosphate
Squalene
synthase

15. cyclization
squalene
lanosterol
Squalene
epoxide
epoxidase
cyclase
O2
First steroid
compound

16. Cutting in
size
lanosterol
zymosterol
desmosterol
cholesterol
3 additional
group of
methyl
removed
Duble bond
migrates
from 8-9 to
5-6
Present in
fetal brain
Absent in
adult in brain
Present in
adult when
brain tumor
(gliomas)
NADPH+H
NADP

17. *
1)Regulation of transcription :-
Regulatory enzyme is HMG-CoA .
Long term regulation involves regulation
of transcription of enzyme .
When sufficient cholesterol is present in
cell , transcription of gene for enzyme is
suppressed & cellular synthesis of
cholesterol is decreased .

18. *When cholesterol is low in diet ,
transcription is increased .
*A specific recognition sequence known as
STEROL REGULATORY ELEMENT (
SRE ) .
*SRE binding by STEROL
REGULATORY ELEMENT BONDING
PROTEIN ( SREBP ) is essential for
transcription of these genes .
*When cholesterol levels are sufficiently
high , SREBP remains as an inactive
precursors .

19. *
*Short term regulation is by covalent
modification of HMG-CoA .
*Cyclic-AMP mediated cascade
phosphorylation of enzyme which is
inactive .
*Dephosphorylation form is active .
*Activity of HMG-CoA reductase is also
regulated by rate of degradation of
enzyme protein .

20. *
*Insulin & thyroxine = increase activity
*Cortisol & glucagon = decrease activity
DRUGS
*Lovastatin and statin group of drugs
are competitive inhibitors of enzyme.
*So , they are used in clinical practice to
reduce cholesterol level in body .

21. *
*Total body cholesterol = 130-150g
*Transport of cholesterol
*LDL = liver-peripheral tissue
*HDL = peripheral tissue-liver
1) Incorporated in cell membrane
2) Metabolized to steroid hormones , especially in adrenal
cortex & gonads .
3) Esterified with saturated FA &stored in cell. ACAT (acyl
cholesterol acyl transferase) helps in reaction .
4) Esterified with PUFA by action of LCAT ( lecithin
cholesterol acyl transferase ) and finally excreted through
liver .

22. *
*Average diet = 300 mg/day
*Cholesterol synthesis = 700 mg/day
*Out of this 1000 mg/day , 500 mg/day
of cholesterol is excreted through bile .
*Partly re-absorbed from intestine .
*Vegetables contain plant sterols which
inhibit reabsorption of cholesterol .

23. *
*Unabsorbed cholesterol is acted upon
by intestinal bacteria to form
cholestanol and coprostanol .
*These are excreted . ( fecal sterols )
*About 500 mg of cholesterol is
converted to bile acids which are
excreted in bile as bile salts .

24. Dietary cholesterol
Chylomicrons
remnants
Cholesterol from
extrahepatic tissue
HDL
Denovo synthesis in liver
Liver cholesterol pool
Secretion of
VLDL
Conversion to
bile acids / salts
Free cholesterol
secreted in bile

25. *
*A major role in controlling of plasma levels of
LDL cholesterol .
a) Liver synthesizes cholesterol .
b) Liver removes cholesterol from lipoprotein
remnants and HDL .
c) Liver is only organ that can excrete
cholesterol through bile .
d) Liver converts cholesterol to bile acids.

26. *