1. 1
•

2. Cholesterol -Introduction
• ‘Chole’ a Greek word meaning bile ‘steros’ means
solid ‘ol’ means alcohol.
• Important animal steroid from which other steroid
compounds are formed.
• Absent in plants , in bacteria and plants similar
compound is hopanoids or ergosterol
• First isolated from gall stones by ‘Poulletier de la
salle’ in 1758.
2

3. Structure of cholesterol
• Cyclopentano perhydro phenanthrene ring (3-cyclohexane ring
A,B,C )(cyclopentane ring D)
• 27 carbon atoms.
• One hydroxyl group at 3rd position (beta oriented )
• Double bond between carbon atoms 5 and 6.
• 8 carbon beta oriented side chain attached to 17th carbon.
3

4. Functions of cholesterol
• As a component of cell membrane ,has modulating
effect on fluid state of membrane.
• Bile salts and acids derived from cholesterol ie.
Important for fat absorbtion.
• Glucocorticoids, androgen and estrogen derived from
cholesterol.
• Vitamin D3 from 7-dehydro-cholesterol
• Nerve conduction-has insulating effect on nerve
fibers.
4

5. Absorption of cholesterol
• Cholesterol ester from diet is hydrolyzed by
cholesterol esterase to free cholesterol.
• Free cholesterol is incorporated into bile salt micelle
and absorbed into mucosal cell.
• In mucosal cell ,cholesterol is re-esterified and
incorporated into chylomicrons.
• This dietary cholesterol reaches liver through
chylomicrons remnants.
5

6. Biosynthesis of cholesterol
 Sir John Cornforth Vladimir Prelog
described the pathway and got noble prize in 1975
• Site : Liver, adrenal cortex, testis, ovaries And intestine.
• All nucleated cells can synthesize cholesterol.
• Area :The enzymes of synthesis are located partly in endoplasmic
reticulum and partly in cytoplasm.
6

7. Biosynthesis of cholesterol(contd.)
• All carbons from acetyl-CoA.(reported by Konard Bolch)
• Requires NADPH,ATP,&O2
• Step 1:Condensation
 acetyl CoA provided by ATP citrate lyase reaction.
 2acetyl CoA
• Step 2 :Production of HMG CoA
 acetoacetyl CoA
+acetyl CoA (beta-hydroxy beta-metyhl
glutaryl CoA)
acetoacetyl CoA synthase
acetoacetyl CoA
HMG CoA synthase
HMG CoA
7

8. 8

9. Biosynthesis of cholesterol(contd.)
• Step 3:The committed step
 HMG CoA
 HMG CoA reductase is a microsomal enzyme.
 This reaction is the rate-limiting step for the pathway
HMG CoA reductase
mevalonate
2NADPH+H+ NADP
9

10. Biosynthesis of cholesterol(contd.)
• Step 4:Production of 5 carbon unit (isoprenoids)
Requires 3 ATP
molecules
One molecule of CO2 is
eliminated
10

11. Biosynthesis of cholesterol(contd.)
• Step 5: Condensation of 5 carbon-units
 6 number of 5 carbon are condensed to form a 30
carbon compound ,squalene.
• Step 6:Cyclization
 Squalene is oxidised by epoxide to form squalene
epoxide using molecular oxygen and NADPH.
 A cyclase convert it to 30 C lanosterol (first steroid
compound synthesised)
11

12. Biosynthesis of cholesterol(contd.)
12

13. 13

14. Biosynthesis of cholesterol(contd.)
• Step 7: Cutting to size
 Removal of three additional methyl groups at carbon
atoms 4 and 14 to produce zymosterol
 Double bond from 8-9th positon to 5-6th positon,
desmosterol is formed
 The double bond in side chain is reduced by NADPH
when cholesterol is formed
14

15. 15

16. Regulation of Cholesterol synthesis
• Regulation at transcription
16

17. Regulation of Cholesterol synthesis(contd.)
• Feeding promotes cholesterol synthesis
 Activates reg. enzymes
 Provides substrate :acetyl CoA
 Provides NADPH
• Role of hormones
 Insulin and thyroxine increases the activity of HMG
CoA reductase.
 Cortisol and glucagon decreases its activity.
17

18. Regulation of Cholesterol synthesis(contd.)
• Covalent modification
 Insulin induces protein phosphatase.
 Activates HMG-CoA reductase by dephosphorylating
it with the help ofprotein phosphatase.
• Regulation by drugs
 “Statin” group of drugs are competitive inhibitors of
HMG CoA reductase (eg. Simvastatin)
18

19. Covalent modification
19

20. Degradation of Cholesterol
• Synthesis of bile acids
• Synthesis if steroid hormones from cholesterol
• Synthesis of vitamin D
20

21. Hypercholesterolemia
• Normal serum cholesterol level 150-200mg/dl
• Increased cholesterol level is seen in following
conditions diabets mellitus, lipid nephrosis,
hypothyroidism
 Atherosclerosis (deposition of cholesterol in arterial
wall)
 Xanthomas (deposition of cholesterol in
subcutaneous tissue)
 Corneal arcus (deposits of lipid in cornea)
21

22. 22