Cholesterol is a 27-carbon compound that is synthesized in the liver and other tissues. It is essential for cell membrane structure and as a precursor for bile acids, steroid hormones, and vitamin D. Cholesterol synthesis is a multi-step process involving acetyl-CoA and HMG-CoA reductase as the rate-limiting enzyme. High cholesterol levels increase risk for atherosclerosis and heart disease. Treatment options for hypercholesterolemia include dietary changes, exercise, and statin drugs that inhibit HMG-CoA reductase to lower cholesterol production.

1. Cholesterol MetabolismCholesterol Metabolism
 Dr. V. Siva PrabodhDr. V. Siva Prabodh MDMD
ProfessorProfessor
Dept. of BiochemistryDept. of Biochemistry
NRI Medical CollegeNRI Medical College

2. CHOLESTEROLCHOLESTEROL
→→ Cholesterol is aCholesterol is a light yellow crystalline solidlight yellow crystalline solid
→→ It is aIt is a 2727 Carbon compoundCarbon compound
→→ containscontains cyclopentano perhydro phenanthrenecyclopentano perhydro phenanthrene
ringring
→→ One hydroxyl groupOne hydroxyl group (OH) at 3(OH) at 3rdrd
positionposition
→→ Double bondDouble bond betweenbetween 5 & 65 & 6 CarbonsCarbons
→→ 8 Carbon side chain8 Carbon side chain at 17at 17thth
CarbonCarbon

4. Significance of CholesterolSignificance of Cholesterol
1)1) Normal levelNormal level 150 – 200 mg/dl150 – 200 mg/dl . Increased levels. Increased levels
increases the risk forincreases the risk for AtherosclerosisAtherosclerosis
2)2) ImportantImportant component of cell membranescomponent of cell membranes whichwhich
affects fluid state of membraneaffects fluid state of membrane
3)3) It is used toIt is used to Insulate Nerve fibersInsulate Nerve fibers..
4)4) Bile acidsBile acids (24 Carbon) are derived from(24 Carbon) are derived from
CholesterolCholesterol
5)5) Steroid hormonesSteroid hormones (21 ‘C’ glucocorticoids, 19 ‘C’(21 ‘C’ glucocorticoids, 19 ‘C’
androgens and 18 ‘C’ estrogens) are producedandrogens and 18 ‘C’ estrogens) are produced
from cholesterolfrom cholesterol
6)6) Vitamin DVitamin D formed from Cholesterolformed from Cholesterol

5. Biosynthesis of CholesterolBiosynthesis of Cholesterol
Major sites –Major sites – Liver, Adrenal Cortex, testis, ovariesLiver, Adrenal Cortex, testis, ovaries andand
IntestineIntestine
80% by Liver80% by Liver
The enzymes involved in synthesis are located partly inThe enzymes involved in synthesis are located partly in
cytoplasmcytoplasm andand endoplasmic reticulumendoplasmic reticulum..
Requirements:Requirements:
1) Acetate of1) Acetate of acetyl CoAacetyl CoA provides all the carbon atoms ofprovides all the carbon atoms of
cholesterolcholesterol
2) Reducing equivalents by2) Reducing equivalents by NADPHNADPH
3) Energy from3) Energy from ATPATP..

6. De novo Synthesis ofDe novo Synthesis of
CholesterolCholesterol
 Primary site: liver (~1g/d)Primary site: liver (~1g/d)
 Secondary sites: adrenal cortex, ovaries,Secondary sites: adrenal cortex, ovaries,
testestestes
 Overall equation:Overall equation:

8. Cholesterol Synthesis inCholesterol Synthesis in 5 stages5 stages
1)1) Synthesis ofSynthesis of HMG CoA (6HMG CoA (6 cc))
2)2) Formation ofFormation of mevalonatemevalonate (6 C)(6 C)
3)3) Production ofProduction of Isoprenoid UnitsIsoprenoid Units (5 C)(5 C)
4)4) Synthesis ofSynthesis of squalenesqualene (30 C)(30 C)
5)5) Conversion ofConversion of Squalene to cholesterolSqualene to cholesterol (27 C)(27 C)
2C►6C►►6C6C ►►5C5C ►►10C10C ►►15C15C ►►30C30C ►►27C27C

9. Step I :Step I : CondensationCondensation
Two molecules of Acetyl CoA condense to formTwo molecules of Acetyl CoA condense to form
Acetoacetyl CoAAcetoacetyl CoA
Enzyme:Enzyme: Acetoacetyl CoA SynthaseAcetoacetyl CoA Synthase
Step II :Step II : Production of HMG CoAProduction of HMG CoA
One acetyl CoA condenses with Acetoacetyl CoA to formOne acetyl CoA condenses with Acetoacetyl CoA to form
ββ-hydroxy-hydroxy ββ-methyl glutaryl CoA-methyl glutaryl CoA (HMG CoA)(HMG CoA)
Enzyme:Enzyme: HMG CoA SynthaseHMG CoA Synthase
Cytosol Mitochondria
Cholesterol Synthesis Ketone bodies synthesis

10. Step III – Regulating StepStep III – Regulating Step
Formation ofFormation of MevalonateMevalonate
Reduction of HMG CoA to MevalonateReduction of HMG CoA to Mevalonate
Enzyme:Enzyme: HMG CoA reductaseHMG CoA reductase
requires 2 NADPHrequires 2 NADPH

11. Step 4 :Step 4 : Formation of Isoprenoid UnitFormation of Isoprenoid Unit (5 C)(5 C)
Mevalonate isMevalonate is phorphorylatedphorphorylated three timesthree times
to formto form 3” phospho 5” pyrophospho3” phospho 5” pyrophospho
mevalonatemevalonate, requires 3 ATP., requires 3 ATP.
This undergoesThis undergoes decarboxylationdecarboxylation to formto form
Isopentanyl PyrophosphateIsopentanyl Pyrophosphate (5 C)(5 C)

12. Step 5:Step 5: Synthesis of Squalence (30 C)Synthesis of Squalence (30 C)
Isopentanyl pyrophosphateIsopentanyl pyrophosphate Isomerizes to formIsomerizes to form
Di methyl allyl pyrophosphateDi methyl allyl pyrophosphate
One molecule ofOne molecule of IPPIPP (5 C) condenses with(5 C) condenses with DMPDMP
(5 C) to form(5 C) to form Geranyl pyrophosphateGeranyl pyrophosphate (10 C)(10 C)
One molecule ofOne molecule of IPPIPP (5 C) condenses with(5 C) condenses with GPGP
(10 C) to form(10 C) to form Farnesyl pyrophosphateFarnesyl pyrophosphate (15 C)(15 C)
Two molecules ofTwo molecules of Farnesyl pyrophosphate (15 C)Farnesyl pyrophosphate (15 C)
condenses to formcondenses to form Squalene (30 CSqualene (30 C))

14. Step 6 :Step 6 : CyclizationCyclization
SqualeneSqualene undergoes oxidation and cyclization toundergoes oxidation and cyclization to
formform LanosterolLanosterol
Lanosterol first formed steroid compound.Lanosterol first formed steroid compound.
2C►6C►►6C6C ►►5C5C ►►10C10C ►►15C15C ►►30C30C ►►27C27C

19. Regulation of CholesterolRegulation of Cholesterol
SynthesisSynthesis
HMG CoA reductaseHMG CoA reductase is the regulating Enzymeis the regulating Enzyme
1.1. Feed back Inhibition:Feed back Inhibition:
The end product cholesterol in excess inhibitsThe end product cholesterol in excess inhibits
the gene which is responsible for production ofthe gene which is responsible for production of
HMG CoA reductaseHMG CoA reductase
2.2. Hormonal regulationHormonal regulation::
Glucogon & GlucocorticoidsGlucogon & Glucocorticoids favor thefavor the
formation of Inactive HMG CoA reductase, thusformation of Inactive HMG CoA reductase, thus
decreasesdecreases the cholesterol synthesisthe cholesterol synthesis
Insulin increasesInsulin increases cholesterol synthesis bycholesterol synthesis by
enhancing the formation of active HMG CoAenhancing the formation of active HMG CoA
reductase.reductase.

20. 3.3. Inhibition by drugs:Inhibition by drugs:
CompactiveCompactive
LovastatinLovastatin
Competitive Inhibitors for HMG CoA reductase.Competitive Inhibitors for HMG CoA reductase.

21. 21
Inhibition of Cholesterol BiosynthesisInhibition of Cholesterol Biosynthesis
COSCoA
HO
CO2
-
CH3
C -S -CoA
HO
CO2
-
CH3
H
OH
][
HO
CO2
-
CH3
OH
HO
CO2
-
H
OH
CH2CH2
N
F
C6H5NHCO Atorvastatin (Lipitor):
resembles intermediate
HMG CoA MevalonateIntermediate
HMGCoA
reductase

22. Degradation of cholesterolDegradation of cholesterol
Cholesterol is not completely degraded toCholesterol is not completely degraded to
CoCo22 & H& H22o.o.
It is converted toIt is converted to Bile acidsBile acids
Steroid hormonesSteroid hormones
Vitamin DVitamin D

23. Bile acids:Bile acids:
24 Carbon compounds with steroid ring.24 Carbon compounds with steroid ring.
Helps in digestion & absorption of lipids.Helps in digestion & absorption of lipids.
Synthesis takes place inSynthesis takes place in LiverLiver
7-hydroxylase is the regulating Enzyme7-hydroxylase is the regulating Enzyme
Primary Bile acids –Primary Bile acids –
cholic acid, chenodeoxy cholic acidcholic acid, chenodeoxy cholic acid
Secondary Bile acids –Secondary Bile acids –
deoxycholic acid, Lithocholic aciddeoxycholic acid, Lithocholic acid

27. Enterohepatic circulationEnterohepatic circulation
The bile salts which are secreted into the intestine areThe bile salts which are secreted into the intestine are
reabsorbed and returned to the liver. This is known asreabsorbed and returned to the liver. This is known as
entero hepatic circulation.entero hepatic circulation.

28.  Bile sequestering agentsBile sequestering agents
Lowering CholesterolLowering Cholesterol
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

30. Cholelithiasis:Cholelithiasis: Bile salts and phospholipids areBile salts and phospholipids are
responsible to keep cholesterol in bile in aresponsible to keep cholesterol in bile in a
soluble state.soluble state.
Deficiency of Bile salts, leads toDeficiency of Bile salts, leads to
precipitation of cholesterol into crystals inprecipitation of cholesterol into crystals in
gall bladder resulting in Gall stones orgall bladder resulting in Gall stones or
cholelithiasischolelithiasis
Causes:Causes: ►►Impairment in LiverImpairment in Liver
►► Obstruction of biliary tractObstruction of biliary tract
►► Defect in EnterohepaticDefect in Enterohepatic
circulation of bile saltscirculation of bile salts

31. 31
Transformations of Cholesterol:Transformations of Cholesterol:
Steroid HormonesSteroid Hormones
O
O
O
OH
OHHO
O
CH3
HO
CH3
Cholesterol
Estradiol
Progesterone
Cortisol
O
OH
TestosteroneHO
OH
CH2
HO
OH
OH
Vitamin D

32. HYPER CHOLESTEROLEMIAHYPER CHOLESTEROLEMIA
Serum cholesterol level is more thanSerum cholesterol level is more than 200mg/dl200mg/dl it isit is
considered as Hypercholesterolemiaconsidered as Hypercholesterolemia
Causes-Causes- 1) Diabetes mellitus1) Diabetes mellitus
2) Hypothyroidism2) Hypothyroidism
3) Obstructive jaundice3) Obstructive jaundice
4) Nephrotic syndrome4) Nephrotic syndrome
Atherosclerosis :Atherosclerosis : Deposition of cholesterol esters andDeposition of cholesterol esters and
other lipids in the internal layers of arterial walls,other lipids in the internal layers of arterial walls,
leading to hardening and closure of coronary & cerebralleading to hardening and closure of coronary & cerebral
arteriesarteries

33. ATHEROSCLEROSISATHEROSCLEROSIS

36. Treatment for HypercholesterolemiaTreatment for Hypercholesterolemia
1)1) Consumption of PUFAConsumption of PUFA
2)2) Dietary fiberDietary fiber
3)3) Avoiding high carbohydrate dietAvoiding high carbohydrate diet
4)4) Drugs like LovastatinDrugs like Lovastatin
AtorvastatinAtorvastatin
CholestyramineCholestyramine
CholestipolCholestipol
Inhibit HMG CoA reductase
bind with bile acid decreases
Entero hepatic circulation

37. Thank youThank you