Cholesterol MetabolismCholesterol Metabolism

Dr. V. Siva Prabodh Dr. V. Siva Prabodh MDMD

ProfessorProfessor

Dept. of BiochemistryDept. of Biochemistry

NRI Medical CollegeNRI Medical College

CHOLESTEROLCHOLESTEROL

→→ Cholesterol is a Cholesterol is a light yellow crystalline solidlight yellow crystalline solid

→ → It is a It is a 2727 Carbon compound Carbon compound

→ → contains contains cyclopentano perhydro phenanthrenecyclopentano perhydro phenanthrene

ringring

→ → One hydroxyl group One hydroxyl group (OH) at 3(OH) at 3rdrd position position

→ → Double bondDouble bond between between 5 & 65 & 6 Carbons Carbons

→ → 8 Carbon side chain8 Carbon side chain at 17 at 17thth Carbon Carbon

Significance of CholesterolSignificance of Cholesterol1)1) Normal level Normal level 150 – 200 mg/dl150 – 200 mg/dl . Increased levels . Increased levels

increases the risk for increases the risk for AtherosclerosisAtherosclerosis

2)2) Important Important component of cell membranescomponent of cell membranes which which affects fluid state of membraneaffects fluid state of membrane

3)3) It is used to It 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 produced androgens and 18 ‘C’ estrogens) are produced from cholesterolfrom cholesterol

6)6) Vitamin DVitamin D formed from Cholesterol formed from Cholesterol

Biosynthesis of CholesterolBiosynthesis of Cholesterol

Major sites – Major sites – Liver, Adrenal Cortex, testis, ovariesLiver, Adrenal Cortex, testis, ovaries and and IntestineIntestine

80% by Liver80% by Liver

The enzymes involved in synthesis are located partly in The enzymes involved in synthesis are located partly in cytoplasmcytoplasm and and endoplasmic reticulumendoplasmic reticulum..

Requirements:Requirements:

1) Acetate of 1) Acetate of acetyl CoAacetyl CoA provides all the carbon atoms of provides all the carbon atoms of cholesterolcholesterol

2) Reducing equivalents by 2) Reducing equivalents by NADPH NADPH

3) Energy from 3) Energy from ATPATP..

De novo Synthesis of De 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:

Cholesterol Synthesis in Cholesterol Synthesis in 5 stages5 stages

1)1) Synthesis of Synthesis of HMG CoA (6 HMG CoA (6 cc))

2)2) Formation of Formation of mevalonate mevalonate (6 C)(6 C)

3)3) Production of Production of Isoprenoid UnitsIsoprenoid Units (5 C)(5 C)

4)4) Synthesis of Synthesis of squalenesqualene (30 C)(30 C)

5)5) Conversion of Conversion of Squalene to cholesterolSqualene to cholesterol (27 C)(27 C)

2C►6C►►6C6C ►►5C5C ► ►10C10C ► ►15C15C ► ►30C30C ► ►27C 27C

Step I : Step I : CondensationCondensation

Two molecules of Acetyl CoA condense to form Two 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 form One 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

Step III – Regulating StepStep III – Regulating Step

Formation of Formation 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

Step 4 : Step 4 : Formation of Isoprenoid UnitFormation of Isoprenoid Unit (5 C) (5 C)

Mevalonate is Mevalonate is phorphorylatedphorphorylated three times three times

to form to form 3” phospho 5” pyrophospho 3” phospho 5” pyrophospho

mevalonatemevalonate, requires 3 ATP. , requires 3 ATP.

This undergoes This undergoes decarboxylationdecarboxylation to form to form

Isopentanyl PyrophosphateIsopentanyl Pyrophosphate (5 C) (5 C)

Step 5: Step 5: Synthesis of Squalence (30 C)Synthesis of Squalence (30 C)

Isopentanyl pyrophosphateIsopentanyl pyrophosphate Isomerizes to form Isomerizes to form

Di methyl allyl pyrophosphateDi methyl allyl pyrophosphate

One molecule of One 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 of One 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 of Two molecules of Farnesyl pyrophosphate (15 C)Farnesyl pyrophosphate (15 C)

condenses to form condenses to form Squalene (30 CSqualene (30 C))

Step 6 : Step 6 : CyclizationCyclization

SqualeneSqualene undergoes oxidation and cyclization to undergoes oxidation and cyclization to form form Lanosterol Lanosterol

Lanosterol first formed steroid compound.Lanosterol first formed steroid compound.

2C►6C►►6C6C ►►5C5C ► ►10C10C ► ►15C15C ► ►30C30C ► ►27C 27C

Regulation of Cholesterol Regulation of Cholesterol SynthesisSynthesis

HMG CoA reductaseHMG CoA reductase is the regulating Enzyme is the regulating Enzyme

1.1. Feed back Inhibition:Feed back Inhibition:The end product cholesterol in excess inhibits The end product cholesterol in excess inhibits

the gene which is responsible for production of the gene which is responsible for production of HMG CoA reductaseHMG CoA reductase

2. 2. Hormonal regulationHormonal regulation::Glucogon & GlucocorticoidsGlucogon & Glucocorticoids favor the favor the

formation of Inactive HMG CoA reductase, thus formation of Inactive HMG CoA reductase, thus decreasesdecreases the cholesterol synthesis the cholesterol synthesis

Insulin increasesInsulin increases cholesterol synthesis by cholesterol synthesis by enhancing the formation of active HMG CoA enhancing the formation of active HMG CoA reductase.reductase.

3. 3. Inhibition by drugs:Inhibition by drugs:

Compactive Compactive

LovastatinLovastatin

Competitive Inhibitors for HMG CoA reductase.Competitive Inhibitors for HMG CoA reductase.

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Inhibition of Cholesterol BiosynthesisInhibition of Cholesterol Biosynthesis

COSCoA

HOCO2

-CH3

C -S -CoA

HOCO2

-CH3

H

OH

][HO

CO2-

CH3

OH

HOCO2

-H

OH

CH2CH2

NF

C6H5NHCO Atorvastatin (Lipitor):resembles intermediate

HMG CoA MevalonateIntermediate

HMGCoAreductase

Degradation of cholesterolDegradation of cholesterol

Cholesterol is not completely degraded to Cholesterol is not completely degraded to

CoCo22 & H & H22o.o.

It is converted to It is converted to Bile acidsBile acids

Steroid hormonesSteroid hormones

Vitamin DVitamin D

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 in Synthesis 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 acid cholic acid, chenodeoxy cholic acid

Secondary Bile acids – Secondary Bile acids –

deoxycholic acid, Lithocholic acid deoxycholic acid, Lithocholic acid

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

Bile sequestering agentsBile sequestering agents

Lowering CholesterolLowering Cholesterol

Bileacids

liver

Bile acids

95 % reabsorbed

5% in feces

NH3+

NH3+

1. Bind bile acid2. Utilize more cholesterol to make bile acids

>10% in feces

Cholelithiasis:Cholelithiasis: Bile salts and phospholipids are Bile salts and phospholipids are responsible to keep cholesterol in bile in a responsible to keep cholesterol in bile in a soluble state.soluble state.Deficiency of Bile salts, leads to Deficiency of Bile salts, leads to precipitation of cholesterol into crystals in precipitation of cholesterol into crystals in gall bladder resulting in Gall stones or gall bladder resulting in Gall stones or cholelithiasischolelithiasis

Causes:Causes: ►►Impairment in LiverImpairment in Liver ►► Obstruction of biliary tractObstruction of biliary tract

►► Defect in Enterohepatic Defect in Enterohepatic circulation of bile saltscirculation of bile salts

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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

HYPER CHOLESTEROLEMIAHYPER CHOLESTEROLEMIA

Serum cholesterol level is more than Serum cholesterol level is more than 200mg/dl 200mg/dl it is it is considered as Hypercholesterolemiaconsidered as Hypercholesterolemia

Causes- Causes- 1) Diabetes mellitus1) Diabetes mellitus2) Hypothyroidism2) Hypothyroidism3) Obstructive jaundice3) Obstructive jaundice4) Nephrotic syndrome4) Nephrotic syndrome

Atherosclerosis :Atherosclerosis : Deposition of cholesterol esters and Deposition 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 & cerebral leading to hardening and closure of coronary & cerebral arteries arteries

ATHEROSCLEROSISATHEROSCLEROSIS

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 Lovastatin Drugs like Lovastatin

AtorvastatinAtorvastatin

CholestyramineCholestyramine

CholestipolCholestipol

Inhibit HMG CoA reductase

bind with bile acid decreases Entero hepatic circulation

Thank youThank you