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CHOLESTEROL METABOLISM

ELAMATHI.T

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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.

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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.

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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.

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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.

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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.

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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 synthaseacetoacetyl CoA

HMG CoA synthase

HMG CoA

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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 mevalonate2NADPH+H+ NADP

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Biosynthesis of cholesterol(contd.)

• Step 4:Production of 5 carbon unit (isoprenoids)

Requires 3 ATP molecules

One molecule of CO2 is eliminated

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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)

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Biosynthesis of cholesterol(contd.)

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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

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Regulation of Cholesterol synthesis

• Regulation at transcription

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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.

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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)

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Covalent modification

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Degradation of Cholesterol

• Synthesis of bile acids • Synthesis if steroid hormones from cholesterol• Synthesis of vitamin D

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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)

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