Chapter VII:

Cholesterol metabolism

Dr. Sameh Sarray Hlaoui

- Atherosclerotic vascular disease: stroke, coronary artery disease

- Structural component of cell membranemodulating their fluidity.- Precursor of bile salts, steroidhormones (sex hormones,mineralocorticoides..) and fat solublevitamins (vit D).- Serve as component of lipoproteins.

Cholesterol

Cholesterol

n A sterol, found in all eukaryotic cells .

n 4 fused hydrocarbon rings (A-D) calledsteroid nucleus.

n Ring A contains an oxygen (as –OH) onC3.

n Ring B has a double bond between C5and C6.

n Eight carbon branched hydrocarbonattached to C17 of D ring

C27 H45 OH

n Most plasma cholesterol is an esterifiedform with a fatty acid attached at C3:cholestryl esters

n Esterification occurs mainly in liver

n Cholesterol is eliminated from the liver asunmodified cholesterol in the bile

orn it can be converted to bile salts that are

secreted into the intestinal lumen.

Cholesterol Synthesis

n Primary site: liver (~1g/d)n Synthesized from Acetyl CoA

n Cytoplasmicn Tightly regulated process

n Over accumulation and deposition in coronary arteries ®atherosclerosis.

Step 1: Formation of HMG-CoA

n Condensation of 2 acetyl-CoA

acetoacetyl-CoA by thiolase

n Acetoacetyl-CoA combines with third acetyl

CoA ® Hydroxymethyl-glutaryl-coenzyme A)

HMG-CoA (6C)

n catalyzed by HMG-CoA Synthase.

Step 2: Synthesis of Mevalonic Acid

n Key step in synthesis of cholesterol

n HMG CoA is reduced by 2 molecules of

NADPH in the presence of HMG-CoA

Reductase: producing mevalonate or

mevalonic acid

Step 3: Synthesis of isopententylPyrophosphate (IPP)

n Steps:

- Mevalonate is phosphorylated by 2sequential Pi transfers from ATP, yieldingthe pyrophosphate derivative.

- Decarboxylation ATP-dependent withdehydration yields isopentenylpyrophosphate (IPP).

- Isopentenyl Pyrophosphate Isomeraseconverts IPP in 3,3-dimethylallylpyrophosphate (DPP).

Consumption of 3 ATP molecules

isomerase

Step 4: synthesis of farnesylpyrophosphate (FPP)

nPrenyl Transferase catalyzes head-to-tail condensations:

nDimethylallyl pyrophosphate (DPP)

condenses with isopentenyl

pyrophosphate (IPP) to form geranyl

pyrophosphate (GPP) (10 C)

nGPP condenses with another IPP ®

farnesyl pyrophosphate (FPP) (15 C).

(10 C)

+

Farnesyl pyrophosphate

(15 C)

Step 5: Synthesis of Squalene & Cholesterol

n Squalene: combine of 2 FPP;(NADPH is a reducing agent)

n Catalyzed by Squalene Synthase

n Cholesterol Synthesis:n Formation of lanosterol by a

sequence of reactions that usemolecular oxygen and NADPH

n Through a series of 19 reactions andshortening of the carbon chain by 3(from 30 to 27), cholesterol is formedfrom lanosterol.

Regulation of cholesterol synthesis

Different types of control:

-HMG CoA reductase

-Hormonal regulation

-Transcriptional regulation

-Drugs

Control of HMG-CoA Reductase

Short-term regulation:-HMG-CoA Reductase is inhibited by phosphorylation, catalyzed by AMP-Kinase(which also regulates fatty acid synthesis)

Long-term regulation

n Feed back inhibition by cholesterol itself, oxidized derivatives of cholesterol(mevalonate…).

n Degradation within proteosome: HMG-CoA Reductase contains a sterol-sensing domain (SSD). When cholesterol level increase in cells, ubiquitin proteinwill be attached to SSD by ubiquitin ligase allowing recognition of HMG CoAreductase by proteosome.

-is a major control point.

2- Hormonal Regulation

n Insulin:

n Binds receptors on the membrane of liver cells.

n Insulin binding→ activation of HMG-CoA → increased cholesterol synthesis

n Glucagon:

n Binds specific receptors on the membrane of liver cells.

n Glucagon binding→ inactivation of HMG-CoA → decreased cholesterol synthesis.

3- Transcriptional Regulation:

The expression of the gene for HMG CoA is controlled by the transcription factor SREBP-2(Sterol regulatory element binding protein-2).

SREPB-2 is a protein of ER membrane, associate with another ER membrane protein SCAP (SREBP cleavage activating protein) and form a complex.

- When cholesterol level is low: the complex moves from ER to Golgi, where SREBP-2 is acted upon by 2 proteases which release domain of SREBP, that enters the nucleus, binds the SRE (sterol regulatory element) (in upstream of reductase gene), acts as transcription factor synthesis of HMG CoA cholesterol.

- When cholesterol is abundant, it binds SCAP at its sterol sensing domain (SSD) and induce the binding of SCAP to other membrane protein. Thus the SREBP-2 is retained in the ER membrane no activation of gene no cholesterol synthesis.

4- Drug Control: Statins

n Statins: (or HMG-CoA reductase inhibitors) are a class of drugs used to lower

cholesterol levels. They act as competitive inhibitors of HMG-CoA reductase:

They get “stuck” in the active site This prevents the enzyme from binding

with its substrate, HMG-CoA.

n Nb of statins are on the market: Statins Trade name

Atorvastatin Lipitor

Fluvastatin Lescol

Lovastatin Mevacor, Altocor

Pravastatin Pravachol, Selektine, Lipostat

Rosuvastatin Crestor

Simvastatin Zocor, Lipex

Degradation of Cholesterol

n Humans cannot degrade cholesterol to CO2 and H2O (we don’t have these enzyme mechanisms)

n Rather, the sterol nucleus is eliminated from the body by:

n Conversion to bile acid and bile salts

n Secretion of cholesterol into bile

Bile Acid/Salt Metabolism

n Major excretory form of cholesteroln Synthesized in liver, from cholesterol(27C) by loss of 3 carbons (24 C).

n Bile acid/salts involved in dietary lipid digestion as emulsifiers

n The double bond in cholesterol B-ring is reduced.

n 2 or 3 hydroxyl groups are added in thesteroid nucleus

n COOH at side chain

(3OH)

(2OH)

Types of Bile Acids/Salts

n Primary bile acidsn Good emulsifying agents

i. Cholic acid (3OH) ii. Chenodeoxycholic acid (2OH)

n Conjugated bile saltsn Amide bonds with glycine or Taurine (organic acid)n Very good emulsifier

BILE SALTSConjugation of bile acids in the liver with glycine or taurine produces bile salts:

Chenodeoxycholic acid (2OH)

The ratio of glycine to taurine forms in the bile is3:1

GlycocholicTaurocholic

Cholic acid(3OH)

BILE ACIDS

BILE SALTSGlycochenodeoxycholicTaurochenodeoxycholic

¨Bacteria in the intestine can deconjugate bile salts

Functions of Bile Salts

Ø Important for cholesterol excretion:

1. As metabolic products of cholesterol

2. As solubilizer of cholesterol in bile

Ø Emulsifying factors for dietary lipids, a pre-requisite step for efficient lipid digestion which facilitate intestinal lipid absorption.

Hormonal Control of Bile Secretion: Cholecystokinin (CCK)

Enterohepatic Circulation

n Most bile salts are reabsorbed by the liver: Enterohepaticcirculation.

n 5% will be lost in feces

CholelithiasisCholesterol Gallstone Disease

aDue to their deficiency, cholesterols crystals precipitate in the gall bladder resulting in cholesterol gallstone disease

aCauses:

Bile salts in bile:

THE END!