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Cholesterol Metabolism

Objectives of the Lecture


The chemical and biochemical aspects of cholesterol regarding
structure, distribution and biological functions in human body. The main steps of synthesis of cholesterol with special reference to the rate-limiting step. The regulation of cholesterol synthesis. The excretion of cholesterol.

Main causes of hypercholesterolemia with reference to biochemical bases of treatment.

Sterols
Sterols:
are steroids with 8-10 carbon atoms in the side chain at C-17 & OH at C-3 Sterols are found in animals & plant

Cholesterol:

is the major sterol in animal tissues

Plant sterols:

as are poorly absorbed by humans, it blocks the absorption of dietary cholesterol Dietary intake of plant steroid esters (trans fatty acid free margarine ) helps in reduction of plasma cholesterol

CHOLESTEROL
Cholesterol is an extremely important biological molecule that has roles in membrane structure as well as being a precursor for the synthesis of the steroid hormones, bile acids & Vitamin D3 Both dietary cholesterol and that synthesized de novo are transported through the circulation in lipoprotein particles.

CHOLESTEROL

cont.

The synthesis and utilization of cholesterol must be tightly regulated in order to prevent over-accumulation and abnormal deposition within the body Such deposition, eventually leading to atherosclerosis, is the leading contributory factor in diseases of the coronary arteries.

Cholesterol & cholesterol esters


Most plasma cholesterol is in an esterified form (with fatty acid attached to C-3), which is more hydropobic than free cholesterol.

Cholesteryl esters (CE) are not found in membranes


CE are normally present in low levels in most cells

Cholesterol & CE must be transported in association with protein in lipoproteins or solubilized by phospholipids & bile salts in the bile (as cholesterol & CE are hydrophobic)

Structure of cholesterol & cholesterol ester

Liver Cholesterol (sources & fate)

PLASMA CHOLESTEROL
Plasma cholesterol level is 150 250 mg/dl (average 175 mg/dl)
Types: 30% of plasma cholesterol are free 70% are esterified with polyunsaturated fatty acids

Biosynthesis of Cholesterol
Cholesterol synthesis by all tissues especially: liver, intestine, adrenal cortex & reproductive tissues It occurs in the cytoplasm with enzymes in both the cytosol and the membrane of the endoplasmic reticulum Cholesterol is synthesized from acetyl CoA molecules Synthesis begins with the transport of acetyl-CoA from the

mitochondria to the cytosol

Transport of acetyl CoA from mitochondria to cytosol

In the cytoplasm, citrate is converted to oxaloacetate & acetyl-CoA by the ATP-citrate lyase reaction.

Biosynthesis of Cholesterol
First two reactions of cholesterol synthesis

cont.

3 Acetyl CoA molecules


Thiolase enzyme HMG CoA synthase

HMG CoA

Biosynthesis of Cholesterol

cont.

In the liver, two isoenzymes of HMG CoA synthase are available:


1- Cytosolic enzyme: for cholesterol synthesis 2- Mitochondrial enzyme: for ketone bodies synthesis

Biosynthesis of Cholesterol

cont.

Third step of cholesterol synthesis:


is the formation of mevalonic acid by the enzyme
3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA reductase)

(Requires 2 NADPH as coenzymes)

This step is the rate limiting step of cholesterol synthesis

6C

5C

10C

15C

27C

Regulation of Cholesterol Synthesis


The cellular supply of cholesterol is maintained at a steady level by three distinct mechanisms: 1. Regulation of HMG CoA reductase activity & levels 2. Regulation of excess intracellular free cholesterol through the activity of acyl-CoA:cholesterol acyltransferase (ACAT) 3. Regulation of plasma cholesterol levels via LDL receptor-mediated uptake & HDL-mediated reverse transport (in liver).

Regulation of Cholesterol Synthesis


Regulation of HMGCoA reductase:
1.Sterol-dependent regulation of gene expression:

cont.

Low cholesterol level activates a transcription factor leading to increased HMG CO reductase synthesis increased cholesterol synthesis

2. Enzyme degradation by cholesterol


Cholesterol decreases the stability of HMG CoA reductase resulting in its rapid degradation

3.Sterol-independent phosphorylation/dephosphorylation
AMP (i.e. decrease ATP availability) causes phosphorylation of HMG CoA reductase causing its inactivation (with decrease cholesterol synthesis)

4.Hormonal regulation
Insulin causes upregulation of expression of the HMG CoA reductase gene leading to increase cholesterol synthesis

5.Inhibition by statin drugs

Insulin favors upregulation of the expression of HMG CoA reductase gene

Statin drugs reversible competitive inhibitors (structural analogs)

SREBP is proteolyticaly cleaved mRNA

Cholesterol also decreases the stability of HMG CoA ptn & mRNA

SRE in DNA transcription of mRNA

Cholesterol Excretion & Degradation


Ring of sterol cant be metabolized to CO2 & H2O in humans

Cholesterol

Converted to

Excreted as such

Bile acids

Bile Juice
intestine

Bile Juice
intestine

Bacterial Reduction to coprostanol & cholestanol

Neutral sterols in stool

Hypercholesterolemia
It is the increase of plasma cholesterol above 250 mg/dl. Hypercholesterolemia is associated with atherosclerosis, coronary heart diseases (CHDs), heart attacks & stroke

Causes:
1- Excessive consumption of diet rich in cholesterol, fats specially saturated FA
or carbohydrates 2- Diabetes mellitus (DM)

3- Hypothyroidism: due to decreased conversion of cholesterol to bile acids


4- Obstructive jaundice: no excretion of cholesterol or bile salts in bile 5- Familial hypercholesterolemia

Treatment of Hypercholesterolemia
1- Diet:
Decrease intake of carbohydrate, saturated fatty acids & cholesterol Increase intake of mono- & polyunsaturated fatty acids Increase intake of fibers-rich diet

2- Hypocholesterolemic drugs:
Statin drugs e.g.atorvastatin (Lipitor) and simvastatin (Zocor) : Statin drugs are competitive inhibitors of HMG CoA reductase resulting in inhibition of cholesterol synthesis
Cholestyramine Binds to bile acids in the GIT & prevents their reabsorption & promote their excretion. Reduced bile acids will relieve inhibition on bile acids synthesis in the liver & thus diverting more cholesterol to be converted to bile acids synthesis

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