Cholesterol Metabolism

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.

Objectives of the Lecture

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 cholesterolDietary intake of plant steroid esters (trans fatty acid – free margarine ) helps in reduction of plasma cholesterol

Sterols

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

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 cont.

• 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)

Cholesterol & cholesterol esters

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

• 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

Biosynthesis of Cholesterol

In the cytoplasm, citrate is converted to oxaloacetate & acetyl-CoA by the

ATP-citrate lyase reaction.

Transport of acetyl CoA from mitochondria to cytosol

Biosynthesis of Cholesterol cont.

HMG CoA

3 Acetyl CoA molecules

First two reactions of cholesterol synthesis

Thiolase enzyme

HMG CoA synthase

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

Biosynthesis of Cholesterol cont.

6C

5C

10C

15C

27C

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:

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

Regulation of Cholesterol Synthesis cont.

transcription of mRNA

SREBP is proteolyticaly cleavedmRNA

-

↑Cholesterol also decreases the stability of HMG CoA ptn

& mRNA

Insulin favors upregulation of the

expression of HMG CoA reductase gene

Statin drugs reversible

competitive inhibitors(structural analogs)

SRE in DNA

Cholesterol Excretion & Degradation

• Ring of sterol can’t be metabolized to CO2 & H2O in humans

Bile acids Bile Juice

Neutral sterols in stool

Cholesterol

Bacterial Reduction to coprostanol & cholestanol

intestine

Bile Juice

Excreted as suchConverted to

intestine

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