Cholesterol Metabolism- CVS

8/13/2019 Cholesterol Metabolism- CVS

1/21

Cholesterol Metabolism


2/21

The chemical and biochemical aspects of cholesterol regardingstructure, distribution and biological functions in human body.

The main steps of synthesis of cholesterol with special referenceto the rate-limiting step.

The regulation of cholesterol synthesis.

The excretion of cholesterol.

Main causes of hypercholesterolemia with reference tobiochemical bases of treatment.

Objectives of the Lecture


3/21

Sterols:are steroids with 8-10 carbon atoms in the side chain at C-17 &OH at C-3Sterols 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 ofdietary cholesterolDietary intake of plant steroid esters (trans fatty acid freemargarine ) helps in reduction of plasma cholesterol

Sterols


4/21

Cholesterol is an extremely important biologicalmembrane structuremolecule that has roles in

as well as being a precursor for the synthesis

&bile acids,the steroid hormonesof3Vitamin D

Bothdietary cholesterol and that

synthesized de novoare transported through.lipoprotein particlesthe circulation in

CHOLESTEROL
http://web.indstate.edu/thcme/mwking/lipoproteins.htmlhttp://web.indstate.edu/thcme/mwking/lipoproteins.html


5/21

The synthesis and utilization of cholesterolmust be tightly regulated in order to preventover-accumulation and abnormal deposition

within the body

Such deposition, eventually leading to

atherosclerosis, is the leading contributoryfactor in diseases of the coronary arteries.

CHOLESTEROL cont.


6/21

Mostplasma cholesterolis in an esterified form(with

fatty acid attached to C-3), which is morehydropobic 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 associationwith protein in lipoproteins or

solubilized byphospholipids & bile salts in the bile(as cholesterol & CE are hydrophobic)

Cholesterol & cholesterol esters


7/21

Structure of cholesterol & cholesterol ester


8/21

Liver Cholesterol (sources & fate)


9/21

PLASMA CHOLESTEROL

Plasma cholesterol level is 150 250 mg/dl (average175 mg/dl)

Types: 30%of plasma cholesterol are free 70%are esterified with polyunsaturated fatty acids


10/21

Cholesterol synthesis by all tissues especially:

liver, intestine, adrenal cortex & reproductive tissues

It occurs in the cytoplasmwith enzymes in both the cytosol and the

membrane of the endoplasmic reticulum

Cholesterol is synthesized from acetyl CoA molecules

Synthesisbegins with the transport of acetyl-CoA from the

mitochondria to the cytosol

Biosynthesis of Cholesterol


11/21

In the cytoplasm, citrateis converted to oxaloacetate& acetyl-CoAby the

.reactionlyasecitrate-ATP

Transport of acetyl CoA from mitochondria to cytosol


12/21

Biosynthesis of Cholesterolcont.

HMG CoA

3 Acetyl CoA molecules

First two reactions ofcholesterol synthesis

Thiolase enzyme

HMG CoA synthase


13/21

areHMG CoA synthaseofisoenzymestwoIn the liver,available:

1- Cytosolic enzyme: for cholesterol synthesis2- Mitochondrial enzyme:for ketone bodies synthesis

Biosynthesis of Cholesterol cont.


14/21

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.


15/21

6C

5C

10C

15C

27C


16/21

The cellular supply of cholesterol is maintained at a steady level bythree distinct mechanisms:

1. Regulation of HMG CoA reductase activity & levels

2. Regulation of excess intracellular free cholesterol through theactivity of acyl-CoA:cholesterol acyltransferase (ACAT)

3. Regulation of plasma cholesterol levelsvia LDL receptor-mediateduptake & HDL-mediated reverse transport (in liver).

Regulation of Cholesterol Synthesis


17/21

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 cholesterolCholesterol 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

Insulincauses upregulation of expression of the HMG CoA reductase gene leading to increase

cholesterol synthesis

5.Inhibition by statin drugs

Regulation of Cholesterol Synthesis cont.


18/21

transcription of mRNA

SREBP is proteolyticaly cleavedmRNA

-

Cholesterol also decreasesthe 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


19/21

Cholesterol Excretion & Degradation

Ring of sterol cantbe metabolized to CO2& H

2O in humans

Bile acids Bile Juice

Neutral sterols in stool

Cholesterol

Bacterial Reduction tocoprostanol & cholestanol

intestine

Bile Juice

as suchExcretedtoConverted

intestine


20/21

Hypercholesterolemia

It is the increase of plasma cholesterol above 250 mg/dl.

Hypercholesterolemia is associated with atherosclerosis, coronaryheart 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


21/21

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 ininhibition of cholesterol synthesis

CholestyramineBinds to bile acids in the GIT & prevents their reabsorption & promote theirexcretion.Reduced bile acids will relieve inhibition on bile acids synthesis in the liver &thus diverting more cholesterol to be converted to bile acids synthesis

Documents

Cholesterol Metabolism- CVS