cholesterol metabolism- cvs
TRANSCRIPT
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Cholesterol Metabolism
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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
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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
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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 -
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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.
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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
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Structure of cholesterol & cholesterol ester
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Liver Cholesterol (sources & fate)
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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
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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
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In the cytoplasm, citrateis converted to oxaloacetate& acetyl-CoAby the
.reactionlyasecitrate-ATP
Transport of acetyl CoA from mitochondria to cytosol
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Biosynthesis of Cholesterolcont.
HMG CoA
3 Acetyl CoA molecules
First two reactions ofcholesterol synthesis
Thiolase enzyme
HMG CoA synthase
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areHMG CoA synthaseofisoenzymestwoIn the liver,available:
1- Cytosolic enzyme: for cholesterol synthesis2- Mitochondrial enzyme:for ketone bodies synthesis
Biosynthesis of Cholesterol cont.
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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.
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6C
5C
10C
15C
27C
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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
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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.
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transcription of mRNA
SREBP is proteolyticaly cleavedmRNA
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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
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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
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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
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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