Cholesterol Metabolism
description
Transcript of Cholesterol Metabolism
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 D3Both 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 cleaved mRNA
-
↑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
intestineBile 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