Transcript Cholesterol metabolism- CVSx

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
3 Acetyl CoA molecules
Thiolase enzyme
HMG CoA synthase
HMG CoA
cont.
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
cont.
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
Statin drugs
reversible
competitive inhibitors
(structural analogs)
Insulin
favors upregulation of the
expression of HMG CoA reductase gene
↑Cholesterol also decreases
the stability of HMG CoA ptn
& mRNA
SREBP is proteolyticaly cleaved
mRNA
SRE in DNA transcription of mRNA
Cholesterol Excretion & Degradation
•
Ring of sterol can’t be metabolized to CO2 & H2O in humans
Cholesterol
Converted to
Bile acids
Excreted as such
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