Cholesterol Metabolism
Sterols: Steroids with 8-10 carbon atoms in the side chain at C-17 & OH at C-3, found in animals
& plant
Cholesterol: the major sterol in animal tissues
Plant sterols: 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 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.
The synthesis and utilization of cholesterol must be tightly regulated in order to prevent overaccumulation 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
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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)
Plasma Cholesterol: 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
 Synthesis by all tissues especially: liver, intestine, adrenal cortex & reproductive tissues
occurs in the cytoplasm with enzymes in both the cytosol and the of ER membrane
synthesized from acetyl CoA molecules
 Synthesis begins with the transport of acetyl-CoA from the mitochondria to the cytosol
In the liver, two isoenzymes of HMG CoA synthase are available:
 Cytosolic enzyme: for cholesterol synthesis
 Mitochondrial enzyme: for ketone bodies synthesis
Third step of cholesterol synthesis:
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
Regulation of Cholesterol Synthesis
The cellular supply of cholesterol is maintained at a steady level by three distinct mechanisms:
Cholesterol Metabolism
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Tasneem Aldraye
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Regulation of HMG CoA reductase activity & levels
Regulation of excess intracellular free cholesterol through the activity of ACAT
Regulation of plasma cholesterol levels via LDL receptor-mediated uptake & HDLmediated reverse transport (in liver).
Regulation of HMGCoA reductase:
Sterol-dependent regulation of gene expression: Low cholesterol level activates a
transcription factor leading to increased HMG CO reductase synthesis – increased cholesterol
synthesis
Enzyme degradation by cholesterol: ↑Cholesterol decreases the stability of HMG CoA
reductase resulting in its rapid degradation
Sterol-independent phosphorylation/dephosphorylation: AMP (i.e. decrease ATP availability)
causes phosphorylation of HMG CoA reductase causing its inactivation (with decrease
cholesterol synthesis)
Hormonal regulation: Insulin causes upregulation of expression of the HMG CoA reductase
gene leading to increase cholesterol synthesis
Inhibition by statin drugs
Hypercholesterolemia: increase of plasma cholesterol above 250 mg/dl.
Associated with atherosclerosis, coronary heart diseases (CHDs), heart attacks & stroke
Causes:
 Excessive consumption of diet rich in cholesterol, fats specially saturated FA or
carbohydrates
 Diabetes mellitus (DM)
 Hypothyroidism: due to decreased conversion of cholesterol to bile acids
 Obstructive jaundice: no excretion of cholesterol or bile salts in bile
 Familial hypercholesterolemia
Treatment:
 Diet:
 Decrease intake of carbohydrate, saturated fatty acids & cholesterol
 Increase intake of mono- & polyunsaturated fatty acids & fiber-rich diet
 Hypocholesterolemic drugs: Statin drugs & Cholestyramine
Cholesterol Metabolism
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Tasneem Aldraye