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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:
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 & 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
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
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
cont.
HMG CoA
Biosynthesis of Cholesterol
cont.
Biosynthesis of Cholesterol
cont.
6C
5C
10C
15C
27C
cont.
Low cholesterol level activates a transcription factor leading to increased HMG CO reductase synthesis increased cholesterol synthesis
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
Cholesterol also decreases the stability of HMG CoA ptn & mRNA
Cholesterol
Converted to
Excreted as such
Bile acids
Bile Juice
intestine
Bile Juice
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)
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