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Cholesterol Metabolism

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 .

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Cholesterol Metabolism

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  1. Cholesterol Metabolism

  2. 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.

  3. 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

  4. CHOLESTEROL Cholesterol is an extremely important biological molecule that has roles inmembrane structure as well as being a precursor for the synthesis of the steroid hormones, bile acids & Vitamin D3 Bothdietary cholesterol and that synthesized de novoare transported through the circulation in lipoprotein particles.

  5. CHOLESTEROL cont. The synthesis and utilization of cholesterolmust 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.

  6. Mostplasma cholesterolis 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

  7. Structure of cholesterol & cholesterol ester

  8. Liver Cholesterol (sources & fate)

  9. 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

  10. 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

  11. Transport of acetyl CoA from mitochondria to cytosol In the cytoplasm, citrateis converted to oxaloacetate& acetyl-CoA by the ATP-citrate lyase reaction.

  12. Biosynthesis of Cholesterolcont. First two reactions of cholesterol synthesis 3 Acetyl CoA molecules Thiolase enzyme HMG CoAsynthase HMG CoA

  13. In the liver, twoisoenzymes of HMG CoA synthase are available:1- Cytosolic enzyme: for cholesterol synthesis 2- Mitochondrial enzyme:for ketone bodies synthesis Biosynthesis of Cholesterol cont.

  14. 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

  15. 6C 5C 10C 15C 27C

  16. Regulation of Cholesterol Synthesis The cellular supply of cholesterol is maintained at a steady level by three distinct mechanisms: 1. Regulation of HMG CoAreductaseactivity & 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).

  17. Regulation of HMGCoAreductase: 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.

  18. Insulin favors upregulation of the expression of HMG CoA reductase gene Statin drugs reversible competitive inhibitors (structural analogs) ↑Cholesterol also decreases the stability of HMG CoA ptn & mRNA - mRNA SREBP is proteolyticaly cleaved transcription of mRNA SRE in DNA

  19. Cholesterol Excretion & Degradation Ring of sterol can’t be metabolized to CO2 & H2O in humans Cholesterol Excreted as such Convertedto Bile acids Bile Juice intestine Bile Juice Bacterial Reduction to coprostanol & cholestanol Neutral sterols in stool intestine

  20. 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

  21. 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

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