MEDICAL FAT METABOLISM AND CHOLESTEROL.pptx

MEDICAL FAT METABOLISM AND CHOLESTEROL

1. LIPID METABOLISM DR. CHIKONDE

2. Fatty Acid METABOLISM Energy – βOxidation of Fatty acids Storage – FA into TAG Synthesis of phospholipids, sphingolipids, cholesterol esters , eicosanoids Free Fatty Acids in blood- 100-200 meq/L Higher levels seen in starvation and uncontrolled diabetes mellitus

3. Oxidation of Fatty Acids FA Oxidation α β ω Perioxisome Unsaturated FA

4. βOxidation of FA Major pathway of oxidation of fatty acids Oxidation occurs at βcarbon of Fatty acids Catabolic pathway of FA A 2 carbon unit, acetyl-Co A is the end product Site - Liver, Kidney, Heart ,major metabolic organs Subcellular site - Inner mitochondrial membrane and matrix

5. βCarbon

6. CHOLESTEROL METABOLISM

7. CHOLESTEROL No vegetable oil contains any cholesterol Cholesterol is the major sterol in animal tissue s Total cholesterol in a 70 kg man: 140 gm (2gm/kg) A portion of the body cholesterol is derived from diet (egg yolk, meat, liver brain) A little more than half of it is synthesized in the body (700 mg/d)

8. FUNCTIONS OF CHOLESTEROL Structural component of cell membrane Steroid hormone (Progesterone, estrogens, glucocorticoid, mineralocorticoids) Vitamin D (from 7-dehydrocholesterol) Bile acids (Cholic acid, Chenodeoxycholic acid) Transport of fatty acid to liver as cholesteryl esters (plasma lipoproteins)

9. STRUCTURE OF CHOLESTEROL

10. CHOLESTEROL BIOSYNTHESIS Virtually all tissues containing nucleated cells are capable Occurs in ER and cytosol Site: Liver (10%), Intestine (10%), Adrenal cortex, Reproductive tissues, Skin All the carbon atoms of cholesterol are derived from acetyl CoA Requirements: Acetyl CoA- 18 moles ATP- 36 moles NADPH- 16 moles

11. STEPS OF DE NOVO CHOLESTEROL SYNTHESIS Step 1—Biosynthesis of Mevalonate (6C) Step 2—Formation of Isoprenoid Units (5C) Step 3—Six Isoprenoid Units Form Squalene (30C) Step 4—Formation of Lanosterol (30C) Step 5—Formation of Cholesterol (27C)

12. Two molecules of acetyl CoA react to form acetoacetyl CoA Another acetyl group is added to form β -hydroxy- β -methylglutaryl CoA (HMG CoA) HMG CoA is reduced to mevalonate Reactions of the first stage

13. HMG-COA REDUCTASE Rate limiting enzyme Present in endoplasmic reticulum Regulated by- Feedback control (mevalonate, cholesterol) Hormonal regulation Insulin, thyroxin (+) Drugs (Statins) Glucagon, glucocorticoid (-) Bile acids, fasting

14. Mevalonate undergoes three successive phosphorylations to form mevalonate-3-phospho-5-pyrophosphate The latter is converted into two types of isoprenoid units The units are isopentenyl pyrophosphate and 3,3-dimethyl allyl pyrophosphate REACTIONS OF THE SECOND STAGE

15. Two isoprenoid units form geranyl pyro-phosphate, a 10-carbon compound Geranyl pyrophosphate and one isoprenoid unit form15-carbon farnesyl pyrophosphate Two molecules of farnesyl pyrophosphate form 30-carbon squalene REACTIONS OF THE THIRD STAGE

16. Squalene is oxidized to squalene oxide Squalene oxide is cyclized to lanosterol By a series of reactions, lanosterol is converted into cholesterol REACTIONS OF THE FOURTH STAGE

17. HMG-CoA reductase (active) HMG-CoA reductase (Inactive) Acetyl-CoA HMG-CoA Mevalonate CHOLESTEROL Insulin Glucagon Increased caloric intake, Thyroid hormone Bile acids, glucocorticoids, Dietary cholesterol P Dephosphorylation Phosphorylation + + + - REGULATION OF DE NOVO SYNTHESIS OF CHOLESTEROL

18. EXCRETION OF CHOLESTEROL Cannot be destroyed by oxidation to CO 2 and H 2 O, because of absence of enzyme capable of catabolising the steroid nucleus 50% is converted to bile acid Cholesterol is excreted in faeces About 1gm of cholesterol is eliminated from the body per day (C-0.6g/d; bile acid-0.4 g/d)

19. BLOOD CHOLESTEROL Plasma cholesterol is associated with different lipoprotein fraction (LDL, HDL, VLDL) Free cholesterol -30%; Ester with long chain FA as cholesteryl ester- 70% Major constituent of gall stone; correlated with atherosclerosis & CHD Blood levels are influenced by both genetic and environmental factors

20. FACTORS AFFECTING SERUM CHOLESTEROL LEVEL Hereditary factors Diet Beneficial- Unsaturated fats ( ω₆, ω₃ FA) Harmful- Saturated fat, sucrose, fructose Lifestyle- High blood pressure, smoking, male gender, obesity, lack of exercise, soft drinks, emotional stress Hypolipidemic drug (atorvastatin, simvastatin, Fluvastatin)- when diet change fail

21. DISORDER OF CHOLESTEROL METABOLISM Familial Hypercholesterolemia Inherited defects in LP metabolism Deficiency or malfunction of LDL receptors Plasma LDL & cholesterol level are elevated Atherosclerosis Deposition of cholesterol and other lipids in the arterial wall Leads to formation of plaque → endothelial damage → IHD

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