Metabolism , Metabolic Fate& disorders of cholesterol.pptx

For Medicals, paramedical, and allied health sciences students

1. Metabolism of Cholesterol

2. Cholesterol Structural component of every cell (in cell membrane) It provides a protective barrier To establish proper membrane permeability, Membrane fluidity & Nerve conduction Major components of lipoproteins Metabolical role It involves Vit -D formation Synthesis of bile acids & Bile salts Steroid hormones Polar head non polar General formula-C 27 H 45 OH Cyclo pentano perhydro-phenanthrene

3. In total cholesterol : About 30% free form (un esterified) & 70% - cholesteryl esters form

4. Biosynthesis of Cholesterol Sites Enzymes location Requirements Stages All nucleated cells including arterial wall. Major sites are liver , intestine Adrenal cortex, testes & ovaries Partly endoplasmic reticulum & partly in cytoplasm . 18moles of Acetyl -CoA provides all carbon atoms 36 moles of ATP 16 moles of NADPH are required Synthesis of HMG -CoA Formation of Mevalonate Production of Isoprenoid units Synthesis of squalene Conversion of squalene to cholesterol

5. Cytoplasmic Stage-1: Synthesis of HMG -CoA

6. Endoplasmic reticulum Stage-2: Formation of Mevalonate CoA-SH

7. Stage-3: Production of Isoprenoid units Mevalonate (6C) Isopentenyl Pyrophosphate (IPP) (5C) 3ATP 3ADP+ Pi+CO 2 3 Phosphorylation reaction & one Decarboxylation reactions Dimethylallyl pyrophosphate (5C) Isomerase IPP is the precursor for vitamin –A, K, Carotenoids & Ubiquinone Dolichol

8. Dimethylallyl pyrophosphate (5C) I PP (5C) I PP (5C) FPP, NADPH +H + NADP + PPi Squalene Synthase ( Mg, Mn ) Stage-4: Synthesis of squalene Transferase P Pi Transferase Geranyl pyrophosphate (10C) Fernesyl pyrophosphate (15C) Squalene PPi Currently bisphosphonates are used for treatments of osteoporosis as inhibit FPP synthesis & inhibit osteoclast activity preventing demineralization in osteoporosis

9. Step 5: Conversion of Squalene to Cholesterol Squalene Squalene monooxygenase 2,3-Oxidosqualene cyclase Lanosterol (30C) 20 Steps Cholesterol NADPH, O 2 Squalene- 2,3-epoxide Shortening of the C-chain from 30 to 27 Removal of the extra methyl groups at C4 Migration of the double bond from C8 to C5 Reduction of one double bond b/w C24 & C25

10. REGULATION

11. Hormonal regulation (Covalent modification) Thyroid hormones Phosphorylated form is inactive Dephosphorylated form is active

12. Regulation of cholesterol biosynthesis by HMG-CoA reductase Durgs , eg . Compactin , statins ( Mevastatin , Lovastatin , Provastatin , Simvastatin )-competitive inhibitors Bile acids High caloric diet

13. Transcriptional regulation of gene for HMG-CoA reductase SCAP (Intracellular cholesterol sensor) Specific recognition sequence

14. Formation of Cholesterol Esters In plasma (HDL) From the peripheral tissues to liver In cells of liver, intestine & adrenal cortex C2 of lecithin containing PUFA Endoplasmic reticulum

15. Wolman’s disorder (Rare genetic disorder) accumulation of CE & TGs in the cells Cause bloating or abdominal distention, vomiting & significant hepatosplenomegaly

16. Excretion : Unabsorbed portion of the cholesterol (50%) by intestinal bacteria form cholestanol & coprostanol excreted fecal Remaining cholesterol (50%) is converted to bile acids ,which are excreted in the bile as bile salts

17. Synthesis of Bile acids in the liver Metabolic Fate of Cholesterol Synthesis of Steroid hormones Required for synthesis of Vit- D Excreted in feces as cholestanol & coprostanol (fecal sterols ) Metabolic Fate of Cholesterol

18. Formation of Bile Acids Vit -C

19. Conjugation in bile Conjugation more with glycine than taurine Na+ & K+ Formation of Bile salts Sodium & potassium glycocholate or taurochenodeoxycholate 99% bile acids in duodenum are reabsorbed. 1% excreted in stools after modification as 2 o bile acids In colon Intestinal bacteria

20. Functions of Bile acids: Act as efficient emulsifying agents Facilitate the enzymatic digestion & absorption of dietary lipids & fat soluble vitamins ( forming mixed micelle ) Conversion of cholesterol into bile acids in the liver - prevents the body from becoming overloaded with cholesterol Act as regulatory molecules: activate nuclear receptors, G-protein coupled receptors TGR5, cell signaling pathways in the liver Bile acids activating signaling pathways are novel drug targets to treat of obesity, Type-2 DM, Hyperlipidemia & atherosclerosis

21. Cholelithiasis (Cholesterol gall stone disease) Due to increased syn of cholesterol & decreased syn of bile acids Bile is supersaturated with cholesterol results crystals that nucleated into solid crystals – forms stones (gall stones) Mucin secreted by gallbladder, promotes the process of nucleation apoproteins A-I & A-II inhibits, thus prevents the gall stone formation

22. Cholecystitis Multiple stones may cause inflammatory changes in the gall bladder Treatment: Chenodeoxy cholic acid is used as a drug to dissolve gall stones. Surgery is required when stones obstructed the bile duct or for removing an inflamed gallbladder

23. Metabolism of Vitamin-D

24. Formation of Vitamin-D

25. Biochemical functions of Vitamin –D Calcitriol regulates serum calcium and phosphorus . Regulates the differentiation & proliferation of various cells Involved in the modulation of the immune system Action on the Intestine Action on the bone Action on renal tubules - Due to ↑se availability of calbindin, the absorption of Ca 2+ is ↑ sed ↑ ses intestinal absorption of Ca 2+ & P from intestine Calcitriol stimulates osteoblasts → secrete ALP → ↑ sed conc. of phosphate. - Ionic products of Ca 2+ & P ↑ ses leads to mineralization Increases reabsorption & decreases excretion of Ca 2+ & P by renal tubules

26. Cholesterol is the major precursor of the 5 classes of steroid hormones Mineralocorticoids ( eg . Aldosterone) Estrogens ( eg : estradiol) Progestin ( eg : progesterone ) Androgens ( eg : Testosterone) Glucocorticoids ( eg . cortisol) SYNTHESIS OF STEROID HORMONES

27. Glucocorticoids ( eg . cortisol) Mineralocorticoids ( eg . Aldosterone) Cholesterol is the major precursor for steroid hormones

28. Hormone Site RH Functions Glucocorticoids (Cortisol / corticosterone ) - produced in adrenal cortex Zona fasciculate cells Adreno corticotropic hormone (ACTH) Helps to promotes gluconeogenesis, favors lipolysis & protein break down. Protects against stress, Helps to maintain BP Mineralocorticoids (Aldosterone) – produced in adrenal cortex Zona glomurulosa cells ACTH - Helps to regulates body’s water & electrolyte balance - Maintains blood volume & BP by increasing Na + reabsorption in exchange for K + & H + Androgens (testosterone) – primarily in the gonads (testicles , ovaries) & also in the adrenal glands Zona reticularis cells ACTH Controls the development of male 2 o sexual characteristics Regulates sperm production P romotes increased muscle mass through increased protein formation, Prevents bone resorption

29. Hormone Site RH Functions Estrogen (produced in ovaries ) Follicle stimulating hormone (FSH) Controls the development of female 2 o sexual characteristics , Regulates menstrual cycle, Contributes to the hormonal regulation of pregnancy & lactation, Prevents bone resorption Progesterone by the ovaries, placenta & adrenal glands Luteinized granulosa cells LH its role in thickening the lining of the uterus each month. Prepares uterus lining for implantation of ovum

30. Disorders of Cholesterol

31. Normal levels of cholesterol in serum is150 to 200mg/dl HYPERCHOLESTEROLEMIA: High conc. of cholesterol in the blood. It is a combination of " hyperlipidemia " (elevated levels of lipids in the blood) & " hyperlipoproteinemia " (elevated levels of lipoproteins in the blood).

32. High conc. of cholesterol in serum Physiological causes Pathological causes Unhealthy Diet: increased intake of Saturated FA or consumption of rich carbohydrates. High consumption alcohol & smoking Lack of physical exercise Type -II Diabetes Mellitus, Obstructive jaundice (due to blockage of excretion) Hypothyroidism ( receptors on liver is reduced due to decreased thyroid hormones) Nephrotic syndrome

33. Atherosclerosis Thickening or hardening & narrowing of coronary arteries due to the accumulation of lipids (cholesterol) in the inner arterial walls & producing blockages in the vessels that carry blood to the heart.

34. Oxidants like superoxide radicals, nitric oxide, H 2 O 2 causes oxidation of LDL Oxidized LDL is taken up by macrophages of the immune system Macrophages engorged with oxidized LDL to form Foam cells . Foam cells are trapped in the walls of the blood vessels, lead to the formation of plaques and narrowing of the arteries Plaques (foam cells) are composed of smooth muscles cells, connective tissues & lipids that accumulate in the intima of the arterial wall . Formation of Plaque and arterial narrowing

35. Foam cells accumulate causing a fatty steak to develop in the blood vessels Damaged endothelial cells cannot produce P rostaglandins I 2 , Prostacyclin & platelets to aggregate, releases Thromboxane -A ( favors thrombus formation & increased BP) Releases P latelet D erived G rowth F actor (PDGE) contributes to plaque formation and narrowing of the arteries

36. Parameter Effect Sex Male are more affected Female incidence is more after menopause Genetic factor Derangement of lipoprotein metabolism leads to high lipid levels and familial hypercholesterolemia Hyperlipidemia Increased levels of serum cholesterol, triglycerides, LDL, Lp -a Low levels of HDL is associated with atherosclerosis Hypertension Mechanical injury to the vessel wall due to raised blood pressure Cigarette smoking Reduced levels of HDL and accumulation of carbon monoxide Diabetes Mellitus Risk due to coexistence of other risk factors like obesity, hypertension and hyperlipidemia Other risk factors Raised LDL and decreased HDL, lack of exercise& more stress, high caloric intake, diet containing large quantities of saturated fats, use of oral contraceptive, alcoholism and diabetes mellitus, Factors Responsible For Atherosclerosis

37. Myocardial Infarction Myocardial ischemia / MI results from reduction of coronary blood flow to an extent that leads to insufficiency of oxygen supply to the myocardial tissue

38. Chronically elevated serum cholesterol (LDL-C) formation of atheromatous plaques in the arteries (atherosclerosis) lead to progressive stenosis (narrowing) or even complete occlusion (blockage) of the involved arteries. leads to obstruct blood flow (low oxygen supply) in coronary artery results in a myocardial infarction or heart attack .

39. Prevention : Avoid smoking : Nicotine increases lipolysis →acetyl CoA → cholesterol P hysical exercise: Lowers LDL-C & raises HDL-C, reduces TG levels Consumption of PUFA : Required for the esterification of cholesterol & ω -3 FAs reduce LDL-C Take more dietary fibers: Increase the reabsorption of bile salts & ↓se the absorption of dietary cholesterol) Consume sufficient natural antioxidants: Prevent the formation of oxidized LDL Restricting consumption of alcohol Drug therapy

40. Hypolipidemic drugs Action Statin s ( lovastatin , simvastatin , atorvastatin , prevastatin , pitavastatin , fluvastatin , rosuvastatin ) - Inhibits HMC-CoA reductase - Improving the endothelial functions - Modulating inflammatory response - Maintaining plaque stability - Preventing blood clot formation Fibrates ( Clofibrate ) Increasing beta oxidation of fatty acids Aspirin Prevents thrombus formation ( antiplatelet activity) Bile acid binding resins ( Cholestyramine ) Cholestyramine & Cholestipol Decreases the reabsorption of bile salts Nicotinic acid Inhibits lipolysis

41. Hypocholesterolemia Decreased cholesterol levels in plasma Causes: Hyper thyroidism liver necrosis Malabsorption syndrome Pernicious anemia Haemolytic jaundice Inherited hypolipoproteinaemias

42. LIPID PROFILE SPECIAL INVESTIGATION Ref. ranges Triglycerides 100-150 mg/dl Cardiac Enzymes CK-MB & LDH 4 Total cholesterol 150- 200 mg/dl Cardiac proteins Myoglobin & Troponin - I LDL cholesterol 60- 140 mg/dl Other investigations Homocysteine & Lipoprotein (a) HDL cholesterol 30- 60 mg/dl VLDL < 35mg/dl Diagnostic Investigations ( Biochemical Markers )

43. OBESITY Anyone who is more than 20% above the standard weight for the same age, sex, and race, is considered to be overweight.

44. Causes Genetic influences Physiological Overeating than caloric requirement, Pregnancy Use of oral contraceptives for prolonged period - Post menopausal women Metabolic Diabetes mellitus, Hyperlipidemia Hormonal Hypothyroidism, Hypogonadism Hypopituitarism , Cushing’s syndrome

45. Metabolic changes in Obesity Serum triglyceride levels are raised due to hyperinsulinism Serum Cholesterol levels are raised Mobilization of Free Fatty Acid is reduced Lipoprotein lipase activity brings delipidation of TG, circulating chylomicrons &VLDL Increased activity of the enzyme would lead to increased FFA accumulation in adipose tissue and leads to fat deposition Promotes lipogenesis and inhibits lipolysis

46. Believe your self Have a nice day to all