Cholestrol & its significance

The slides deal with the cholesterol structure,its metabolism and clinical significance

1. Cholesterol & its significance Presented by Melbia shiny First MDS Oral medicine & radiology

2. Introduction Light yellow crystalline solid Soluble in chloroform, & fat solvents Distributed in brain ,nerves, muscle,adipose tissue ,skin ,blood, liver,& spleen. Absent in plant.

3. Structure has cyclopentano perhydrophenanthrene ring ,A,B,C,D rings are present. Has 27 carbon atoms. One hydroxyl group on third carbon atom Double bond between 5&6 C atoms 8 C side chain.

4. function Cholesterol is precursor for synthesis of vitamin D & bile acids . Cell membrane- it has modulating effect on fluid state of membrane. Nerve conduction –it is used to insulate nerve fibers. Fatty acids transported to liver as cholesterol esters for oxidation.

5. 5.Steroid hormones - glucocorticods , androgene , estrogen are synthesized from cholestrol . 6.Essential ingredient in structure of lipoprotein.

6. Excreation Cholesterol is excreted through bile prior esterification with PUFA Partly reabsorbed from intestine Unabsorbed portion is acted by intestinal bacteria to form cholestanol & coprostanol which is excreated as fecal sterols Another part is converted into bile acids ,excreted as bilesalts .

7. Degradation of cholesterol Synthesis of bile acids

8. Synthesis of vitamin D cholestrol 7 dehydrocholesterol uv rays cholecalciferol in liver 25 cholecalciferol in kidney( parathromone ) 1,25 dehydrocholecalciferol (active vitD )

9. Transport of cholesterol in blood Being lipid it is insoluble in water Cholestrol is complexed with protein to form lipoprotein. Protein part is apolipoprotein LACT(lecithin cholesterol acyltransferase ) is responsible for transport & elimination of cholesterol from body

10. Classification of lipoprotein Chylomicrons Very low density lipoprotein(VLDL) Intermediate density lipoprotein(IDL) Low density lipoprotein(LDL) High density lipoprotein(HDL) Free fatty acids

11. General characteristics of lipoprotein Lipoprotein have polar periphery made of proteins (apolipoprotein), phospholipids, & cholestrol. Inner core consists of hydrophobic TAG & phospholipids

12. Synthesis of lipoprotein Chylomicrons – intestinal mucosal cells VLDL – in liver from glycerol & fatty acid LDL – from VLDL , rich in cholestrol HDL - intestinal cells Free fatty acids – from lipolysis of triglycerides

13. Metabolism of lipoprotein Chylomicrons lipoprotein lipase Storage in adipose tissues Remnants taken by liver VLDL Activates lipoproteinlipase taken by adipose tissue & muscle Remanent is IDL , loses triglycerides, form LDL Lipoprotein cascade pathway

14. LDL LDL receptors- clathrin coated pits Receptor-LDL complex internalized by endocytosis Vesicle fuse with lysosomes Lysosomal enzyme degrade to form free cholesterol

15. HDL Intestinal cells – release nascent HDL (discoid) LACT catalyses esterification of free cholesterol & transfer to HDL HDL also recieves free cholesterol from peripheral tissues Apoprotein A promote LACT activity Enter liver & are degraded

16. Functions of lipoprotein Chylomicrons - transport of dietary triglycerides from intestine to adipose tissue for storage. VLDL – transport of endogenous triglycerides from liver to peripheral tissues for energy LDL - transport cholesterol from liver to peripheral tissues HDL – transport of cholestrol from peripheral tissue to liver (reverse cholesterol transport.)

17. Clinical significance Atherosclerosis: Deposition of LDL esp oxidised LDL in the subintimal regions of arteries is atherosclerosis . are taken by macrophages or scavengers – a starting event in atherosclerosis leading to myocardial infarction. LDL cholestrol is deposited in tissues hence called bad cholestrol .

18. The hallmark of atherosclerotic plaque are the foam cells (LDL degraded by macrophages get overloaded with cholesterol) Progression of atherosclerosis atherosclerotic plaque lead to narrowing of vessel wall when proliferative changes occur .fibrous proliferation is due to liberation of growth factors by macrophages & platelets

19. Blood flow through narrow lumen is turbulent, so clot is formed which occludes major vessels. Thrombosis leads to ischemia & finally infarction. Early stages it is reversible by lowering LDL level As lesion progresses arterial change become irreversible.

20. Risk factor for atherosclerosis : 1)serum cholesterol level Normal cholesterol level – below 180 mg/dl Value above 240mg/dl need active treatment 2)LDL cholesterol normal – under 130mg/dl above 160mg/dl - risk

21. 3)HDL level Is inversely related to myocardial infarction is antiatherogenic . above 65mg/dl protect heart disease Level below 40mg/dl – risk of CAD Total cholesterol : HDL cholesterol > 3.5 , dangerous LDL : HDL > 2.5 also dangerous 4) Apoprotein level apo B : apo A1 is more reliable 0.4 is good , 1.4 risk of CAD

22. 5)Lipoprotein lipase inhibit fibrinolysis > 30mg/dl increases risk 6)Smoking nicotine cause lipolysis & increase acetyl coA & cholesterol synthesis also cause constriction of arteries

23. 7)Hypertension systolic pressure > 160 – risk of CAD 8)Diabetic mellitus absence of insulin activates lipase , so production of acetyl coA & finally cholesterol synthesis. 9)Serum triglyceride normal level- 50-150 mg/dl

24. 10)Obesity & sedentary life Prevention of atherosclerosis 1)Reduction of dietary cholesterol egg yolk & meat high cholesterol 2)Vegetable oil & PUFA PUFA- esterification of cholesterol omega 3 fatty acid in fish oil decrease LDL

25. 3)Moderation in fat intake 20 – 25g of oil & 2-3 g of PUFA per day 4)Green leafy vegetable high fiber content- more bowel motility & reduced reabsorption of bile salts Sitosterol (plant sterol) decrease cholesterol absorption 5)Avoid sucrose & smoking

26. 6)Exercise moderate – lower LDL & raise HDL 7) Hypolipidemic drugs atarvostatin , lovastatin & simvostatin ( HMGCoA reductase inhibitors) Cholestyramine & colestipol (bile salt binding drug) – promote synthesis of bile salts & LDL uptake by liver Clofibrate - increase activity of lipoprotein lipase

27. 8)Antioxidants Decrease oxidation of LDL Vitamine E &C or beta carotene

28. hypercholesterolemia Increase in plasma cholesterol (> 200 mg/dl) Observed in : Diabetics mellitus Hypothyroidism ( myxedema ) Obstructive jaundice Nephrotic syndrome

29. hypocholestrolemia Seen in Hyperthyroidsm Pernicious anaemia Malabsorption syndrome Hemolytic jaundice

30. Disorders of plasma lipoprotein Inherited disorders of lipoproteins are primary hyper / hypolipoproteinemias Secondary lipoprotein disorders are due to some other diseases

31. Hyperlipoproteinemias Elevation in one or more lipoprotein Frederickson classification: Type I Lipoprotein lipase deficiency > chylomicrons Type IIa / hyperbetalipoproteinemia defect in LDL receptor LDL elevated

32. Type IIb LDL & VLDL elevated Due to overproduction of apo B Type III/broad beta disease > IDL Type IV > VLD Type V Chylomicrons & VLDL are elevated

33. Hypolipoproteinemias Familial hypobetalipoproteinemia Impaired synthesis of apoprotein B Abetalipoproteinemia Defect in synthesis of apo B Total absence of beta lipoprotein Less absorption of fat & fat soluble vitamins Familial alpha lipoprotein deficiency(tangier disease) HDL is absent

34. Other conditions Xanthomas -deposition of lipids in subcutaneous tissues Xanthelesma - lipids deposited in periorbital skin & contain cholesterol Corneal arcus – deposits of lipids in cornea xanthomatosis - deposition of lipids in liver , spleen, & flat bone in skull Fatty liver- Triglyceride synthesis & accumulation Impaired lipoprotein synthesis