Metabolism of lipids I V .

1. Metabolism of lipids IV.

2. Lipid transport process serves four main purposes Dietary fat Triglicerides Intestine Liver Triglycerides Fatty acids Cholesterol Triglicerides Adipose tissue Fatty acids Cholesterol Heart, muscle, kidneys, etc

3. Transport of lipids Problem: hydrophobic lipids in an aqueous environment More insoluble lipids (triacylglycerols & cholesterol esters) associated with more polar ones (phospholipids, cholesterol) and protein è HYDROPHILIC LIPOPROTEIN COMPLEX

4. Transport of lipids • FFA – free fatty acids • Unesterified long-chain fatty acids • (less than 5 % of the total)

5. Lipids of the blood plasma

6. Lipids of the blood plasma • Importance: • 50 % of the adult population lipid transport abnormalities • Risk factors

7. Metabolism of plasma FFA ADIPOCYTES Triglicerides HORMONE SENSITIVE LIPASE FFA FFA / ALBUMIN EXTRAHEPATIC TISSUES LIVER OXYDATION ENERGY SYNTHESIS OF TISSUE LIPIDS SYNTHESIS OF TISSUE LIPIDS KETONE BODIES

8. FFA – FREE FATTY ACIDS Source Lipolysis of TG in adipose tissue Lipoprotein lipase during uptake of TG from plasmainto tissues In albumin binding 0.1 - 2 meq/mL 6-16 mg/100 ml

9. FFA – FREE FATTY ACIDS Level Low – in fully fed condition High – in fully fasting state, vigorous exercise in uncontrolled diabetes Between meal Falls, after eating Rises, prior to the next meal

10. FFA – FREE FATTY ACIDS Removal rapid In fasting 20-25 % of the energy is supplied by FFA • can be utilized for the synthesis of lipids in tissues • FFA taken up by the liver – substrate for ketone body production • not in the brain!

11. Lipoproteins

12. APOPROTEINS

15. Patterns with Lipoprotein electrophoresis have been changing by using Bezafibrate SR tablets.

16. Chylomicron & VLDL Ch. Clearance from the blood is rapid Half time > 1 hour Adipose tissue Heart Muscle On the walls of capillaries LIPOPROTEIN LIPASE Bound to heparan sulfate

17. Heparin • Releases LIPORPOTEIN LIPASE into the circulation • CLEARING OF LIPEMIA

18. TAKEN UP BY TISSUES FFA back to the circulation

19. Chylomicron & VLDL • PL& apo C-II are cofactors • Chylomicrons & VLDL provide both • its substrate (TG) and • cofactors CPL, apo C-II) • Lipoprotein lipase • in heart • Km for TG low • In adipose tissue • Km is 10 times greater • In starvation TG â • Heart enzyme remains saturated • During lactation / mammary gland

20. Lipoprotein lipase action • Loss of 90 % of TG and apo C • Remnant • Half diameter • Relatively enriched in cholesterol • Remnants are taken up by the liver • Receptor: specific for apo E

21. From the liver Apo B100 - precursor of LDL too In tissues Lipoprotein lipase â IDL relatively rich in cholesterol Disappears from the blood within 2-6 hours In liver - it binds to LDL receptors -affinity for apo E is higher than for B100 - endocytosis by the liver Rest in the circulationèapo E Converted to LDL VLDL

22. Nascent HDL – secreted by the liver (by the intestine) â PL bilayer + apo C, apo A Lecithin-cholesterol acyl-transferase (LCAT) Cholesterol esters are formed Move into the hydrophobic interior of PL bilayer pushes bilayer apart until spherical, pseudomicellar HDL is formed Esterified cholesterols transferred from HDL to chylomicron, VLDL, IDL by cholesterol ester tranfer protein TRANSPORT OF CHOLESTEROL FROM TISSUES TO THE LIVER HDL

24. Transport of triglycerides from the intestine to the extrahepatic tissues and the liver. Chylomicrons Adipose, Muscle, Heart

25. Transport of triglycerides from the liver to the extrahepatic tissues. VLDL TG, from diet synthesized Cholesterol, from membranedegradation `Transport of cholesterol HDL, LDL

26. LDL • Generally in lipoproteins: • In the central core • Nonploar lipids • Triglicerides • choelsteryl ester • Surrounded by • phospholipids • unesterified cholesterol apoproteins LDL receptor: recognize B-100 apoprotein (or apo E)

27. LDL • Phospholipids, unesterified cholesterol apoproteins • Amphipatic Nonpolar groups Interact with lipids in the central core Polar groups On the surface Interact with water and ions of the plasma

28. Extrahepatic tissues VLDL Cholesterol Nascent HDL Cholesterol esters TG LCAT PL ApoA ApoC Lipids Lipids HDL2 HDL3 Apoproteins Apoproteins E, C TG / Che á Uptake by the liver VLDL Ch

30. LDL receptor Recognizes Apo B-100 Apo E Mediates the clearance of LDL from the plasma (also of IDL, + recognition factor is ApoE) (VLDL is not binding to B-100 or E receptor, as apo C-III inhibits binding) On binding to the receptor endocytic vesicles are formed

31. LDL receptor The expression of the LDL receptor is regulated by the need fo the cell for cholesterol Down-regulated – when sufficient cholesterol is available Up-regulated – when the cell requires additional cholesterol

33. LDL receptor • LDL receptors • Liver • Ovary • Adrenal cortex • Cholesterol metabolism is controlled by cholesterol released from LDL

34. Regulation of cholesterol levels in humans • Plasma cholesterol – in lipoproteins • Normal cholesterol concentration is • between 3.1 – 5.7 mmol/L (120-220 mg/100 ml) • 65 % is esterified • After an overnight fasting noCHYLOMICRONS • 70 % of cholesterol in LDL

35. Regulation of cholesterol levels in humans Cholesterol free diet è 10 % to 25 % decrease in plasma cholesterol concentration Larger decrease only through inhibition of cholesterol biosynthesis. Dietary cholesterol restriction is recommended for everyone especially for patients with hypercholesterolemia > 5.2 mmol/L greater tendency to atherosclerosis Saturated fatty acids è plasma cholesterol concentration is increased

36. Regulation of cholesterol levels in humans • Reduces the plasma cholesterol concentration by 30 % - 50 % • Minimum toxicity

37. Lovastatin, compactin, pravastatin, lovastatin

38. The main route of cholesterol metabolism is conversion to bile acids • 0.8 mmol/day of bile acids are lost • (constant level is the body: 15-30 g) • Bile acid – binding resin • Decreases bile acid reabsorption • increases the loss of cholesterol

39. Dietary restriction of cholesterol • Bile acid – binding resin • Cholesterol synthesis – inhibitor • Cholesterol for bile acid synthesis is provided by LDLè Plasma cholesterol concentration is decreased

40. Familial hypercholesterolemia • The absence or deficiency of functional receptors for LDL • Normal LDL level: 175 mg/dl • High concentration of LDL-cholesterol in the plasma • Mutation at a single autosomal locus

41. Familial hypercholesterolemia • Heterozygotes • One gene • ~ 300 mg/dl LDL in the plasma • Atherosclerosis before the age of 37

42. Familial hypercholesterolemia • Homozygotes • One mutant gene from both parents • ~ 700 mg/dl LDL in the plasma • Coronary artery disease in childhood

43. Familial hypercholesterolemia • Homozygotes • Lack of LDL receptors • Heterozygotes • Half of the normal number • Entry of LDL into liver & other cells is impaired â Increased plasma LDL level Entry of IDL is also impared è more LDL is formed In Homozygotes:Liver transplantation

44. Familial hypercholesterolemia • Therapy for heterozygotes • To stimulate the single normal gene to produce more LDL receptors • When cholesterol is required in cells the amount of mRNA for LDL receptor rises & more receptor is synthesized

45. High HDL level • protection against coronary heart disease • Cholesterol • in form of HDL – “good” cholesterol • In form of LDL - harmful

46. Liver cells LDL uptake Synthesis HMG-CoA Cholesterol Bile acids

47. Liver cells LDL uptake Synthesis HMG-CoA Cholesterol The polymer binds bile salts in the intestine Bile acids

48. Liver cells LDL uptake Synthesis HMG-CoA Cholesterol Inhibitors of cholesterol synthesis Bile acids