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lipoprotein metabolism.ppt
- 1. Basics of Lipidand Lipoprotein Metabolism Faisal , M.D. Associate Professor
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- 3. HMG CoA Reductase (MoreThan Cholesterol Synthesis) Acetyl CoA HMG CoA Mevalonate Farnesyl Pyrophosphate Cholesterol HMG CoA Reductase Isopentenyl adenine (transfer RNA) Prenylation of signalling peptides (ras, rho, etc.) Ubiquinones (CoQ-10, etc.) Dolichols Inhibition of other key products of mevalonate may relate to nonlipid effects & rare side effects of statins.
- 4. NORMAL CHOLESTEROL METABOLISM Tissue pools 70G 0.8G SYN CHOL* *SYN CHOL = CHOLESTEROL SYNTHESIS 0.4 G CHOL
- 5. NORMAL CHOLESTEROL METABOLISM Tissue pools 70G .65G .20 G .20 G CHOL 0.65 G CHOL 0.85 G ABS CHOL 50% 0.4 G CHOL 0.8 G SYN CHOL* *SYN CHOL = CHOLESTEROL SYNTHESIS 1.3 G CHOL
- 6. Key concepts:synthesis – Primary synthetic sites are extrahepatic, but liver is key regulator of homeostasis Key concepts: absorption – Largest source is biliary secretion, not diet. – Normal absorption: 50% – For cholesterol to be absorbed it must: • undergo hydrolysis (de-esterification by esterases) • be incorporated into micelles • be taken up by cholesterol transporter • be re-esterified and incorporated into chylomicrons NORMAL CHOLESTEROL METABOLISM
- 7. 400 mg/day 1,300 mg/day NORMALCHOLESTEROL ABSORPTION Oil phase
- 8. 400 mg/day 1,300 mg/day 17,400mg/day NORMAL CHOLESTEROL ABSORPTION Plant sterols compete For cholesterol here Oil phase
- 9. STRUCTURE OF PLANTSTEROL ESTERS HO Cholesterol Sitosterol HO O C - O Sitosterol Ester
- 10. 400 mg/day 1,300 mg/day 17,400mg/day 850 mg/day NORMAL CHOLESTEROL ABSORPTION Ezetimibe competes For cholesterol here Oil phase
- 11. 400 mg/day 1,300 mg/day 17,400mg/day 850 mg/day NORMAL CHOLESTEROL ABSORPTION Defect in ABCG5/G8 transporter causes phytosterolemia Oil phase
- 12. Role ofBile Salts, cholesterol, phospholipids in gall stone formation. Importance of Bile Salts for cholesterol absorption NORMAL CHOLESTEROL METABOLISM Key concepts: bile salt absorption inhibitors – Bile acid binding compounds: • Welchol • Cholestyramine • Colestipol • Fiber – Surgery: Partial ileal bypass.
- 13. Bile Acid Synthesis HO Cholesterol OH OH OH COOH OHOH COOH OH COOH OH OH COOH Chenodeoxycholic Acid Lithocholic Acid Cholic Acid Deoxycholic Acid
- 14. NORMAL CHOLESTEROL METABOLISM Tissue pools 70G 0.8G SYN CHOL .65 G .20 G 0.85 G ABS CHOL 50% 0.4 G CHOL 1.3 G CHOL .20 G CHOL 0.65 G CHOL
- 15. 17 G BA* NORMAL CHOLESTEROLMETABOLISM Tissue pools 70G 0.8 G SYN CHOL 17.35 G BA* 0.85 G ABS CHOL 0.35 G BA* .35 G .65 G .20 G 1.20 G CHOL + BA 50% 95% 0.4 G CHOL 1.3 G CHOL * BA = BILE ACIDS .20 G CHOL 0.65 G CHOL
- 16. Key concepts:absorption – Triglyceride (i.e. energy) assimilation is key to the survival of the organism. – Dietary triglyceride must be hydrolyzed to fatty acids, mono-glycerides and glycerol prior to absorption. – Fatty acids must partition to micellar phase for absorption. – For transport, triglyceride must be reconstituted from glycerol and fatty acid and incorporated into chylomicrons. NORMAL TRIGLYCERIDE METABOLISM
- 17. Structures of FattyAcids C HO O C HO O C HO O C HO O C HO O 18:0 cis-18:1 -6 trans-18:1 -6 18:2 -6 18:3 -3
- 18. Structures of FattyAcids C HO O C HO O C HO O C HO O C HO O 16:0 (palmitic) cis-18:1 -6 (oleic) trans-18:1 -6 (elaidic 18:2 -6 (linoleic) 18:3 -3 (alpha linolenic) C HO O 20:5 -3 (EPA)
- 20. FATTY ACIDS (ALBUMIN) TG (VLDL) TG (CHYLO- MICRONS) LIPO- PROTEIN LIPASE FattyAcid and Triglyceride Flux
- 21. Plasma Triglyceride (VLDL) Dietary Carbohydrate Increases VLDLProduction Dietary Carbohydrate
- 22. Effect of CarbohydrateRestriction on Carbohydrate-induced Hypertriglyceridemia 0 500 1000 1500 2000 2500 3000 Initial Level End of Fast Inpatient Low CHO Diet Outpatient Low CHO Diet Reisell et al., Am J Clin Nutr 1966;19:84 Treatment: Fast for average 5 days, then consume low CHO diet. Composition of diet: 7-15% CHO 25-30% Prot 60-65% Fat
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- 24. Cholesterol Ester Synthesis HO Cholesterol COOH COO COO OPOO N + Cholesterol Ester COO COO COO OPOO N + Lysolecithin Lecithin-CholesterolAcyl Transferase (LCAT) Acyl-Cholesterol Acyl Transferase (ACAT)
- 29. Lipoproteins: Separation by – Electrophoresis Density Sizeby Electron Microscopy
- 32. Pancreatic Lipase Movement Mostpancreatic lipase is secreted into the pancreatic duct, but some moves back into capillaries.
- 33. Chylomicron Role inPancreatitis Pancreatic lipase acts on chylomicrons adherent to capillary endothelium, producing fatty acid anions, or soaps. By detergent action, cell membranes are disrupted, releasing more lipase, and additional fatty acid anions are produced in a vicious cycle.
- 38. Apolipoproteins B/E receptor ligand*E2:IDL; *E4: Diet Responsivity apoE LpL inhibitor; antagonizes apoE apoC-III LpL activator apoC-II Inhibit Lp binding to LDL R; LCAT activator apoC-I apoB-48 Structural protein of all LP except HDL Binding to LDL receptor apoB-100 Tg metabolism; LCAT activator; diet response apoA-IV HL activation apoA-II HDL structural protein; LCAT activator;RCT apoA-I
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- 41. Role of CETPin Triglyceride/ Cholesteryl Ester Exchange VLDL CETP HDL TG CE LDL CETP HDL TG CE
- 42. Role of Triglyceridesin Producing Small Dense LDL or HDL TG TG TG CE CE CE CETP Lipase 1. CE exchanged for TG 2. TG removed
- 43. FREE FATTY ACIDS Dyslipidemia of MetabolicSyndrome VLDL CETP TG CE HDL LDL CETP TG CE LIPASE sdLDL FATTY ACIDS GLYCEROL HDL CATABOLISM UNINHIBITED LYPOLYSIS
- 44. Distribution of LDLSize Phenotypes According to Triglyceride Levels 0 10 20 30 40 50 60 70 80 90 100 0 50 100 150 200 250 300 Phenotype A (light fluffy LDL) Phenotype B (small dense LDL) Cumulative percent of cases Triglyceride (mg/dl) Austin et al, Circulation 1990; 82:495
- 45. Peroxisome Proliferator-Activated Receptor: ANuclear Receptor for Metabolic Genes a, Basic mechanism of action of nuclear hormone receptors: bind to a specific sequence in the promoter of target genes (called hormone response elements), and activate transcription upon binding of ligand. Several nuclear hormone receptors, including the retinoic acid receptor, the vitamin D receptor and PPAR, can bind to DNA only as a heterodimer with the retinoid X receptor, RXR, as shown. b, some PPAR and PPAR ligands. Kersten et al. Roles of PPARs in health and disease. Nature 2000; 405: 421-424
- 46. Role of PPAR* and in VLDL, LDL and HDL metabolism * Peroxisome Proliferator Activated Receptor PPAR Tissues: Liver, kidney, heart, muscle. Ligands: fatty acids, fibrates Actions: Stimulate production of apo A I, lipoprotein lipase, increase expression of ABC A-1, increase FFA uptake and catabolism, decrease FFA and VLDL synthesis. PPAR Tissues: Adipose tissue and intestine. Ligands: arachidonic acid, Glitazones Actions: increase expression of ABC A-1, increase FFA synthesis and uptake by adipocytes, increase insulin sensitivity (?)
- 47. HDL and ReverseCholesterol Transport
- 48. HDL and ReverseCholesterol Transport Tangier Disease
- 49. HDL and ReverseCholesterol Transport
- 50. HDL and ReverseCholesterol Transport
- 51. HDL and ReverseCholesterol Transport
- 52. LDL-R HDL and ReverseCholesterol Transport
- 53. LDL-R 50% of HDLC may Return to the liver On LDL via CETP HDL and Reverse Cholesterol Transport
- 54. • An atherogeniclipoprotein containing apo(a) and apoB. • 20-30% of people have levels suggesting C-V risk. • Black subjects have Lp(a) normal range twice as high as white and Asiatic subjects. • Apo(a) sequence similar to plasminogen, and Lp(a) interferes with spontaneous thrombolysis. • Lp(a) levels highly genetic, resistant to diet and drug therapy, although niacin may help. “LDL” Apo(a) -S-S- Lipoprotein(a), or Lp(a)
- 57. Summary – Lipidand Lipoprotein Metabolism • Cholesterol absorption, synthesis, and disposition • Triglyceride/fatty acid transformations and energy metabolism • Lipoprotein core and surface components • Lipoprotein origins and destinations governed by apo’s • Derangement in the metabolic syndrome • Reverse cholesterol transport – the dominant direction • Lipoprotein(a) • Lipoproteins in the arterial wall