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Basics of Lipid and Lipoprotein Metabolism

John R. Guyton, M.D. Associate Professor of Medicine Duke University Durham, NC. Basics of Lipid and Lipoprotein Metabolism. Lipid Structure. Cholesterol. HO. Fatty Acids. Triglycerides. COOH. COO. COOH. COO. COOH. COO. HO. Phospholipid: Lecithin. +. Glycerol. COO. HO. COO.

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Basics of Lipid and Lipoprotein Metabolism

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  1. John R. Guyton, M.D. Associate Professor of Medicine Duke University Durham, NC Basics of Lipid andLipoprotein Metabolism

  2. Lipid Structure Cholesterol HO Fatty Acids Triglycerides COOH COO COOH COO COOH COO HO Phospholipid: Lecithin + Glycerol COO HO COO HO + OPOO N

  3. HMG CoA Reductase (More Than 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 0.8 G SYN CHOL* 0.4 G CHOL *SYN CHOL = CHOLESTEROL SYNTHESIS

  5. NORMAL CHOLESTEROL METABOLISM Tissue pools 70G 0.85 G ABS CHOL 0.8 G SYN CHOL* 1.3 G CHOL .20 G CHOL 0.65 G CHOL 50% .20 G 0.4 G CHOL .65 G *SYN CHOL = CHOLESTEROL SYNTHESIS

  6. NORMAL CHOLESTEROL METABOLISM • 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

  7. NORMAL CHOLESTEROL ABSORPTION 1,300 mg/day 400 mg/day Oil phase

  8. NORMAL CHOLESTEROL ABSORPTION 1,300 mg/day 400 mg/day 17,400 mg/day Oil phase Plant sterols compete For cholesterol here

  9. STRUCTURE OF PLANT STEROL ESTERS Cholesterol Sitosterol HO HO O C - O Sitosterol Ester

  10. NORMAL CHOLESTEROL ABSORPTION 1,300 mg/day 400 mg/day 17,400 mg/day Oil phase 850 mg/day Ezetimibe competes For cholesterol here

  11. NORMAL CHOLESTEROL ABSORPTION 1,300 mg/day 400 mg/day 17,400 mg/day Oil phase 850 mg/day Defect in ABCG5/G8 transporter causes phytosterolemia

  12. NORMAL CHOLESTEROL METABOLISM • Role of Bile Salts, cholesterol, phospholipids in gall stone formation. • Importance of Bile Salts for cholesterol absorption • Key concepts: bile salt absorption inhibitors • Bile acid binding compounds: • Welchol • Cholestyramine • Colestipol • Fiber • Surgery: Partial ileal bypass.

  13. Cholesterol Bile Acid Synthesis HO OH COOH COOH OH OH OH OH Chenodeoxycholic Acid Cholic Acid OH COOH COOH Deoxycholic Acid Lithocholic Acid OH OH

  14. NORMAL CHOLESTEROL METABOLISM Tissue pools 70G 0.85 G ABS CHOL 0.8 G SYN CHOL 1.3 G CHOL .20 G CHOL 0.65 G CHOL 50% .20 G 0.4 G CHOL .65 G

  15. NORMAL CHOLESTEROL METABOLISM Tissue pools 70G 0.85 G ABS CHOL 0.8 G SYN CHOL 0.35 G BA* 1.3 G CHOL 17.35 G BA* 17 G BA* .20 G CHOL 0.65 G CHOL 50% 95% .20 G 0.4 G CHOL .65 G .35 G 1.20 G CHOL + BA * BA = BILE ACIDS

  16. NORMAL TRIGLYCERIDE METABOLISM • 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.

  17. Structures of Fatty Acids O 18:0 C HO O C cis-18:1 -6 HO O trans-18:1 -6 C HO O C 18:2 -6 HO O 18:3 -3 C HO

  18. Structures of Fatty Acids O 16:0 (palmitic) C HO O C cis-18:1 -6 (oleic) HO O trans-18:1 -6 (elaidic) C HO O C 18:2 -6 (linoleic) HO (alpha linolenic) O 18:3 -3 C HO O 20:5 -3 (EPA) C HO

  19. Fatty Acid and Triglyceride Flux FATTY ACIDS (ALBUMIN) TG (VLDL) LIPO- PROTEIN LIPASE TG (CHYLO- MICRONS)

  20. Dietary Carbohydrate Increases VLDL Production PlasmaTriglyceride (VLDL) DietaryCarbohydrate

  21. Effect of Carbohydrate Restriction on Carbohydrate-induced Hypertriglyceridemia Treatment: Fast for average 5 days, then consume low CHO diet. Compositionof diet: 7-15% CHO25-30% Prot60-65% Fat Reisell et al., Am J Clin Nutr 1966;19:84

  22. Lipoprotein Metabolism

  23. Cholesterol Ester Synthesis Acyl-Cholesterol Acyl Transferase (ACAT) Cholesterol Cholesterol Ester HO COOH COO Lecithin-Cholesterol Acyl Transferase (LCAT) Lysolecithin COO COO COO COO + + OPOO OPOO N N

  24. Lipoproteins: Separation by – Electrophoresis Density Size by Electron Microscopy

  25. Pancreatic Lipase Movement Most pancreatic lipase is secreted into the pancreatic duct, but some moves back into capillaries.

  26. Chylomicron Role in Pancreatitis 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.

  27. apoA-I HDL structural protein; LCAT activator;RCT apoA-II HL activation apoA-IV Tg metabolism; LCAT activator; diet response apoB-100 Structural protein of all LP except HDL Binding to LDL receptor apoB-48 apoC-I Inhibit Lp binding to LDL R; LCAT activator apoC-II LpL activator apoC-III LpL inhibitor; antagonizes apoE apoE B/E receptor ligand *E2:IDL; *E4: Diet Responsivity Apolipoproteins

  28. Metabolic RelationshipsAmong Lipoproteins 1. VLDL LDL 3. 2. TG HDL LipoproteinLipase`

  29.  TRIGLYCERIDES SMALL DENSE LDL  HDL

  30. Role of CETP in Triglyceride/Cholesteryl Ester Exchange VLDL LDL TG TG HDL HDL CETP CETP CE CE

  31. Role of Triglycerides in Producing Small Dense LDL or HDL CETP Lipase CE CE CE TG TG TG 1. CE exchanged for TG 2. TG removed

  32. sdLDL LIPASE TG TG CETP CETP CE CE Dyslipidemia of Metabolic Syndrome UNINHIBITEDLYPOLYSIS FREE FATTY ACIDS VLDL HDL LDL FATTY ACIDSGLYCEROL HDL CATABOLISM

  33. Distribution of LDL Size Phenotypes According to Triglyceride Levels Cumulative percent of cases Phenotype A (light fluffy LDL) Phenotype B (small dense LDL) Austin et al, Circulation 1990; 82:495 Triglyceride (mg/dl)

  34. Peroxisome Proliferator-Activated Receptor: A Nuclear 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

  35. Role of PPAR* and  in VLDL, LDLand HDL metabolism 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 (?) * Peroxisome Proliferator Activated Receptor

  36. HDL and Reverse Cholesterol Transport

  37. HDL and Reverse Cholesterol Transport Tangier Disease

  38. HDL and Reverse Cholesterol Transport

  39. HDL and Reverse Cholesterol Transport

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