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D-Transport of Fat: Lipoproteins

D-Transport of Fat: Lipoproteins. Chylomicrons Triglyceride storage in adipose VLDL, LDL, IDL, HDL Reverse Cholesterol Transport Medical implications Nutritional regulation of lipoproteins. Stipanuk 351-364. Overview. Transport dietary lipids from intestine to liver (exogenous)

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D-Transport of Fat: Lipoproteins

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  1. D-Transport of Fat: Lipoproteins • Chylomicrons • Triglyceride storage in adipose • VLDL, LDL, IDL, HDL • Reverse Cholesterol Transport • Medical implications • Nutritional regulation of lipoproteins Stipanuk 351-364

  2. Overview • Transport dietary lipids from intestine to liver (exogenous) • Transport lipids from liver to peripheral tissues (endogenous) • Lipoproteins • Core of TG and CE • Surface of phospholipids and some cholesterol • Apolipoproteins (regulators of LP metabolism) • CM, VLDL, IDL, LDL, HDL • Clinical importance for disease

  3. Chylomicron Assembly • assembled in enterocyte golgi/ER • Apolipoprotein (Apo) B organizes assembly • B48 • Requires phospholipids • 2 forms of apo B • B100, large- liver • B48, smaller – intestine • Picks up apo A,C and E in plasma • - TG composition closely resembles dietary intake

  4. Microsomal Transfer Protein Lipid exchange protein Heterodimer (55 kDa/97 kDa) Protein disulphide isomerase Defects in MTP Gordon et al. Trends in Cell Biology 5:1995

  5. Abetalipoproteinemia • Rare genetic disease • No apo-B containing lipoproteins in plasma • Cholesterol is ~25% of normal • Mutation in MTP

  6. CIII A Apo B48 Apo B48 CII TG/CE Liver Dietary TG CE cholesterol FFA FFA-FABP TG micelle chylomicron ER/golgi enterocyte Plasma

  7. Type Association Function B48 Chylomicron Carry cholesterol esters Lacks LDL recpt binding domain B100 VLDL,IDL,LDL Binds LDL recpt. C-II Chyl. VLDL, IDL, HDL Activates LPL C-III Chyl. VLDL, IDL, HDL Inhibits LPL E Chyl. Remnant, VLDL, IDL Binds LDL recpt HDL A-1 HDL/Chylomicron LCAT activator (lecithin:cholesterol acyltransferase)

  8. CIII CIII CII CII E B48 B48 Lipoprotein Lipase Lipoprotein Lipase TG/CE TG/CE Plasma TG FFA Oxidation muscle chylomicron FFA FFA Chylomicron remnant liver G3P Triglyceride storage adipose

  9. CIII CII LPL B48 TG/CE Fat accumulation in adipose: High I/G (Fed) Capillary endothelium (+) insulin Glucose FFA chylomicron glut4 (+) Insulin regulated glucose transport CoA G3P Fatty acyl CoA Triglycerides adipose

  10. CIII CII LPL B48 TG/CE Fat accumulation in adipose: Low I/G (ketogenic) Capillary endothelium (-) insulin FFA-albumin (oxidation) Glucose FFA chylomicron (-) Insulin regulated glucose transport glut4 CoA G3P Fatty acyl CoA Triglycerides adipose

  11. LPL: “Metabolic Gatekeeper?” • LPL deficiency (chylomicronaemia) • Massive accumulation of chylomicron-TG in plasma • Cannot clear TG normally • Normal fat storage and body weight ???!?!? • How? • Knockout mice – lethal • LPL overexpression • Decrease plasma TG • Increase FA uptake in skeletal muscle • Protect against obesity when fed high-fat diet

  12. Hormones and Adipose Tissue • Adipose tissue is not just a big fat depot • Produces a number of hormones that regulate fat storage • 1. Leptin – decrease food intake/increase energy utilization • * Adequate fat store = release leptin = decrease food • intake and increase energy utilization • 2. Acylating stimulating protein (ASP) • chylomicrons stimulate production of ASP • similar anabolic effects as insulin (different mechanisms) • Promote adipocyte glucose uptake and • FA reesterification

  13. Ob mice

  14. Regulation of Lipoprotein Lipase Fed state - LPL synthesis and activity (adipocytes) LPL synthesis and activity (skeletal and heart muscle) Fasted/ - exercise state LPL synthesis and activity (adipocytes) LPL synthesis and activity (muscle) Lactating - Mammary gland LPL activity

  15. E B100 B48 CE/TG TG/CE Plasma Dietary Carbohydrate LIVER glucose pyruvate Acetyl CoA LDL receptor Acetyl CoA mitochondria TG Cholesterol (endogenous) CMr cholesterol (exogenous) VLDL FFA TG FFA VLDL

  16. Dietary factors affecting Chylomicron and Chylomicron remnant clearance • elevated postprandial lipoproteins and cardiovascular disease • Diets rich in PUFA can reduce postprandial TG response • compared to diets rich in SFA • Increased LPL activity = Increased TG clearance from CM • Preferential hydrolysis of PUFA-containing CM • Increased clearance of CMr • Human data are less convincing than animal studies • Omega 3 > Omega 6 > SFA • Not much work with MUFA although may be helpful (OLIVE OIL)

  17. Endogenous Lipid Transport

  18. B100 CE/TG Plasma Dietary Carbohydrate LIVER glucose pyruvate Acetyl CoA Acetyl CoA mitochondria cholesterol (exogenous) TG Cholesterol (endogenous) VLDL FFA TG FFA VLDL

  19. B100 B100 B100 E E E CE CII CE/TG LPL CE/TG Cholesterol. In bile From liver LIVER Endogenous cholesterol VLDL LDL receptor IDL FA LDL Extrahepatic tissue FFA muscle LDL receptor adipose

  20. Nobel Prize Alert: 1985 A Receptor-Mediated Pathway for Cholesterol Homeostasis Joseph Goldstein Michael S. Brown

  21. Function of LDL receptor • Endocytosis of LDL and other LP • Release free cholesterol into liver • Incorporate into plasma membrane • Inhibit new LDL receptors • Inhibit cholesterol synthesis • Promote ACAT activity (FC -> CE) • Regulated by SREBP monitors free cholesterol Free cholesterol = LDL receptors, chol. synthesis ACAT

  22. A A A Steroidogenic cells Pre-β-HDL Pre-β-HDL HDL Formation Cholesterol to other lipoproteins 2. Cholesterol for steroid synthesis Liver 3. Cholesterol-ester transfer protein (CETP) 1. Cholesterol to liver HDL ApoA Lecithin-cholesterol acyl transferase (LCAT) Cholesterol from Liver and intestinal Cells via ABCA1 Discoidal/lipid poor Unesterified cholesterol-rich

  23. LDL VLDL IDL CETP exchanges cholesterol esters in HDLs for triglycerides in B100 LPs CE CETP FFA LPL TG Liver (LDL receptor) TG HDL CETP CE LPL TG FFA CETP Liver (LDL receptor) CE

  24. A A Pre-β-HDL Reverse Cholesterol Transport: Indirect Extrahepatic tissues Liver Cholesterol esters Cholesterol is reused or excreted in bile hydrolysis Direct Free cholesterol ABCA1 LCAT CETP Cholesterol to VLDL, IDL,LDL HDL

  25. Reverse Cholesterol Transport : Direct SR-BI (scavenger receptor, class B, type 2)

  26. LCAT deficiency? • CETP deficiency? • apo AI deficiency?

  27. Postprandial Changes in Plasma Lipid Metabolism Fat storage via LPL Transfer of cholesterol from cells into plasma reverse transport of cholesterol from peripheral tissue to liver Exchange of cholesterol for VLDL TG in HDL (CETP) LCAT activity = esterification of free cholesterol (HDL) These postprandial changes are beneficial in maintaining whole body homeostatsis of glycerides and cholesterol

  28. VLDL Chylomicron Dietary Regulation of Lipoprotein Synthesis Chylomicron Synthesis VLDL Synthesis (Liver) (+) High CARB Insulin FA/TG (+) Acetyl CoA Dietary Fat Intestinal Epithelium (+) Glucose

  29. LDL Liver Dietary fat Bile salts Endogenous cholesterol extrahepatic tissue small intestine Exogenous cholesterol HDL chylomicrons reminants chylomicrons VLDL IDL capillaries Lipoprotein Lipase Lipoprotein Lipase FFA FFA Adipose, muscle

  30. Atherogenic Particles Apolipoprotein B MEASUREMENTS: Non-HDL-C VLDL VLDLR IDL LDL Small,denseLDL TG-rich lipoproteins Thanks to Lipids Online: http://www.lipidsonline.org/

  31. Hypertriglyceridemia and CHD Risk: Associated Abnormalities • Accumulation of chylomicron remnants • Accumulation of VLDL remnants • Generation of small, dense LDL • Association with low HDL • Increased coagulability • - á plasminogen activator inhibitor (PAI-1) • - á factor VIIc • - Activation of prothrombin to thrombin

  32. Relationship between HDL/LDL and heart disease: One Theory Monocyte (white blood cell) Cholesterol to liver LDL vascular endothelium (+) differentiate Oxidized LDL Arterial intima Macrophage LDL (+) (-) HDL Foam cells (fatty streak)

  33. Alcohol Increases HDL-C Level • Alcohol increases HDL-C level in a dose-dependent manner. • Half bottle of wine per day (39 g alcohol) for 6 weeks significantly increased mean HDL-C level by 7 mg/dL in 12 healthy subjects.1 • Wine intake did not significantly affect Total-C, Total-TG, or LDL-C.1 • One beer per day (13.5 g alcohol) for 6 weeks significantly increased mean HDL-C level by 2 mg/dL in 20 healthy subjects.2 • Beer intake did not significantly affect LDL-C, VLDL-C, TG, or apolipoproteins. 1. Thornton J et al. Lancet 1983;ii:819–822 2. McConnell MV et al. Am J Cardiol 1997;80:1226–1228

  34. Journal Papers and Revision Out of 10 points Revisions – 30 pts Clear, concise writing Extend discussion – Additional references- email author w/ ? and include in revised report Current and future research

  35. Next Week • Feb 23 – Dr. Neile Edens – Ross Labs • Feb 25 – Beta oxidation/Cholesterol • Feb 27 – Exam Review/Rough Draft revisions

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