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D- Lipid Transport

D- Lipid Transport. Lipoprotein Structure, Function, and Metabolism. Clinical Case. 8 y.o. girl Admitted for heart/lung transplantation Medical history Xanthomas at 2 yo MI symptoms at 7 yo TC=1240mg/dl TG=350mg/dl Diet & statin & cholestyramine Mother TC= 355, father TC=310

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D- Lipid Transport

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  1. D-Lipid Transport Lipoprotein Structure, Function, and Metabolism

  2. Clinical Case • 8 y.o. girl • Admitted for heart/lung transplantation • Medical history • Xanthomas at 2 yo • MI symptoms at 7 yo • TC=1240mg/dl • TG=350mg/dl • Diet & statin & cholestyramine • Mother TC= 355, father TC=310 • Coronary artery bypass at 7 yo • 8 yo severe angina, second bypass • TC = 1000mg/dl • Transplantation successful • TC=260mg/dl, xanthomas regressing

  3. Plasma LipoproteinsStructurefigure 19-1 • LP core • Triglycerides • Cholesterol esters • LP surface • Phospholipids • Proteins • cholesterol

  4. Plasma LipoproteinsClasses & Functions • Chylomicrons • Synthesized in small intestine • Transport dietary lipids • 98% lipid, large sized, lowest density • Apo B-48 • Receptor binding • Apo C-II • Lipoprotein lipase activator • Apo E • Remnant receptor binding

  5. Chylomicron Metabolismfigure 19-3 • Nascent chylomicron (B-48) • Mature chylomicron (+apo C & apo E) • Lipoprotein lipase • Chylomicron remnant • Apo C removed • Removed in liver

  6. Plasma LipoproteinsClasses & Functions • Very Low Density Lipoprotein (VLDL) • Synthesized in liver • Transport endogenous triglycerides • 90% lipid, 10% protein • Apo B-100 • Receptor binding • Apo C-II • LPL activator • Apo E • Remnant receptor binding

  7. Plasma LipoproteinsClasses & Functions • Intermediate Density Lipoprotein (IDL) • Synthesized from VLDL during VLDL degradation • Triglyceride transport and precurser to LDL • Apo B-100 • Receptor binding • Apo C-II • LPL activator • Apo E • Receptor binding

  8. Plasma LipoproteinsClasses & Functions • Low Density Lipoprotein (LDL) • Synthesized from IDL • Cholesterol transport • 78% lipid, 58% cholesterol & CE • Apo B-100 • Receptor binding

  9. VLDL Metabolismfigure 19-4 • Nascent VLDL (B-100) + HDL (apo C & E) = VLDL • LPL hydrolyzes TG forming IDL • IDL loses apo C-II (reduces affinity for LPL) • 75% of IDL removed by liver • Apo E and Apo B mediated receptors • 25% of IDL converted to LDL by hepatic lipase • Loses apo E to HDL

  10. Plasma LipoproteinsClasses & Functions • High Density Lipoprotein (HDL) • Synthesized in liver and intestine • Reservoir of apoproteins • Reverse cholesterol transport • 52% protein, 48% lipid, 35% C & CE • Apo A • Activates lecithin-cholesterol acyltransferase (LCAT) • Apo C • Activates LPL • Apo E • Remnant receptor binding

  11. LDL Metabolism • LDL receptor-mediated endocytosis • LDL receptors on ‘coated pits’ • Clathrin: a protein polymer that stabilizes pit • Endocytosis • Loss of clathrin coating • uncoupling of receptor, returns to surface • Fusing of endosome with lysosome • Frees cholesterol & amino acids

  12. Coordinate Control of Cholesterol Uptake and Synthesis • Increased uptake of LDL-cholesterol results in: • inhibition of HMG-CoA reductase • reduced cholesterol synthesis • stimulation of acyl CoA:cholesterol acyl transferase (ACAT) • increased cholesterol storage • TG + C -> DG + CE • decreased synthesis of LDL-receptors • “down-regulation” • decreased LDL uptake

  13. Heterogeneity of LDL-particles • Not all LDL-particles the same • Small dense LDL (diameter <256A) • Large buoyant LDL (diameter >256 A) • Lamarche B, St-Pierre AC, Ruel IL, et al. A prospective, population-based study of low density lipoprotein particle size as a risk factor for  Can J Cardiol 2001;17:859-65. • 2057 men with hi LDL, 5 year follow-up • Those with elevated small dense LDL had RR of 2.2 for IHD compared to men with elevated large buoyant LDL • Detection expensive • Treatment for lowering small dense LDL similar to lowering all LDL (diet, exercise, drugs) • Some drugs (niacin, fibrates) may be more effective at lowering small dense LDL.

  14. LDL Particle Size andApolipoprotein B Predict Ischemic Heart Disease: Quebec Cardiovascular Study 6.2 (p<0.001) Apo B 2.0 >120 mg/dl 1.0 1.0 <120 mg/dl >25.64 <25.64 LDL Peak Particle Diameter (nm) Lamarche B et al. Circulation 1997;95:69-75.

  15. HDL Metabolism: Functions • Apoprotein exchange • provides apo C and apo E to/from VLDL and chylomicrons • Reverse cholesterol transport

  16. Reverse cholesterol transportfigure 19-6 • Uptake of cholesterol from peripheral tissues (binding by apo-A-I) • Esterification of HDL-C by LCAT • LCAT activated by apoA1 • Transfer of CE to lipoprotein remnants (IDL and CR) by CETP • removal of CE-rich remnants by liver, converted to bile acids and excreted

  17. Resolution of Clinical Case • Familial hypercholesterolemia (FH) • Family history • Early xanthomas and very high TC • Absence of LDL-receptors • Homozygous FH • Parent TC consistent with heterozygous FH • 1/500 Americans with heterozygous FH, treatable with diet/drugs • 1/106 with homozygous FH • Diet and drugs relatively ineffective • Liver has ~70% of LDL-receptors • Combined liver/heart recommended because of advance CHD

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