1 / 19

Lipid Transport

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

lotus
Download Presentation

Lipid Transport

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. 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

  18. Exam 2Monday, July 18 • Lipid Transport • Chapter 19 • MAAG chapter 54 • Type 2 Diabetes and Insulin Resistance in Adipose • Effect on LPL causing hyperlipidemia • Signaling fault resulting in inappropriate lipolysis • Cholesterol Metabolism • Chapter 21 • MAAG chapter 32 • Format • Multiple choice questions • Short essay questions

More Related