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Lipid Transport Lipoprotein Structure, Function, and Metabolism.

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Presentation on theme: "Lipid Transport Lipoprotein Structure, Function, and Metabolism."— 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 Lipoproteins Structure figure 19-1 LP core Triglycerides Cholesterol esters LP surface Phospholipids Proteins cholesterol

4 Plasma Lipoproteins Classes & 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 Metabolism figure 19-3 Nascent chylomicron (B-48) Mature chylomicron (+apo C & apo E) Lipoprotein lipase Chylomicron remnant Apo C removed Removed in liver

6 Plasma Lipoproteins Classes & 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 Lipoproteins Classes & 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 Lipoproteins Classes & Functions Low Density Lipoprotein (LDL) Synthesized from IDL Cholesterol transport 78% lipid, 58% cholesterol & CE Apo B-100 Receptor binding

9 VLDL Metabolism figure 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 Lipoproteins Classes & 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: 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 and Apolipoprotein B Predict Ischemic Heart Disease: Quebec Cardiovascular Study Lamarche B et al. Circulation 1997;95: >25.64 <25.64 LDL Peak Particle Diameter (nm) (p<0.001) Apo B >120 mg/dl 2.0 <120 mg/dl

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

16 Reverse cholesterol transport figure 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 1/10 6 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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19 Exam 2 Monday, 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


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