Presentation on theme: "Lipoprotein Structure, Function, and Metabolism"— Presentation transcript:
1 Lipoprotein Structure, Function, and Metabolism Lipid TransportLipoprotein Structure, Function, and Metabolism
2 Clinical Case 8 y.o. girl Medical history Transplantation successful Admitted for heart/lung transplantationMedical historyXanthomas at 2 yoMI symptoms at 7 yoTC=1240mg/dlTG=350mg/dlDiet & statin & cholestyramineMother TC= 355, father TC=310Coronary artery bypass at 7 yo8 yo severe angina, second bypassTC = 1000mg/dlTransplantation successfulTC=260mg/dl, xanthomas regressing
4 Plasma Lipoproteins Classes & Functions ChylomicronsSynthesized in small intestineTransport dietary lipids98% lipid, large sized, lowest densityApo B-48Receptor bindingApo C-IILipoprotein lipase activatorApo ERemnant receptor binding
5 Chylomicron Metabolism figure 19-3 Nascent chylomicron (B-48)Mature chylomicron (+apo C & apo E)Lipoprotein lipaseChylomicron remnantApo C removedRemoved in liver
6 Plasma Lipoproteins Classes & Functions Very Low Density Lipoprotein (VLDL)Synthesized in liverTransport endogenous triglycerides90% lipid, 10% proteinApo B-100Receptor bindingApo C-IILPL activatorApo ERemnant receptor binding
7 Plasma Lipoproteins Classes & Functions Intermediate Density Lipoprotein (IDL)Synthesized from VLDL during VLDL degradationTriglyceride transport and precurser to LDLApo B-100Receptor bindingApo C-IILPL activatorApo E
8 Plasma Lipoproteins Classes & Functions Low Density Lipoprotein (LDL)Synthesized from IDLCholesterol transport78% lipid, 58% cholesterol & CEApo B-100Receptor binding
9 VLDL Metabolism figure 19-4 Nascent VLDL (B-100) + HDL (apo C & E) = VLDLLPL hydrolyzes TG forming IDLIDL loses apo C-II (reduces affinity for LPL)75% of IDL removed by liverApo E and Apo B mediated receptors25% of IDL converted to LDL by hepatic lipaseLoses apo E to HDL
10 Plasma Lipoproteins Classes & Functions High Density Lipoprotein (HDL)Synthesized in liver and intestineReservoir of apoproteinsReverse cholesterol transport52% protein, 48% lipid, 35% C & CEApo AActivates lecithin-cholesterol acyltransferase (LCAT)Apo CActivates LPLApo ERemnant receptor binding
11 LDL Metabolism LDL receptor-mediated endocytosis LDL receptors on ‘coated pits’Clathrin: a protein polymer that stabilizes pitEndocytosisLoss of clathrin coatinguncoupling of receptor, returns to surfaceFusing of endosome with lysosomeFrees cholesterol & amino acids
12 Coordinate Control of Cholesterol Uptake and Synthesis Increased uptake of LDL-cholesterol results in:inhibition of HMG-CoA reductasereduced cholesterol synthesisstimulation of acyl CoA:cholesterol acyl transferase (ACAT)increased cholesterol storageTG + C -> DG + CEdecreased synthesis of LDL-receptors“down-regulation”decreased LDL uptake
13 Heterogeneity of LDL-particles Not all LDL-particles the sameSmall 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;17:2057 men with hi LDL, 5 year follow-upThose with elevated small dense LDL had RR of 2.2 for IHD compared to men with elevated large buoyant LDLDetection expensiveTreatment 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 Peak Particle Diameter (nm) LDL Particle Size and Apolipoprotein B Predict Ischemic Heart Disease: Quebec Cardiovascular Study6.2(p<0.001)Apo B2.0>120 mg/dlLDL Particle Size and Apolipoprotein B Predict Ischemic Heart Disease: Quebec Cardiovascular StudyIn another analysis from the Quebec Cardiovascular Study, men were stratified by apo B level and LDL particle size. High apo B was associated with CHD, and the presence of both high apo B and small, dense LDL was associated with a marked increase in CHD risk. One interpretation of these findings is that concomitant interventions should be used both to lower apo B, such as with a statin, and to improve LDL particle size, such as with fibrates or high-dose statins. However, another interpretation is that if apo B is reduced to less than 120 mg/dL, LDL particle size no longer has an effect, perhaps because if there are few enough apo B-containing particles, it may not matter how atherogenic these particles are. This is a fairly controversial area, although a number of other epidemiological studies also suggest that this might be true. However, the effects of triglyceride level, for instance, which is strongly correlated to LDL particle size, appear to be considerably more important in people with high LDL/HDL ratio, apo B level, or total cholesterol level, as has been seen in the observational Paris Prospective Study and Prospective Cardiovascular Münster (PROCAM) Study and the interventional Helsinki Heart Study.Reference:Lamarche B, Tchernof A, Moorjani S, Cantin B, Dagenais GR, Lupien PJ, Despres JP. Small, dense low-density lipoprotein particles as a predictor of the risk of ischemic heart disease in men: prospective results from the Quebec Cardiovascular Study. Circulation 1997;95:69-75.1.01.0<120 mg/dl>25.64<25.64LDL Peak Particle Diameter (nm)Lamarche B et al. Circulation 1997;95:69-75.
15 HDL Metabolism: Functions Apoprotein exchangeprovides apo C and apo E to/from VLDL and chylomicronsReverse 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 LCATLCAT activated by apoA1Transfer of CE to lipoprotein remnants (IDL and CR) by CETPremoval of CE-rich remnants by liver, converted to bile acids and excreted
17 Resolution of Clinical Case Familial hypercholesterolemia (FH)Family historyEarly xanthomas and very high TCAbsence of LDL-receptorsHomozygous FHParent TC consistent with heterozygous FH1/500 Americans with heterozygous FH, treatable with diet/drugs1/106 with homozygous FHDiet and drugs relatively ineffectiveLiver has ~70% of LDL-receptorsCombined liver/heart recommended because of advance CHD
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