Dysfunctional HDL containing L159R ApoA-I leads to exacerbation of atherosclerosis in hyperlipidemic mice |
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Authors: | Mary G Sorci-Thomas Manal Zabalawi Manish S Bharadwaj Ashley J WilhelmJohn S Owen Bela F AsztalosShaila Bhat Michael J Thomas |
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Institution: | a Department of Pathology, Section on Lipid Sciences, Wake Forest School of Medicine, Winston-Salem, USAb Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, USAc Lipid Metabolism Laboratory, Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA |
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Abstract: | The mutation L159R apoA-I or apoA-IL159R (FIN) is a single amino acid substitution within the sixth helical repeat of apoA-I. It is associated with a dominant negative phenotype, displaying hypoalphaproteinemia and an increased risk for atherosclerosis in humans. Mice lacking both mouse apoA-I and LDL receptor (LDL−/−, apoA-I−/−) (double knockout or DKO) were crossed > 9 generations with mice transgenic for human FIN to obtain L159R apoA-I, LDLr−/−, ApoA-I−/− (FIN-DKO) mice. A similar cross was also performed with human wild-type (WT) apoA-I (WT-DKO). In addition, FIN-DKO and WT-DKO were crossed to obtain WT/FIN-DKO mice. To determine the effects of the apoA-I mutations on atherosclerosis, groups of each genotype were fed either chow or an atherogenic diet for 12 weeks. Interestingly, the production of dysfunctional HDL-like particles occurred in DKO and FIN-DKO mice. These particles were distinct with respect to size, and their enrichment in apoE and cholesterol esters. Two-dimensional gel electrophoresis indicated that particles found in the plasma of FIN-DKO mice migrated as large α3-HDL. Atherosclerosis analysis showed that FIN-DKO mice developed the greatest extent of aortic cholesterol accumulation compared to all other genotypes, including DKO mice which lack any apoA-I. Taken together these data suggest that the presence of large apoE enriched HDL particles containing apoA-I L159R lack the normal cholesterol efflux promoting properties of HDL, rendering them dysfunctional and pro-atherogenic. In conclusion, large HDL-like particles containing apoE and apoA-IL159R contribute rather than protect against atherosclerosis, possibly through defective efflux properties and their potential for aggregation at their site of interaction in the aorta. This article is part of a Special Issue entitled Advances in High Density Lipoprotein Formation and Metabolism: A Tribute to John F. Oram (1945-2010). |
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Keywords: | apoA-I apolipoprotein A-I apoA-IWT unmutated apolipoprotein A-I ABCA1 ATP binding cassette transporter A1 CHD coronary heart disease ELISA enzyme-linked immunosorbent assay FPLC fast protein liquid chromatography apoA-IL159R FIN-mutation of apolipoprotein A-I apoA-IMilano or R173C apoA-I FX1 Fraction 1 FX2 Fraction 2 FX3 Fraction 3 HEK human embryonic kidney cells LCAT lecithin cholesterol acyltransferase LC-MS liquid chromatography-mass spectrometry LDLr low density lipoprotein receptor nHDL nascent HDL rHDL recombinant HDL RCT reverse cholesterol transport SIM selected ion monitoring SDS-PAGE sodium dodecyl sulfate-polyacrylamide gel electrophoresis DKO low density lipoprotein receptor and apoA-I double knockout mice FIN apoA-IL159R |
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