Dysfunctional HDL containing L159R ApoA-I leads to exacerbation of atherosclerosis in hyperlipidemic mice. Biochim Biophys Acta 2012 Mar;1821(3):502-12
Date
09/29/2011Pubmed ID
21944998Pubmed Central ID
PMC3690280DOI
10.1016/j.bbalip.2011.08.019Scopus ID
2-s2.0-84857635187 (requires institutional sign-in at Scopus site) 17 CitationsAbstract
The mutation L159R apoA-I or apoA-I(L159R) (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 12weeks. 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 α(3)-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-I(L159R) 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).
Author List
Sorci-Thomas MG, Zabalawi M, Bharadwaj MS, Wilhelm AJ, Owen JS, Asztalos BF, Bhat S, Thomas MJAuthors
Mary Sorci Thomas PhD Professor in the Medicine department at Medical College of WisconsinMichael J. Thomas PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsAorta
Apolipoprotein A-I
Apolipoproteins
Apolipoproteins E
Atherosclerosis
Cells, Cultured
Cholesterol
Diet, Atherogenic
Female
Gene Expression
Humans
Hyperlipidemias
Lipoproteins, HDL
Lipoproteins, LDL
Male
Mice
Mice, Inbred C57BL
Mice, Inbred DBA
Mice, Transgenic
Mutation, Missense
Triglycerides
