John Owen - Dysfunctional HDL containing L159R ApoA-I leads to exacerbation of atherosclerosis in hyperlipidemic mice.

Document created by John Owen on Aug 22, 2014
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  Publication Details (including relevant citation   information):

  Biochim Biophys Acta, In Press (PMID 21944998)


  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).

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