Dysfunctional HDL containing L159R ApoA-I leads to exacerbation of atherosclerosis in hyperlipidemic mice.
Biochim Biophys Acta
; 1821(3): 502-12, 2012 Mar.
Article
en En
| MEDLINE
| ID: mdl-21944998
ABSTRACT
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).
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Apolipoproteína A-I
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Mutación Missense
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Aterosclerosis
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Hiperlipidemias
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Lipoproteínas HDL
Límite:
Animals
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Female
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Humans
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Male
Idioma:
En
Revista:
Biochim Biophys Acta
Año:
2012
Tipo del documento:
Article
País de afiliación:
Estados Unidos