Tissue-specific roles of ABCA1 influence susceptibility to atherosclerosis.

TitleTissue-specific roles of ABCA1 influence susceptibility to atherosclerosis.
Publication TypeJournal Article
Year of Publication2009
AuthorsBrunham, LR, Singaraja, RR, Duong, MN, Timmins, JM, Fievet, C, Bissada, N, Kang, MH, Samra, A, Fruchart, J-C, McManus, B, Staels, B, Parks, JS, Hayden, MR
JournalArterioscler Thromb Vasc Biol
Volume29
Issue4
Pagination548-54
Date Published2009 Apr
ISSN1524-4636
KeywordsAnimals, Apolipoproteins E, Atherosclerosis, ATP Binding Cassette Transporter 1, ATP-Binding Cassette Transporters, Cholesterol, HDL, Cholesterol, LDL, Cholesterol, VLDL, Chromosomes, Artificial, Bacterial, Dietary Fats, Disease Models, Animal, Genetic Predisposition to Disease, Humans, Liver, Macrophages, Peritoneal, Mice, Mice, Knockout, Mice, Transgenic, Phenotype, Receptors, LDL
Abstract

OBJECTIVE: The ATP-binding cassette transporter, subfamily A, member 1 (ABCA1) plays a key role in HDL cholesterol metabolism. However, the role of ABCA1 in modulating susceptibility to atherosclerosis is controversial.METHODS AND RESULTS: We investigated the role of ABCA1 in atherosclerosis using a combination of overexpression and selective deletion models. First, we examined the effect of transgenic overexpression of a full-length human ABCA1-containing bacterial artificial chromosome (BAC) in the presence or absence of the endogenous mouse Abca1 gene. ABCA1 overexpression in the atherosclerosis-susceptible Ldlr(-/-) background significantly reduced the development of atherosclerosis in both the presence and absence of mouse Abca1. Next, we used mice with tissue-specific inactivation of Abca1 to dissect the discrete roles of Abca1 in different tissues on susceptibility to atherosclerosis. On the Apoe(-/-) background, mice lacking hepatic Abca1 had significantly reduced HDL cholesterol and accelerated atherosclerosis, indicating that the liver is an important site at which Abca1 plays an antiatherogenic role. In contrast, mice with macrophage-specific inactivation of Abca1 on the Ldlr(-/-) background displayed no change in atherosclerotic lesion area.CONCLUSIONS: These data indicate that physiological expression of Abca1 modulates the susceptibility to atherosclerosis and establish hepatic Abca1 expression as an important site of atheroprotection. In contrast, we show that selective deletion of macrophage Abca1 does not significantly modulate atherogenesis.

DOI10.1161/ATVBAHA.108.182303
Alternate JournalArterioscler. Thromb. Vasc. Biol.
PubMed ID19201688
Grant ListHL 49373 / HL / NHLBI NIH HHS / United States
P01 HL049373 / HL / NHLBI NIH HHS / United States
R01 HL094525 / HL / NHLBI NIH HHS / United States