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J. Biol. Chem., Vol. 279, Issue 9, 7384-7394, February 27, 2004

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Molecular and Cellular Physiology of Apolipoprotein A-I Lipidation by the ATP-binding Cassette Transporter A1 (ABCA1)^*

Maxime Denis¶, Bassam Haidar, Michel Marcil, Michel Bouvier, Larbi Krimbou, and Jacques Genest, Jr.||

From the Cardiovascular Genetics Laboratory, Cardiology Division, McGill University Health Center, Royal Victoria Hospital, Montréal, Québec H3A 1A1, Canada and the Department of Biochemistry, Université de Montréal, Montreal, Quebec H3C 3J7, Canada

The dynamics of ABCA1-mediated apoA-I lipidation were investigated in intact human fibroblasts induced with 22(R)-hydroxycholesterol and 9-cis-retinoic acid (stimulated cells). Specific binding parameters of ¹²⁵I-apoA-I to ABCA1 at 37 °C were determined: K_d = 0.65 µg/ml, B_max = 0.10 ng/µg cell protein. Lipid-free apoA-I inhibited the binding of ¹²⁵I-apoA-I to ABCA1 more efficiently than pre-₁-LpA-I, reconstituted HDL particles r(LpA-I), or HDL₃ (IC₅₀ = 0.35 ± 1.14, apoA-I; 1.69 ± 1.07, pre-₁-LpA-I; 17.91 ± 1.39, r(LpA-I); and 48.15 ± 1.72 µg/ml, HDL₃). Treatment of intact cells with either phosphatidylcholine-specific phospholipase C or sphingomyelinase affected neither ¹²⁵I-apoA-I binding nor ¹²⁵I-apoA-I/ABCA1 cross-linking. We next investigated the dynamics of apoA-I lipidation by monitoring the kinetic of apoA-I dissociation from ABCA1. The dissociation of ¹²⁵I-apoA-I from normal cells at 37 °C was rapid (t = 1.4 ± 0.66 h; n = 3) but almost completely inhibited at either 15 or 4 °C. A time course analysis of apoA-I-containing particles released during the dissociation period showed nascent apoA-I-phospholipid complexes that exhibited -electrophoretic mobility with a particle size ranging from 9 to 20 nm (designated -LpA-I-like particles), whereas lipid-free apoA-I incubated with ABCA1 mutant (Q597R) cells was unable to form such particles. These results demonstrate that: 1) the physical interaction of apoA-I with ABCA1 does not depend on membrane phosphatidylcholine or sphingomyelin; 2) the association of apoA-I with lipids reduces its ability to interact with ABCA1; and 3) the lipid translocase activity of ABCA1 generates -LpA-I-like particles. This process plays in vivo a key role in HDL biogenesis.

Received for publication, June 30, 2003 , and in revised form, December 1, 2003.

^* This work was supported by Grants MOP 15042 from the Canadian Institutes of Health Research (CIHR) and the Heart and Stroke Foundation of Canada. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ Supported by a personnel award from the Heart and Stroke Foundation of Canada.

^|| Holds the McGill University-Novartis Chair in Cardiology. To whom correspondence should be addressed: Division of Cardiology, McGill University Health Center/Royal Victoria Hospital, 687 Pine Ave. West, Montreal, QC H3A 1A1, Canada. Tel.: 514-842-1231 (ext. 34642); Fax: 514-843-2813; E-mail: jacques.genest{at}muhc.mcgill.ca.

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