J. Lipid Res.
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Originally published In Press as doi:10.1194/jlr.M500531-JLR200 on January 17, 2006

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Journal of Lipid Research, Vol. 47, 832-843, April 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

Characterization of nascent HDL particles and microparticles formed by ABCA1-mediated efflux of cellular lipids to apoA-I

Phu T. Duong, Heidi L. Collins, Margaret Nickel, Sissel Lund-Katz, George H. Rothblat and Michael C. Phillips1

Division of GI/Nutrition, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-4318

Published, JLR Papers in Press, January 17, 2006.

1 To whom correspondence should be addressed. e-mail: phillipsmi{at}email.chop.edu

The nascent HDL created by ABCA1-mediated efflux of cellular phospholipid (PL) and free (unesterified) cholesterol (FC) to apolipoprotein A-I (apoA-I) has not been defined. To address this issue, we characterized the lipid particles released when J774 mouse macrophages and human skin fibroblasts in which ABCA1 is activated are incubated with human apoA-I. In both cases, three types of nascent HDL containing two, three, or four molecules of apoA-I per particle are formed. With J774 cells, the predominant species have hydrodynamic diameters of ~9 and 12 nm. These discoidal HDL particles have different FC contents and PL compositions, and the presence of acidic PL causes them to exhibit {alpha}-electrophoretic mobility. These results are consistent with ABCA1 located in more than one membrane microenvironment being responsible for the production of the heterogeneous HDL. Activation of ABCA1 also leads to the release of apoA-I-free plasma membrane vesicles (microparticles). These larger, spherical particles released from J774 cells have the same PL composition as the 12 nm HDL and contain CD14 and ganglioside, consistent with their origin being plasma membrane raft domains. The various HDL particles and microparticles are created concurrently, and there is no precursor-product relationship between them. Importantly, a large fraction of the cellular FC effluxed from these cells by ABCA1 is located in microparticles. Collectively, these results show that the products of the apoA-I/ABCA1 interaction include discoidal HDL particles containing different numbers of apoA-I molecules. The cellular PLs and cholesterol incorporated into these nascent HDL particles originate from different cell membrane domains.

Supplementary key words phospholipids • cholesterol • lipoprotein • reverse cholesterol transport • mouse macrophages • human skin fibroblasts • cell membranes • high density lipoprotein • ATP binding cassette transporter A1 • apolipoprotein A-I

Abbreviations: apoA-I, apolipoprotein A-I; BS3, bis(sulfosuccinimidyl) suberate; FC, free (unesterified) cholesterol; FPLC, fast-protein liquid chromatography; GM1, ganglioside; PC, phosphatidylcholine; PE, phosphatidylethanolanime; PL, phospholipid; PS, phosphatidylserine; SM, sphingomyelin


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