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Journal of Lipid Research, Vol. 49, 2390-2401, November 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Initial interaction of apoA-I with ABCA1 impacts in vivo metabolic fate of nascent HDL^*,

Anny Mulya^1,*, Ji-Young Lee^2,*, Abraham K. Gebre^*, Elena Y. Boudyguina^*, Soon-Kyu Chung^*, Thomas L. Smith, Perry L. Colvin, Xian-Cheng Jiang^** and John S. Parks^3,*

^* Department of Pathology, Wake Forest University Health Sciences, Winston-Salem, NC
Department of Orthopaedic Surgery, Wake Forest University Health Sciences, Winston-Salem, NC
Division of Gerontology, University of Maryland School of Medicine, and Department of Veterans Affairs and Veterans Affairs Medical Center Baltimore, Geriatric Research, Education and Clinical Center, Baltimore, MD
^** Department of Anatomy and Cell Biology, State University of New York, Downstate Medical Center, Brooklyn, NY
¹ Present address of A. Mulya: Department of Cell Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195.
² Present address of J-Y. Lee: Department of Nutrition and Health Sciences, University of Nebraska, Lincoln, NE 68583.

^* This work was supported by National Institutes of Health Grants HL-049373 (J.S.P.), HL-054176 (J.S.P.), and AT027820 (J.S.P.), and an American Heart Association Mid-Atlantic Affiliate Pre-doctoral Fellowship 0515420U (A.M.).

The online version of this article (available at http://www.jlr.org) contains supplementary data in the form of a figure.

Published, JLR Papers in Press, June 25, 2008.

³ To whom correspondence should be addressed. e-mail: jparks{at}wfubmc.edu

We investigated the in vivo metabolic fate of pre-β HDL particles in human apolipoprotein A-I transgenic (hA-I ^Tg) mice. Pre-β HDL tracers were assembled by incubation of [¹²⁵I]tyramine cellobiose-labeled apolipoprotein A-I (apoA-I) with HEK293 cells expressing ABCA1. Radiolabeled pre-β HDLs of increasing size (pre-β1, -2, -3, and -4 HDLs) were isolated by fast-protein liquid chromatography and injected into hA-I ^Tg-recipient mice, after which plasma decay, in vivo remodeling, and tissue uptake were monitored. Pre-β2, -3, and -4 had similar plasma die-away rates, whereas pre-β1 HDL was removed 7-fold more rapidly. Radiolabel recovered in liver and kidney 24 h after tracer injection suggested increased (P < 0.001) liver and decreased kidney catabolism as pre-β HDL size increased. In plasma, pre-β1 and -2 were rapidly (<5 min) remodeled into larger HDLs, whereas pre-β3 and -4 were remodeled into smaller HDLs. Pre-β HDLs were similarly remodeled in vitro with control or LCAT-immunodepleted plasma, but not when incubated with phospholipid transfer protein knockout plasma. Our results suggest that initial interaction of apoA-I with ABCA1 imparts a unique conformation that partially determines the in vivo metabolic fate of apoA-I, resulting in increased liver and decreased kidney catabolism as pre-β HDL particle size increases.

Supplementary key words Apolipoprotein A-I • phospholipid transfer protein • lecithin:cholesterol acyltransferase • in vivo catabolism • high density lipoproteins • ABCA1 transporter

Abbreviations: ABCA1, ATP binding cassette transporter A1; apoA-I, apolipoprotein A-I; hA-I ^Tg, human apolipoprotein A-I transgenic; CE, cholesteryl ester; FCR, fractional catabolic rate; FPLC, fast-protein liquid chromatography; MPM, mouse peritoneal macrophage; NDGGE, nondenaturing gradient gel electrophoresis; PL, phospholipid; PLTP, phospholipid transfer protein; RCT, reverse cholesterol transport; SR-BI, scavenger receptor class B type I; TC, tyramine cellobiose; TG, triglyceride

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