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J. Biol. Chem., Vol. 279, Issue 25, 25966-25977, June 18, 2004

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Apolipoprotein A-I-stimulated Apolipoprotein E Secretion from Human Macrophages Is Independent of Cholesterol Efflux^*

From the ^a Macrophage Biology Group, Centre for Vascular Research, University of New South Wales, Sydney 2052, Australia, ^b The Heart Research Institute, Sydney 2050, Australia, the ^c Baker Heart Research Institute, Melbourne 8008, Australia, the ^d Department of Clinical Biochemistry, Royal Prince Alfred Hospital, University of Sydney, Sydney 2050, Australia, the ^e Department of Core Clinical Pathology and Biochemistry, Royal Perth Hospital, School of Medicine & Pharmacology, University of Western Australia, Perth 6847, Australia, the ^f Institut für Arterioskleroseforschung an der Westfälischen Wilhelms-Universität Münster, Münster 48149, Germany, the ^g University of Alabama at Birmingham Medical Center, Birmingham, Alabama 35294, the ^hChildren's Hospital of Philadelphia, Stokes Research Institute, Philadelphia, Pennsylvania 19104-4318, the ⁱ University of Canberra, Australian Capital Territory 2601, Australia, and the ^j Department of Cardiology Concord Hospital, University of Sydney, Sydney 2139, Australia

Apolipoprotein A-I (apoA-I)-mediated cholesterol efflux involves the binding of apoA-I to the plasma membrane via its C terminus and requires cellular ATP-binding cassette transporter (ABCA1) activity. ApoA-I also stimulates secretion of apolipoprotein E (apoE) from macrophage foam cells, although the mechanism of this process is not understood. In this study, we demonstrate that apoA-I stimulates secretion of apoE independently of both ABCA1-mediated cholesterol efflux and of lipid binding by its C terminus. Pulse-chase experiments using ³⁵S-labeled cellular apoE demonstrate that macrophage apoE exists in both relatively mobile (E_m) and stable (E_s) pools, that apoA-I diverts apoE from degradation to secretion, and that only a small proportion of apoA-I-mobilized apoE is derived from the cell surface. The structural requirements for induction of apoE secretion and cholesterol efflux are clearly dissociated, as C-terminal deletions in recombinant apoA-I reduce cholesterol efflux but increase apoE secretion, and deletion of central helices 5 and 6 decreases apoE secretion without perturbing cholesterol efflux. Moreover, a range of 11- and 22-mer -helical peptides representing amphipathic -helical segments of apoA-I stimulate apoE secretion whereas only the C-terminal -helix (domains 220–241) stimulates cholesterol efflux. Other -helix-containing apolipoproteins (apoA-II, apoA-IV, apoE2, apoE3, apoE4) also stimulate apoE secretion, implying a positive feedback autocrine loop for apoE secretion, although apoE4 is less effective. Finally, apoA-I stimulates apoE secretion normally from macrophages of two unrelated subjects with genetically confirmed Tangier Disease (mutations C733R and c.5220–5222delTCT; and mutations A1046D and c.4629–4630insA), despite severely inhibited cholesterol efflux. We conclude that apoA-I stimulates secretion of apoE independently of cholesterol efflux, and that this represents a novel, ABCA-1-independent, positive feedback pathway for stimulation of potentially anti-atherogenic apoE secretion by -helix-containing molecules including apoA-I and apoE.

Received for publication, February 3, 2004 , and in revised form, March 29, 2004.

^* This work was supported by grants in aid (to W. J. and L. K.) and Fellowship (to W. J.) from the National Health and Medical Research Council of Australia, by National Institutes of Health Grants HL22633 and HL34343, the National Heart Foundation of Australia, and the Australian Research Council (to K. G.). 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.

^k To whom correspondence should be addressed: Macrophage Biology Group, Centre for Vascular Research, 4th Floor Wallace Wurth Bldg., University of New South Wales, UNSW, Sydney, NSW 2052, Australia. Tel.: 61-2-93851179; Fax: 61-2-93851389; E-mail: l.kritharides{at}unsw.edu.au.

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