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

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

  1. Leonard Kritharidesabjk
  1. 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
  1. 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.

Abstract

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 (Em) and stable (Es) 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 α-helical peptides representing amphipathic α-helical segments of apoA-I stimulate apoE secretion whereas only the C-terminal α-helix (domains 220–241) stimulates cholesterol efflux. Other α-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 α-helix-containing molecules including apoA-I and apoE.

  • Received February 3, 2004.
  • Revision received March 29, 2004.
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