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J. Biol. Chem., Vol. 279, Issue 53, 55483-55492, December 31, 2004

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Impaired Recycling of Apolipoprotein E4 Is Associated with Intracellular Cholesterol Accumulation^*

Joerg Heeren¶, Thomas Grewal||, Alexander Laatsch**, Nils Becker, Franz Rinninger, Kerry-Anne Rye, and Ulrike Beisiegel

From the Institute for Biochemistry and Molecular Biology II: Molecular Cell Biology and Department of Internal Medicine, University Hospital Eppendorf, D-20246 Hamburg, Germany, ^||Centre for Immunology, St. Vincent's Hospital, University of New South Wales, Darlinghurst, New South Wales 2010, Australia, and Heart Research Institute, Camperdown, Sydney, New South Wales 2050, Australia

After internalization of triglyceride-rich lipoproteins (TRL) in hepatoma cells, TRL particles are immediately disintegrated in the early endosomal compartment. This involves the targeting of lipids and apoprotein B along the degradative pathway and the recycling of TRL-derived apoE through recycling endosomes. Re-secretion of apoE is accompanied by the concomitant association of apoE and cellular cholesterol with high-density lipoproteins (HDL). Since epidemiological data showed that apoE3 and apoE4 have differential effects on HDL metabolism, we investigated whether the intracellular processing of TRL-derived apoE4 differs from apoE3-TRL. In this study, we demonstrated by radioactive and immunofluorescence uptake experiments that cell-surface binding and internalization of TRL-derived apoE4 are increased compared with apoE3 in hepatoma cells. Pulse-chase experiments revealed that HDL-induced recycling, but not disintegration and degradation, of apoE4-enriched TRL is strongly reduced in these cells. Furthermore, impaired HDL-induced apoE4 recycling is associated with reduced cholesterol efflux. Studies performed in Tangier fibroblasts showed that apoE recycling does not depend on ATP-binding cassette transporter A1 activity. These studies provide initial evidence that impaired recycling of apoE4 could interfere with intracellular cholesterol transport and contribute to the pathophysiological lipoprotein profile observed in apoE4 homozygotes.

Received for publication, August 13, 2004 , and in revised form, October 7, 2004.

^* This work was supported by the Deutsche Forschungsgemeinschaft Research Grants HE 3645/2-1, Be 829/5-1, Gr 258/10-2, Ri 436/8-1, the GRK 366 "Molecular Endocrinology and Metabolism," and the Gretl Raymond Foundation (to T. 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.

Both authors contributed equally to this work.

^** Supported by a fellowship from the Studienstiftung des Deutschen Volkes.

^¶ To whom correspondence should be addressed: IBM II: Molecular Cell Biology, University Hospital Eppendorf, Martinistrasse 52, D-20246 Hamburg, Germany. Tel.: 49-40-42803-3917; Fax: 49-40-42803-4592; E-mail: heeren{at}uke.uni-hamburg.de.

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