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J. Biol. Chem., Vol. 280, Issue 26, 24515-24523, July 1, 2005

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Glycosphingolipid Accumulation Inhibits Cholesterol Efflux via the ABCA1/Apolipoprotein A-I Pathway

1-PHENYL-2-DECANOYLAMINO-3-MORPHOLINO-1-PROPANOL IS A NOVEL CHOLESTEROL EFFLUX ACCELERATOR^*

Elias N. Glaros, Woojin Scott Kim, Carmel M. Quinn, Jenny Wong, Ingrid Gelissen, Wendy Jessup, and Brett Garner

From the Centre for Vascular Research, University of New South Wales, Sydney, New South Wales 2052, Australia

Cellular glycosphingolipid (GSL) storage is known to promote cholesterol accumulation. Although physical interactions between GSLs and cholesterol are thought to cause intracellular cholesterol "trapping," it is not known whether cholesterol homeostatic mechanisms are also impaired under these conditions. ApoA-I-mediated cholesterol efflux via ABCA1 (ATP-binding cassette transporter A1) is a key regulator of cellular cholesterol balance. Here, we show that apoA-I-mediated cholesterol efflux was inhibited (by up to 53% over 8 h) when fibroblasts were treated with lactosylceramide or the glucocerebrosidase inhibitor conduritol B epoxide. Furthermore, apoA-I-mediated cholesterol efflux from fibroblasts derived from patients with genetic GSL storage diseases (Fabry disease, Sandhoff disease, and GM1 gangliosidosis) was impaired compared with control cells. Conversely, apoA-I-mediated cholesterol efflux from fibroblasts and cholesterol-loaded macrophage foam cells was dose-dependently stimulated (by up to 6-fold over 8 h) by the GSL synthesis inhibitor 1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP). Unexpectedly, a structurally unrelated GSL synthesis inhibitor, N-butyldeoxynojirimycin, was unable to stimulate apoA-I-mediated cholesterol efflux despite achieving similar GSL depletion. PDMP was found to up-regulate ABCA1 mRNA and protein expression, thereby identifying a contributing mechanism for the observed acceleration of cholesterol efflux to apoA-I. This study reveals a novel defect in cellular cholesterol homeostasis induced by GSL storage and identifies PDMP as a new agent for enhancing cholesterol efflux via the ABCA1/apoA-I pathway.

Received for publication, December 9, 2004 , and in revised form, April 15, 2005.

^* This work was supported by National Heart Foundation of Australia Grant G02S0799 (to B. G. and W. J.) and by Australian National Health and Medical Research Council Grants 189990 and 350810 (to B. G.) and Grant 222722 (to W. J.). 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.

To whom correspondence should be addressed: Centre for Vascular Research, School of Medical Sciences, University of New South Wales, High St., Sydney, NSW 2052, Australia. Tel.: 61-2-9385-8730; Fax: 61-2-9385-1389; E-mail: brett.garner{at}unsw.edu.au.

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