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J. Biol. Chem., Vol. 281, Issue 52, 39971-39981, December 29, 2006

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Cathepsin D, a Lysosomal Protease, Regulates ABCA1-mediated Lipid Efflux^*

Bassam Haidar¹, Robert S. Kiss, Lea Sarov-Blat, Roch Brunet, Christopher Harder, Ruth McPherson, and Yves L. Marcel²

From the Lipoprotein and Atherosclerosis Research Group, University of Ottawa Heart Institute, and Departments of Biochemistry, Microbiology, and Immunology, and Pathology and Laboratory Medicine, and Medicine (Cardiology), University of Ottawa, Ottawa, Ontario, K1Y 4W7, Canada and GlaxoSmithKline, King of Prussia, Pennsylvania 19406

To identify genes involved in the regulation of plasma high density lipoprotein (HDL) cholesterol (HDL-C) levels, patients with low HDL-C and age- and sex-matched controls (normal HDL-C) were extensively characterized. Comparative transcriptome analysis was carried out in cholesterol-loaded monocyte-derived macrophages from low HDL subjects segregated into groups with or without cholesterol efflux defects or ABCA1 mutations. Clusters of differentially regulated genes were evident in the low HDL groups as compared with controls. Of particular note, expression of cathepsin D (CTSD), a lysosomal proteinase, was reduced by 50% in monocyte-derived macrophages of low HDL-C subjects, most significantly those with cholesterol efflux defects but without mutations in ABCA1 (p < 0.01). These results were verified by reverse transcription-PCR and replicated in a second cohort. We show here that blocking the activity or expression of CTSD, by pepstatin or CTSD small interfering RNA, respectively, reduced ABCA1 expression and protein abundance in both macrophages and CHO cells and apolipoprotein A-I-mediated lipid efflux by more than 70%. Conversely, expression of CTSD increased both ABCA1 mRNA expression and cellular ABCA1 protein. Consistent with its role in the proteolytic processing of prosaposin, inactivation of CTSD function resulted in the accumulation of glycosphingo-lipid and free cholesterol in late endosomes/lysosomes, a phenotype similar to NPC1 deficiency. Inhibition of CTSD also caused retention of ABCA1 in lysosomal compartments, reducing its trafficking to the plasma membrane. These studies demonstrate a novel and potentially important role for CTSD in intracellular cholesterol trafficking and ABCA1-mediated efflux. Therefore, decreased CTSD expression may contribute to low plasma HDL-C levels.

Received for publication, May 30, 2006 , and in revised form, October 5, 2006.

^* This work was supported in part by grants from the Ontario Heart and Stroke Foundation (to Y. L. M.) and from the Canadian Institutes of Health Research (Grant 44359 (to Y. L. M.) and group Grant 64519). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table 1.

¹ Supported by a postdoctoral fellowship from the Heart and Stroke Foundation of Canada.

² To whom correspondence should be addressed: University of Ottawa Heart Institute, 40 Ruskin St., Ottawa, Ontario K1Y 4W7, Canada. Tel.: 613-761-5254; Fax: 613-761-5281; E-mail: ylmarcel{at}ottawaheart.ca.

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