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J. Biol. Chem., Vol. 282, Issue 30, 21704-21711, July 27, 2007

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Regulation of Adipocyte Lipolysis by Degradation of the Perilipin Protein

NELFINAVIR ENHANCES LYSOSOME-MEDIATED PERILIPIN PROTEOLYSIS^*

Julia Kovsan, Ronit Ben-Romano, Sandra C. Souza, Andrew S. Greenberg, and Assaf Rudich^¶1

From the Department of Clinical Biochemistry and the ^¶S. Daniel Abraham Center for Health and Nutrition, Faculty of Health Sciences, Ben-Gurion University, Beer-Sheva 84103, Israel, and the Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts 02111

A decrease in the lipid droplet-associated protein perilipin may constitute a mechanism for enhanced adipocyte lipolysis under nonstimulated (basal) conditions, and increased basal lipolysis has been linked to whole body metabolic dysregulation. Here we investigated whether the lipolytic actions of the human immunodeficiency virus protease inhibitor, nelfinavir, are mediated by decreased perilipin protein content and studied the mechanisms by which it occurs. Time course analysis revealed that the decrease in perilipin protein content preceded the increase in lipolysis. A causative relationship was suggested by demonstrating that nelfinavir potently increased lipolysis in adipocytes derived from mouse embryonal fibroblasts expressing perilipin but not in mouse embryonal fibroblast adipocytes devoid of perilipin and that adenoviral mediated overexpression of perilipin in 3T3-L1 adipocytes blocked the lipolytic actions of nelfinavir. Nelfinavir did not alter mRNA content of perilipin but rather decreased perilipin proteins t from >70 to 12 h. Protein degradation of perilipin in both control and nelfinavir-treated adipocytes could be prevented by inhibiting lysosomal proteolysis using leupeptin or NH₄Cl but not by the proteasome inhibitor MG-132. We propose that proteolysis of perilipin involving the lysosomal protein degradation machinery may constitute a novel mechanism for enhancing adipocyte lipolysis.

Received for publication, March 14, 2007 , and in revised form, May 7, 2007.

^* This work was supported by United States-Israel Binational Science Foundation Grant 2003088 (to A. S. G. and A. R.), by Israel Science Foundation Grant 912/05 (to A. R.), and by the National Institutes of Health Grant IH DK-50647 and United States Department of Agriculture-Agricultural Research Service Co-Operative Agreement 58 1950-4-401 (to A. S. 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.

¹ To whom correspondence should be addressed: Dept. of Clinical Biochemistry, Faculty of Health Sciences, Ben-Gurion University, Beer-Sheva, 84103, Israel. Tel.: 972-8-647-9934; Fax: 972-8-647-9931; E-mail: rudich{at}bgu.ac.il.

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