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J. Biol. Chem., Vol. 278, Issue 51, 51535-51542, December 19, 2003

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Lipase-selective Functional Domains of Perilipin A Differentially Regulate Constitutive and Protein Kinase A-stimulated Lipolysis^*

Hui H. Zhang, Sandra C. Souza, Kizito V. Muliro, Fredric B. Kraemer, Martin S. Obin, and Andrew S. Greenberg¶

From the Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts 02111 and the Veterans Affairs Palo Alto Health Care System and Stanford University, Palo Alto, California 94305

Perilipin (Peri) A is a lipid droplet-associated phosphoprotein that acts dually as a suppressor of basal (constitutive) lipolysis and as an enhancer of cyclic AMP-dependent protein kinase (PKA)-stimulated lipolysis by both hormone-sensitive lipase (HSL) and non-HSL(s). To identify domains of Peri A that mediate these multiple actions, we introduced adenoviruses expressing truncated or mutated Peri A and HSL into NIH 3T3 fibroblasts lacking endogenous perilipins and HSL but overexpressing acyl-CoA synthetase 1 and fatty acid transporter 1. We identified two lipase-selective functional domains: 1) Peri A (amino acids 1–300), which inhibits basal lipolysis and promotes PKA-stimulated lipolysis by HSL, and 2) Peri A (amino acids 301–517), which inhibits basal lipolysis by non-HSL and promotes PKA-stimulated lipolysis by both HSL and non-HSL. PKA site mutagenesis revealed that PKA-stimulated lipolysis by HSL requires phosphorylation of one or more sites within Peri 1–300 (Ser⁸¹, Ser²²², and Ser²⁷⁶). PKA-stimulated lipolysis by non-HSL additionally requires phosphorylation of one or more PKA sites within Peri 301–517 (Ser⁴³³, Ser⁴⁹², and Ser⁵¹⁷). Peri 301–517 promoted PKA-stimulated lipolysis by HSL yet did not block HSL-mediated basal lipolysis, indicating that an additional region(s) within Peri 301–517 promotes hormone-stimulated lipolysis by HSL. These results suggest a model of Peri A function in which 1) lipase-specific "barrier" domains block basal lipolysis by HSL and non-HSL, 2) differential PKA site phosphorylation allows PKA-stimulated lipolysis by HSL and non-HSL, respectively, and 3) additional domains within Peri A further facilitate PKA-stimulated lipolysis, again with lipase selectivity.

Received for publication, August 28, 2003

^* This work was supported in part by the United States Department of Agriculture under Agreement 581950-9-001, by National Institutes of Health Grant DK 50647 (to A. S. G.), and by research awards from the American Diabetes Association (to A. S. G.). This work was supported in part by the Molecular Biology Core of the Gastroenterology Research on Absorptive and Secretory Processes, Grant P30 DK 34928. Portions of this work were presented at the 63rd (2003) Annual Meeting of the American Diabetes Association. 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: JM USDA/HNRCA at Tufts University, Rm. 603, 711 Washington St., Boston, MA 02111. Tel.: 617-556-3144; Fax: 617-556-3224; E-mail: andrew.greenberg{at}tufts.edu.

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