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J. Biol. Chem., Vol. 282, Issue 2, 996-1002, January 12, 2007

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Control of Adipose Triglyceride Lipase Action by Serine 517 of Perilipin A Globally Regulates Protein Kinase A-stimulated Lipolysis in Adipocytes^*

Hideaki Miyoshi, James W. Perfield, II, Sandra C. Souza, Wen-Jun Shen^¶, Hui-Hong Zhang, Zlatina S. Stancheva, Fredric B. Kraemer^¶, Martin S. Obin¹, and Andrew S. Greenberg²

From the Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts 02111, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan, and ^¶Veterans Affairs Palo Alto Health Care System and Stanford University, Palo Alto, California 94305

Phosphorylation of the lipid droplet-associated protein perilipin A (Peri A) mediates the actions of cyclic AMP-dependent protein kinase A (PKA) to stimulate triglyceride hydrolysis (lipolysis) in adipocytes. Studies addressing how Peri A PKA sites regulate adipocyte lipolysis have relied on non-adipocyte cell models, which express neither adipose triglyceride lipase (ATGL), the rate-limiting enzyme for triglyceride catabolism in mice, nor the "downstream" lipase, hormone-sensitive lipase (HSL). ATGL and HSL are robustly expressed by adipocytes that we generated from murine embryonic fibroblasts of perilipin knock-out mice. Adenoviral expression of Peri A PKA site mutants in these cells reveals that mutation of serine 517 alone is sufficient to abrogate 95% of PKA (forskolin)-stimulated fatty acid (FA) and glycerol release. Moreover, a "phosphomimetic" (aspartic acid) substitution at serine 517 enhances PKA-stimulated FA release over levels obtained with wild type Peri A. Studies with ATGL-and HSL-directed small hairpin RNAs demonstrate that 1) ATGL activity is required for all PKA-stimulated FA and glycerol release in murine embryonic fibroblast adipocytes and 2) all PKA-stimulated FA release in the absence of HSL activity requires serine 517 phosphorylation. These results provide the first demonstration that Peri A regulates ATGL-dependent lipolysis and identify serine 517 as the Peri A PKA site essential for this regulation. The contributions of other PKA sites to PKA-stimulated lipolysis are manifested only in the presence of phosphorylated or phosphomimetic serine 517. Thus, serine 517 is a novel "master regulator" of PKA-stimulated adipocyte lipolysis.

Received for publication, June 15, 2006 , and in revised form, November 15, 2006.

^* This work was supported by National Institutes of Health Grant DK-50647 and United States Department of Agriculture Agricultural Research Service Co-Operative Agreement 58 1950-4-401 (to A. S. G.), National Institutes of Health Grant AG024635, Center for Digestive Disease Research, National Institutes of Health Grant P30 DK-34928, and American Diabetes Association Grant 1-06-RA-96 (to M. S. O.), Tufts Center for Neuroscience Research National Institutes of Health Grant P30 NS047243, GRASP (Center for Gastroenterology Research on Absorptive and Secretory Processes) Center P30 DK-34928, and the Research Service of the Department of the Veterans Affairs (to F. B. K.). 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 Fig. 1.

¹ To whom correspondence may be addressed: JMUSDA-HNRCA at Tufts, 711 Washington St., Boston MA 02111. Tel.: 617-556-3079; Fax: 617-556-3224; E-mail: martin.obin{at}tufts.edu. ² To whom correspondence may be addressed: JMUSDA-HNRCA at Tufts, 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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