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J. Biol. Chem., Vol. 280, Issue 20, 20148-20153, May 20, 2005

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Acid Ceramidase Overexpression Prevents the Inhibitory Effects of Saturated Fatty Acids on Insulin Signaling^*

Jose Antonio Chavez, William L. Holland, Julia Bär, Konrad Sandhoff, and Scott A. Summers¶

From the Department of Internal Medicine, Division of Endocrinology, Metabolism, and Diabetes, University of Utah, Salt Lake City, Utah 84132 and Kekule-Institut fur Organische Chemie und Biochemie, Universitat Bonn, Gerhard-Domagk-Strassel, D-53121 Bonn, Germany

Recent studies indicate that insulin resistance and type 2 diabetes result from the accumulation of lipids in tissues not suited for fat storage, such as skeletal muscle and the liver. To elucidate the mechanisms linking exogenous fats to the inhibition of insulin action, we evaluated the effects of free fatty acids (FFAs) on insulin signal transduction in cultured C2C12 myotubes. As we described previously (Chavez, J. A., and Summers, S. A. (2003) Arch. Biochem. Biophys. 419, 101–109), long-chain saturated FFAs inhibited insulin stimulation of Akt/protein kinase B, a central regulator of glucose uptake and anabolic metabolism. Moreover, these FFAs stimulated the de novo synthesis of ceramide and sphingosine, two sphingolipids shown previously to inhibit insulin action. To determine the contribution of either sphingolipid in FFA-dependent inhibition of insulin action, we generated C2C12 myotubes that constitutively overexpress acid ceramidase (AC), an enzyme that catalyzes the lysosomal conversion of ceramide to sphingosine. AC overexpression negated the inhibitory effects of saturated FFAs on insulin signaling while blocking their stimulation of ceramide accumulation. By contrast, AC overexpression stimulated the accrual of sphingosine. These results support a role for aberrant accumulation of ceramide, but not sphingosine, in the inhibition of muscle insulin sensitivity by exogenous FFAs.

Received for publication, November 11, 2004 , and in revised form, February 16, 2005.

^* This work was supported by National Institutes of Health Grant R01-DK58784 (to S. A. S.), the American Diabetes Association (to S. A. S.), Deutsche Forschungsgemeinschaft Grant SFB 645 (to K. S.), and the Ben and Iris Margolis Foundation. 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. Tel.: 801-585-0950; Fax: 801-585-0956; E-mail: scott.summers{at}hsc.utah.edu.

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