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Papers In Press, published online ahead of print September 1, 2009
J. Lipid Res., doi:10.1194/jlr.M800635-JLR200

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Journal of Lipid Research, Vol. 50, 1852-1862, September 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

Palmitate increases sphingosine-1-phosphate in C2C12 myotubes via upregulation of sphingosine kinase message and activity^[S]

Wei Hu^*, Jacek Bielawski^*, Fahumiya Samad, Alfred H. Merrill, Jr. and L. Ashley Cowart^1,*,**

^* Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC
Department of Biochemistry and Molecular Biology, Torrey Pines Institute for Molecular Studies, San Diego, CA
School of Biology and Petit Institute of Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA
^** School of Biology and Petit Institute of Bioengineering and Bioscience, Ralph H. Johnson Veteran's Affairs Medical Center, Charleston, SC

¹ To whom correspondence should be addressed. e-mail: cowartl{at}musc.edu

Studies in skeletal muscle demonstrate that elevation of plasma FFAs increases the sphingolipid ceramide. We aimed to determine the impact of FFA oversupply on total sphingolipid profiles in a skeletal muscle model. C2C12 myotubes were treated with palmitate (PAL). Lipidomics analysis revealed pleiotropic effects of PAL on cell sphingolipids not limited to ceramides. ¹³C labeling demonstrated that PAL activated several branches of sphingolipid synthesis by distinct mechanisms. Intriguingly, PAL increased sphingosine-1-phosphate independently of de novo synthesis. Quantitative real-time PCR demonstrated that PAL increased sphingosine kinase 1 (SK1) mRNA by approximately 4-fold. This was accompanied by a 2.3-fold increase in sphingosine kinase enzyme activity. This upregulation did not occur upon treatment with oleate, suggesting some level of specificity for PAL. These findings were recapitulated in the diet-induced obesity mouse model, in which high-fat feeding increased SK1 message in skeletal muscle over 2.3-fold. These data suggest that the impact of elevated FFA on sphingolipids reaches beyond ceramides and de novo sphingolipid synthesis. Moreover, these findings identify PAL as a novel regulatory stimulus for SK1.

Supplementary key words free fatty acid • sphingolipid • ceramide • skeletal muscle • insulin resistance • diabetes • obesity • lipotoxicity

Abbreviations: C1P, ceramide-1-phosphate; CERK, ceramide kinase; CerS, ceramide synthase, DHSph, dihydrosphingosine; DHSph-1-P, dihydrosphingosine-1-phosphate; PAL, palmitate; S1P, sphingosine-1-phosphate; SK, sphingosine kinase; SPH, sphingosine; SPT, serine palmitoyltransferase

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