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J. Biol. Chem., Vol. 280, Issue 30, 27879-27887, July 29, 2005

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Roles for C₁₆-ceramide and Sphingosine 1-Phosphate in Regulating Hepatocyte Apoptosis in Response to Tumor Necrosis Factor-^*

Yosuke Osawa, Hiroshi Uchinami, Jacek Bielawski, Robert F. Schwabe, Yusuf A. Hannun, and David A. Brenner¶

From the Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, New York 10032 and the Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina 29425

Tumor necrosis factor (TNF)- signals cell death and simultaneously induces the generation of ceramide, which is metabolized to sphingosine and sphingosine 1-phosphate (S1P) by ceramidase (CDase) and sphingosine kinase. Because the dynamic balance between the intracellular levels of ceramide and S1P (the "ceramide/S1P rheostat") may determine cell survival, we investigated these sphingolipid signaling pathways in TNF--induced apoptosis of primary hepatocytes. Endogenous C₁₆-ceramide was elevated during TNF--induced apoptosis in both rat and mouse primary hepatocytes. The putative acid sphingomyelinase (ASMase) inhibitor imipramine inhibited TNF--induced apoptosis and C₁₆-ceramide increase as did the knock out of ASMase. Overexpression of neutral CDase (NCDase) inhibited the TNF--induced increase of C₁₆-ceramide and apoptosis in rat primary hepatocytes. Moreover, NCDase inhibited liver injury and hepatocyte apoptosis in mice treated with D-galactosamine plus TNF-. This protective effect was abrogated by the sphingosine kinase inhibitor N,N-demethylsphingosine, suggesting that the survival effect of NCDase is due to not only C₁₆-ceramide reduction but also S1P formation. Administration of S1P or overexpression of NCDase activated the pro-survival kinase AKT, and overexpression of dominant negative AKT blocked the survival effect of NCDase. In conclusion, activation of ASMase and generation of C₁₆-ceramide contributed to TNF--induced hepatocyte apoptosis. NCDase prevented apoptosis both by reducing C₁₆-ceramide and by activation of AKT through S1P formation. Therefore, the cross-talk between sphingolipids and AKT pathway may determine hepatocyte apoptosis by TNF-.

Received for publication, March 18, 2005 , and in revised form, May 23, 2005.

^* This work was supported by National Institutes of Health Grant PPG DK59340 and by the Mochida Memorial Foundation for Medical Pharmaceutical Research. 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 Figs. S1 and S2.

^¶ To whom correspondence should be addressed: Dept. of Medicine, Columbia University, College of Physicians and Surgeons, 622 West 168th St., PH 8E-105J, New York, NY 10032. Tel.: 212-305-5838; Fax: 212-305-9822; E-mail: dab2106{at}columbia.edu.

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