Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• The Journal of biological chemistry, 2005-07, Vol.280 (30), p.27879-27887

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2005

Quelle

MEDLINE

Beschreibungen/Notizen

• Tumor necrosis factor (TNF)-α 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-α-induced apoptosis of primary hepatocytes. Endogenous C16-ceramide was elevated during TNF-α-induced apoptosis in both rat and mouse primary hepatocytes. The putative acid sphingomyelinase (ASMase) inhibitor imipramine inhibited TNF-α-induced apoptosis and C16-ceramide increase as did the knock out of ASMase. Overexpression of neutral CDase (NCDase) inhibited the TNF-α-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-α. 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-α-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-α.