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http://purl.uniprot.org/citations/15946935http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/15946935http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/15946935http://www.w3.org/2000/01/rdf-schema#comment"Tumor necrosis factor (TNF)-alpha 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-alpha-induced apoptosis of primary hepatocytes. Endogenous C16-ceramide was elevated during TNF-alpha-induced apoptosis in both rat and mouse primary hepatocytes. The putative acid sphingomyelinase (ASMase) inhibitor imipramine inhibited TNF-alpha-induced apoptosis and C16-ceramide increase as did the knock out of ASMase. Overexpression of neutral CDase (NCDase) inhibited the TNF-alpha-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-alpha. 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-alpha-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-alpha."xsd:string
http://purl.uniprot.org/citations/15946935http://purl.org/dc/terms/identifier"doi:10.1074/jbc.m503002200"xsd:string
http://purl.uniprot.org/citations/15946935http://purl.org/dc/terms/identifier"doi:10.1074/jbc.m503002200"xsd:string
http://purl.uniprot.org/citations/15946935http://purl.uniprot.org/core/author"Osawa Y."xsd:string
http://purl.uniprot.org/citations/15946935http://purl.uniprot.org/core/author"Osawa Y."xsd:string
http://purl.uniprot.org/citations/15946935http://purl.uniprot.org/core/author"Bielawski J."xsd:string
http://purl.uniprot.org/citations/15946935http://purl.uniprot.org/core/author"Bielawski J."xsd:string
http://purl.uniprot.org/citations/15946935http://purl.uniprot.org/core/author"Hannun Y.A."xsd:string
http://purl.uniprot.org/citations/15946935http://purl.uniprot.org/core/author"Hannun Y.A."xsd:string
http://purl.uniprot.org/citations/15946935http://purl.uniprot.org/core/author"Brenner D.A."xsd:string
http://purl.uniprot.org/citations/15946935http://purl.uniprot.org/core/author"Brenner D.A."xsd:string
http://purl.uniprot.org/citations/15946935http://purl.uniprot.org/core/author"Schwabe R.F."xsd:string
http://purl.uniprot.org/citations/15946935http://purl.uniprot.org/core/author"Schwabe R.F."xsd:string
http://purl.uniprot.org/citations/15946935http://purl.uniprot.org/core/author"Uchinami H."xsd:string
http://purl.uniprot.org/citations/15946935http://purl.uniprot.org/core/author"Uchinami H."xsd:string
http://purl.uniprot.org/citations/15946935http://purl.uniprot.org/core/date"2005"xsd:gYear
http://purl.uniprot.org/citations/15946935http://purl.uniprot.org/core/date"2005"xsd:gYear
http://purl.uniprot.org/citations/15946935http://purl.uniprot.org/core/name"J. Biol. Chem."xsd:string
http://purl.uniprot.org/citations/15946935http://purl.uniprot.org/core/name"J. Biol. Chem."xsd:string
http://purl.uniprot.org/citations/15946935http://purl.uniprot.org/core/pages"27879-27887"xsd:string
http://purl.uniprot.org/citations/15946935http://purl.uniprot.org/core/pages"27879-27887"xsd:string
http://purl.uniprot.org/citations/15946935http://purl.uniprot.org/core/title"Roles for C16-ceramide and sphingosine 1-phosphate in regulating hepatocyte apoptosis in response to tumor necrosis factor-alpha."xsd:string
http://purl.uniprot.org/citations/15946935http://purl.uniprot.org/core/title"Roles for C16-ceramide and sphingosine 1-phosphate in regulating hepatocyte apoptosis in response to tumor necrosis factor-alpha."xsd:string
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