| http://purl.uniprot.org/citations/33566377 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
| http://purl.uniprot.org/citations/33566377 | http://www.w3.org/2000/01/rdf-schema#comment | "Acute liver failure (ALF) causes severe liver dysfunction that can lead to multi-organ failure and death. Previous studies suggest that sphingosine kinase 1 (SphK1) protects against hepatocyte injury, yet not much is still known about its involvement in ALF. This study examines the role of SphK1 in D-galactosamine (GalN)/lipopolysaccharide (LPS)-induced ALF, which is a well-established experimental mouse model that mimics the fulminant hepatitis. Here we report that deletion of SphK1, but not SphK2, dramatically decreased GalN/LPS-induced liver damage, hepatic apoptosis, serum alanine aminotransferase levels, and mortality rate compared to wild-type mice. Whereas GalN/LPS treatment-induced hepatic activation of NF-κB and JNK in wild-type and SphK2-/- mice, these signaling pathways were reduced in SphK1-/- mice. Moreover, repression of ALF in SphK1-/- mice correlated with decreased expression of the pro-inflammatory cytokine TNFα. Adoptive transfer experiments indicated that SphK1 in bone marrow-derived infiltrating immune cells but not in host liver-resident cells, contribute to the development of ALF. Interestingly, LPS-induced TNFα production was drastically suppressed in SphK1-deleted macrophages, whereas IL-10 expression was markedly enhanced, suggesting a switch to the anti-inflammatory phenotype. Finally, treatment with a specific SphK1 inhibitor ameliorated inflammation and protected mice from ALF. Our findings suggest that SphK1 regulates TNFα secretion from macrophages and inhibition or deletion of SphK1 mitigated ALF. Thus, a potent inhibitor of SphK1 could potentially be a therapeutic agent for fulminant hepatitis."xsd:string |
| http://purl.uniprot.org/citations/33566377 | http://purl.org/dc/terms/identifier | "doi:10.1096/fj.202002540r"xsd:string |
| http://purl.uniprot.org/citations/33566377 | http://purl.uniprot.org/core/author | "Harikumar K.B."xsd:string |
| http://purl.uniprot.org/citations/33566377 | http://purl.uniprot.org/core/author | "Spiegel S."xsd:string |
| http://purl.uniprot.org/citations/33566377 | http://purl.uniprot.org/core/author | "Sanyal A.J."xsd:string |
| http://purl.uniprot.org/citations/33566377 | http://purl.uniprot.org/core/author | "Avni D."xsd:string |
| http://purl.uniprot.org/citations/33566377 | http://purl.uniprot.org/core/date | "2021"xsd:gYear |
| http://purl.uniprot.org/citations/33566377 | http://purl.uniprot.org/core/name | "FASEB J"xsd:string |
| http://purl.uniprot.org/citations/33566377 | http://purl.uniprot.org/core/pages | "e21415"xsd:string |
| http://purl.uniprot.org/citations/33566377 | http://purl.uniprot.org/core/title | "Deletion or inhibition of SphK1 mitigates fulminant hepatic failure by suppressing TNFalpha-dependent inflammation and apoptosis."xsd:string |
| http://purl.uniprot.org/citations/33566377 | http://purl.uniprot.org/core/volume | "35"xsd:string |
| http://purl.uniprot.org/citations/33566377 | http://www.w3.org/2004/02/skos/core#exactMatch | http://purl.uniprot.org/pubmed/33566377 |
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