{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T12:55:18Z","timestamp":1771592118619,"version":"3.50.1"},"reference-count":59,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2021,2,10]],"date-time":"2021-02-10T00:00:00Z","timestamp":1612915200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["RO1GM043880"],"award-info":[{"award-number":["RO1GM043880"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2021,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Acute liver failure (ALF) causes severe liver dysfunction that can lead to multi\u2010organ 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\u2010galactosamine (GalN)\/lipopolysaccharide (LPS)\u2010induced ALF, which is a well\u2010established experimental mouse model that mimics the fulminant hepatitis. Here we report that deletion of SphK1, but not SphK2, dramatically decreased GalN\/LPS\u2010induced liver damage, hepatic apoptosis, serum alanine aminotransferase levels, and mortality rate compared to wild\u2010type mice. Whereas GalN\/LPS treatment\u2010induced hepatic activation of NF\u2010\u03baB and JNK in wild\u2010type and SphK2\n                    <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    mice, these signaling pathways were reduced in SphK1\n                    <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    mice. Moreover, repression of ALF in SphK1\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice correlated with decreased expression of the pro\u2010inflammatory cytokine TNF\u03b1. Adoptive transfer experiments indicated that SphK1 in bone marrow\u2010derived infiltrating immune cells but not in host liver\u2010resident cells, contribute to the development of ALF. Interestingly, LPS\u2010induced TNF\u03b1 production was drastically suppressed in SphK1\u2010deleted macrophages, whereas IL\u201010 expression was markedly enhanced, suggesting a switch to the anti\u2010inflammatory phenotype. Finally, treatment with a specific SphK1 inhibitor ameliorated inflammation and protected mice from ALF. Our findings suggest that SphK1 regulates TNF\u03b1 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.\n                  <\/jats:p>","DOI":"10.1096\/fj.202002540r","type":"journal-article","created":{"date-parts":[[2021,2,11]],"date-time":"2021-02-11T00:03:36Z","timestamp":1613001816000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Deletion or inhibition of SphK1 mitigates fulminant hepatic failure by suppressing TNF\u03b1\u2010dependent inflammation and apoptosis"],"prefix":"10.1096","volume":"35","author":[{"given":"Dorit","family":"Avni","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Virginia Commonwealth University School of Medicine Richmond VA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kuzhuvelil B.","family":"Harikumar","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Virginia Commonwealth University School of Medicine Richmond VA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arun J.","family":"Sanyal","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Hepatology, and Nutrition Department of Internal Medicine Virginia Commonwealth University School of Medicine Richmond VA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah","family":"Spiegel","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Virginia Commonwealth University School of Medicine Richmond VA 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