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Article: IRhom2 inhibits bile duct obstruction–induced liver fibrosis

TitleIRhom2 inhibits bile duct obstruction–induced liver fibrosis
Authors
Issue Date2019
Citation
Science Signaling, 2019, v. 12, n. 605, article no. eaax1194 How to Cite?
AbstractCopyright © 2019 The Authors Chronic liver disease can induce prolonged activation of hepatic stellate cells, which may result in liver fibrosis. Inactive rhomboid protein 2 (iRhom2) is required for the maturation of A disintegrin and metalloprotease 17 (ADAM17, also called TACE), which is responsible for the cleavage of membrane-bound tumor necrosis factor–α (TNF-α) and its receptors (TNFRs). Here, using the murine bile duct ligation (BDL) model, we showed that the abundance of iRhom2 and activation of ADAM17 increased during liver fibrosis. Consistent with this, concentrations of ADAM17 substrates were increased in plasma samples from mice after BDL and in patients suffering from liver cirrhosis. We observed increased liver fibrosis, accelerated disease progression, and an increase in activated stellate cells after BDL in mice lacking iRhom2 (Rhbdf2−/−) compared to that in controls. In vitro primary mouse hepatic stellate cells exhibited iRhom2-dependent shedding of the ADAM17 substrates TNFR1 and TNFR2. In vivo TNFR shedding after BDL also depended on iRhom2. Treatment of Rhbdf2−/− mice with the TNF-α inhibitor etanercept reduced the presence of activated stellate cells and alleviated liver fibrosis after BDL. Together, these data suggest that iRhom2-mediated inhibition of TNFR signaling protects against liver fibrosis.
Persistent Identifierhttp://hdl.handle.net/10722/292130
ISSN
2023 Impact Factor: 6.7
2023 SCImago Journal Rankings: 2.341
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorSundaram, Balamurugan-
dc.contributor.authorBehnke, Kristina-
dc.contributor.authorBelancic, Andrea-
dc.contributor.authorAl-Salihi, Mazin A.-
dc.contributor.authorThabet, Yasser-
dc.contributor.authorPolz, Robin-
dc.contributor.authorPellegrino, Rossella-
dc.contributor.authorZhuang, Yuan-
dc.contributor.authorShinde, Prashant V.-
dc.contributor.authorXu, Haifeng C.-
dc.contributor.authorVasilevska, Jelena-
dc.contributor.authorLongerich, Thomas-
dc.contributor.authorHerebian, Diran-
dc.contributor.authorMayatepek, Ertan-
dc.contributor.authorBock, Hans H.-
dc.contributor.authorMay, Petra-
dc.contributor.authorKordes, Claus-
dc.contributor.authorAghaeepour, Nima-
dc.contributor.authorMak, Tak W.-
dc.contributor.authorKeitel, Verena-
dc.contributor.authorHäussinger, Dieter-
dc.contributor.authorScheller, Jürgen-
dc.contributor.authorPandyra, Aleksandra A.-
dc.contributor.authorLang, Karl S.-
dc.contributor.authorLang, Philipp A.-
dc.date.accessioned2020-11-17T14:55:49Z-
dc.date.available2020-11-17T14:55:49Z-
dc.date.issued2019-
dc.identifier.citationScience Signaling, 2019, v. 12, n. 605, article no. eaax1194-
dc.identifier.issn1945-0877-
dc.identifier.urihttp://hdl.handle.net/10722/292130-
dc.description.abstractCopyright © 2019 The Authors Chronic liver disease can induce prolonged activation of hepatic stellate cells, which may result in liver fibrosis. Inactive rhomboid protein 2 (iRhom2) is required for the maturation of A disintegrin and metalloprotease 17 (ADAM17, also called TACE), which is responsible for the cleavage of membrane-bound tumor necrosis factor–α (TNF-α) and its receptors (TNFRs). Here, using the murine bile duct ligation (BDL) model, we showed that the abundance of iRhom2 and activation of ADAM17 increased during liver fibrosis. Consistent with this, concentrations of ADAM17 substrates were increased in plasma samples from mice after BDL and in patients suffering from liver cirrhosis. We observed increased liver fibrosis, accelerated disease progression, and an increase in activated stellate cells after BDL in mice lacking iRhom2 (Rhbdf2−/−) compared to that in controls. In vitro primary mouse hepatic stellate cells exhibited iRhom2-dependent shedding of the ADAM17 substrates TNFR1 and TNFR2. In vivo TNFR shedding after BDL also depended on iRhom2. Treatment of Rhbdf2−/− mice with the TNF-α inhibitor etanercept reduced the presence of activated stellate cells and alleviated liver fibrosis after BDL. Together, these data suggest that iRhom2-mediated inhibition of TNFR signaling protects against liver fibrosis.-
dc.languageeng-
dc.relation.ispartofScience Signaling-
dc.titleIRhom2 inhibits bile duct obstruction–induced liver fibrosis-
dc.typeArticle-
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1126/scisignal.aax1194-
dc.identifier.pmid31662486-
dc.identifier.scopuseid_2-s2.0-85074258919-
dc.identifier.volume12-
dc.identifier.issue605-
dc.identifier.spagearticle no. eaax1194-
dc.identifier.epagearticle no. eaax1194-
dc.identifier.eissn1937-9145-
dc.identifier.isiWOS:000493726500002-
dc.identifier.issnl1945-0877-

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