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dc.contributor.authorBlokker, Britt A.
dc.contributor.authorMaijo, Monica
dc.contributor.authorEcheandia, Marta
dc.contributor.authorGalduroz, Mikel
dc.contributor.authorPatterson, Angela M.
dc.contributor.authorTen, Anna
dc.contributor.authorPhilo, Mark
dc.contributor.authorSchungel, Rebecca
dc.contributor.authorGutierrez de Juan, Virginia
dc.contributor.authorHalilbasic, Emina
dc.contributor.authorFuchs, Claudia
dc.contributor.authorLe Gall, Gwenaelle
dc.contributor.authorMilkiewicz, Malgorzata
dc.contributor.authorMilkiewicz, Piotr
dc.contributor.authorBañales Asurmendi, Jesús María
dc.contributor.authorRushbrook, Simon M.
dc.contributor.authorMato, José M.
dc.contributor.authorTrauner, Michael
dc.contributor.authorMüller, Michael
dc.contributor.authorMartínez-Chantar, María Luz
dc.contributor.authorVarela Rey, Marta
dc.contributor.authorBeraza, Naiara
dc.date.accessioned2019-03-22T11:26:52Z
dc.date.available2019-03-22T11:26:52Z
dc.date.issued2019-02
dc.identifier.citationHepatology 69(2) : 699-716 (2019)es_ES
dc.identifier.issn0270-9139
dc.identifier.issn1527-3350
dc.identifier.urihttp://hdl.handle.net/10810/32113
dc.description.abstractCholestasis comprises aetiologically heterogeneous conditions characterized by accumulation of bile acids in the liver that actively contribute to liver damage. Sirtuin 1 (SIRT1) regulates liver regeneration and bile acid metabolism by modulating farnesoid X receptor (FXR); we here investigate its role in cholestatic liver disease. We determined SIRT1 expression in livers from patients with cholestatic disease, in two experimental models of cholestasis, as well as in human and murine liver cells in response to bile acid loading. SIRT1-overexpressing (SIRToe) and hepatocyte-specific SIRT1-KO (knockout) mice (SIRThep-/-) were subjected to bile duct ligation (BDL) and were fed with a 0.1% DDC (3,5-diethoxycarbonyl-1,4-dihydrocollidine) diet to determine the biological relevance of SIRT1 during cholestasis. The effect of NorUDCA (24-norursodeoxycholic acid) was tested in BDL/SIRToe mice. We found that SIRT1 was highly expressed in livers from cholestatic patients, mice after BDL, and Mdr2 knockout mice (Mdr2(-/-)) animals. The detrimental effects of SIRT1 during cholestasis were validated in vivo and in vitro. SIRToe mice showed exacerbated parenchymal injury whereas SIRThep-/- mice evidenced a moderate improvement after BDL and 0.1% DDC feeding. Likewise, hepatocytes isolated from SIRToe mice showed increased apoptosis in response to bile acids, whereas a significant reduction was observed in SIRThep-/- hepatocytes. Importantly, the decrease, but not complete inhibition, of SIRT1 exerted by norUDCA treatment correlated with pronounced improvement in liver parenchyma in BDL/SIRToe mice. Interestingly, both SIRT1 overexpression and hepatocyte-specific SIRT1 depletion correlated with inhibition of FXR, whereas modulation of SIRT1 by NorUDCA associated with restored FXR signaling. Conclusion: SIRT1 expression is increased during human and murine cholestasis. Fine-tuning expression of SIRT1 is essential to protect the liver from cholestatic liver damage.es_ES
dc.description.sponsorshipSupported by the Biotechnology and Biological Sciences Research Council (BBSRC) by the BBSRC Institute Strategic Programme Gut Health and Food Safety and Gut Microbes and Health BBS/E/F/00044509 (to N.B.), the NRP Science Links Seed Corn Fund grant (to N.B., S.R.), Biotechnology and Biological Sciences Research Council (BBSRC) Doctoral Training Partnership programme (to N.B., A.T.), and Instituto de Salud Carlos III; FIS, PS12/00402 (to N.B. and M.V.R.). N.B. was funded by the BBSRC Institute Strategic Programme Gut Health and Food Safety BB/J004529/1, the Program Ramon y Cajal (Ministry of Economy and Competitiveness, Spain) and Ikerbaske foundation (Basque government, Spain). FIS PI12/00380, FIS PI15/01132, and Miguel Servet Program CON14/00129 cofinanced by "Fondo Europeo de Desarrollo Regional" (FEDER; to J.M.B.). Gobierno Vasco-Departamento de Salud 2013111114 (to M.L.M.-C.), MINECO: SAF2014-54658-R, EITB Maratoia BIO15/CA/014 (to M.L.M.C.) Asociacion Espanola contra el Cancer. Ciberehd is funded by the Instituto de Salud Carlos III. Work produced with the support of a 2017 Leonardo Grant for Researchers and Cultural Creators, BBVA Foundation (to M.V.R.). M.E. and M.G. were supported by the Camara de Comercio de Navarra.es_ES
dc.language.isoenges_ES
dc.publisherWileyes_ES
dc.relationinfo:eu-repo/grantAgreement/MINECO/SAF2014-54658-Res_ES
dc.relationinfo:eu-repo/grantAgreement/MINECO/ BIO15/CA/014es_ES
dc.rightsinfo:eu-repo/semantics/openAccesses_ES
dc.rights.urihttp://creativecommons.org/licenses/by/3.0/es/*
dc.subjectfarnesoid x receptores_ES
dc.subjectbile-acid metabolismes_ES
dc.subjectnorursodeoxycholic acides_ES
dc.subjectsclerosing cholangitises_ES
dc.subjectursodeoxycholic acides_ES
dc.subjectobeticholic acides_ES
dc.subjectgrowth-factores_ES
dc.subjectfxres_ES
dc.subjectproliferationes_ES
dc.subjectpathogenesises_ES
dc.titleFine-Tuning of Sirtuin 1 Expression Is Essential to Protect the Liver From Cholestatic Liver Diseasees_ES
dc.typeinfo:eu-repo/semantics/articlees_ES
dc.rights.holderThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.es_ES
dc.rights.holderAtribución 3.0 España*
dc.relation.publisherversionhttps://aasldpubs.onlinelibrary.wiley.com/doi/full/10.1002/hep.30275es_ES
dc.identifier.doi10.1002/hep.30275
dc.departamentoesMedicinaes_ES
dc.departamentoeuMedikuntzaes_ES


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This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Except where otherwise noted, this item's license is described as This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.