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dc.contributor.authorBárcena, Cristina-
dc.contributor.authorStefanovic, Milica-
dc.contributor.authorTutusaus, Anna-
dc.contributor.authorMenendez, Anghara-
dc.contributor.authorGarcía-Ruiz, Carmen-
dc.contributor.authorMarí, Montserrat-
dc.contributor.authorFernández-Checa, José C.-
dc.contributor.authorGarcía de Frutos, Pablo-
dc.contributor.authorMorales, Albert-
dc.date.accessioned2015-11-06T10:22:57Z-
dc.date.available2015-11-06T10:22:57Z-
dc.date.issued2015-09-01-
dc.identifierdoi: 10.1016/j.jhep.2015.04.013-
dc.identifierissn: 1600-0641-
dc.identifier.citationJournal of Hepatology 63(3): 670-678 (2015)-
dc.identifier.urihttp://hdl.handle.net/10261/124600-
dc.description.abstract© 2015 European Association for the Study of the Liver. Background & Aims Liver fibrosis, an important health concern associated to chronic liver injury that provides a permissive environment for cancer development, is characterized by accumulation of extracellular matrix components mainly derived from activated hepatic stellate cells (HSCs). Axl, a receptor tyrosine kinase and its ligand Gas6, are involved in cell differentiation, immune response and carcinogenesis. Methods HSCs were obtained from WT and Axl<sup>-/-</sup> mice, treated with recombinant Gas6 protein (rGas6), Axl siRNAs or the Axl inhibitor BGB324, and analyzed by western blot and real-time PCR. Experimental fibrosis was studied in CCl<inf>4</inf>-treated WT and Axl<sup>-/-</sup> mice, and in combination with Axl inhibitor. Gas6 and Axl serum levels were measured in alcoholic liver disease (ALD) and hepatitis C virus (HCV) patients. Results In primary mouse HSCs, Gas6 and Axl levels paralleled HSC activation. rGas6 phosphorylated Axl and AKT prior to HSC phenotypic changes, while Axl siRNA silencing reduced HSC activation. Moreover, BGB324 blocked Axl/AKT phosphorylation and diminished HSC activation. In addition, Axl<sup>-/-</sup> mice displayed decreased HSC activation in vitro and liver fibrogenesis after chronic damage by CCl<inf>4</inf> administration. Similarly, BGB324 reduced collagen deposition and CCl<inf>4</inf>-induced liver fibrosis in mice. Importantly, Gas6 and Axl serum levels increased in ALD and HCV patients, inversely correlating with liver functionality. Conclusions The Gas6/Axl axis is required for full HSC activation. Gas6 and Axl serum levels increase in parallel to chronic liver disease progression. Axl targeting may be a therapeutic strategy for liver fibrosis management.-
dc.description.sponsorshipThis study was funded by grants from the Instituto de Salud Carlos III (FIS PI12/00110, PI09/00056 to A.M., FIS PI13/00374 to M.M., PI12/01265 to J.C., PI14/00320 to P.S-B. and PI11/0325 to J.F.C.), Ministerio de Economía y Competitividad (BFU2010-22185 to P.G.F., SAF2012/34831 to J.F.C. and SAF2011-23031 to C.G.R.) and co-funded by FEDER (Fondo Europeo de Desarrollo Regional, Unión Europea. “Una manera de hacer Europa”); center grant P50-AA-11999 from Research Center for Liver and Pancreatic Diseases, (US NIAAA to J.F.C.); National Institutes of Health (R01 AI089824 to C.V.R); Fundació la Marató de TV3 to J.F.C.; Fundación Mutua Madrileña (AP103502012 to C.G.R.) and by CIBERehd from the Instituto de Salud Carlos III-
dc.publisherEuropean Association for the Study of the Liver-
dc.publisherElsevier-
dc.relation.isversionofPostprint-
dc.rightsopenAccessen_EN
dc.subjectChronic liver patients-
dc.subjectExperimental fibrosis-
dc.subjectGas6/Axl serum levels-
dc.subjectHSC activation-
dc.subjectTAM receptors-
dc.titleGas6/Axl pathway is activated in chronic liver disease and its targeting reduces fibrosis via hepatic stellate cell inactivation-
dc.typeartículo-
dc.identifier.doi10.1016/j.jhep.2015.04.013-
dc.relation.publisherversionhttp://dx.doi.org/10.1016/j.jhep.2015.04.013-
dc.date.updated2015-11-06T10:22:57Z-
dc.description.versionPeer Reviewed-
dc.language.rfc3066eng-
dc.contributor.funderInstituto de Salud Carlos III-
dc.contributor.funderMinisterio de Economía y Competitividad (España)-
dc.contributor.funderNational Institutes of Health (US)-
dc.contributor.funderFundació La Marató de TV3-
dc.contributor.funderFundación Mutua Madrileña-
dc.contributor.funderEuropean Commission-
dc.relation.csic-
dc.identifier.funderhttp://dx.doi.org/10.13039/501100004587es_ES
dc.identifier.funderhttp://dx.doi.org/10.13039/501100003329es_ES
dc.identifier.funderhttp://dx.doi.org/10.13039/100000002es_ES
dc.identifier.funderhttp://dx.doi.org/10.13039/100008666es_ES
dc.identifier.funderhttp://dx.doi.org/10.13039/100008061es_ES
dc.identifier.funderhttp://dx.doi.org/10.13039/501100000780es_ES
item.fulltextWith Fulltext-
item.openairetypeartículo-
item.cerifentitytypePublications-
item.openairecristypehttp://purl.org/coar/resource_type/c_18cf-
item.grantfulltextopen-
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