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dc.contributor.authorManieri, Elisa 
dc.contributor.authorFolgueira, Cintia
dc.contributor.authorRodríguez, María Elena
dc.contributor.authorLeiva-Vega, Luis 
dc.contributor.authorEsteban-Lafuente, Laura
dc.contributor.authorChen, Chaobo
dc.contributor.authorCubero, Francisco Javier
dc.contributor.authorBarrett, Tamera
dc.contributor.authorCavanagh-Kyros, Julie
dc.contributor.authorSeruggia, Davide
dc.contributor.authorRosell, Alejandro
dc.contributor.authorSanchez-Cabo, Fatima 
dc.contributor.authorGomez, Manuel J 
dc.contributor.authorMonte, Maria J
dc.contributor.authorG Marin, Jose J
dc.contributor.authorDavis, Roger J
dc.contributor.authorMora, Alfonso 
dc.contributor.authorSabio, Guadalupe
dc.identifier.citationProc Natl Acad Sci U S A. 2020; 117(28):16492-16499es_ES
dc.description.abstractMetabolic stress causes activation of the cJun NH2-terminal kinase (JNK) signal transduction pathway. It is established that one consequence of JNK activation is the development of insulin resistance and hepatic steatosis through inhibition of the transcription factor PPARα. Indeed, JNK1/2 deficiency in hepatocytes protects against the development of steatosis, suggesting that JNK inhibition represents a possible treatment for this disease. However, the long-term consequences of JNK inhibition have not been evaluated. Here we demonstrate that hepatic JNK controls bile acid production. We found that hepatic JNK deficiency alters cholesterol metabolism and bile acid synthesis, conjugation, and transport, resulting in cholestasis, increased cholangiocyte proliferation, and intrahepatic cholangiocarcinoma. Gene ablation studies confirmed that PPARα mediated these effects of JNK in hepatocytes. This analysis highlights potential consequences of long-term use of JNK inhibitors for the treatment of metabolic syndrome.es_ES
dc.description.sponsorshipG.S. (RYC-2009-04972) and F.J.C. (RYC-2014-15242) are investigators of the Ramón y Cajal Program. E.M. was awarded a La Caixa fellowship. C.F. was awarded a Sara Borrell contract (CD19/00078). This work was funded by grants supported in part by funds from the European Regional Development Fund: EU’s Seventh Framework Programme (FP7/2007-2013) ERC 260464, EFSD/Lilly European Diabetes Research Programme Dr. Sabio, 2017 Leonardo Grant for Researchers and Cultural Creators, BBVA Foundation (Investigadores-BBVA-2017) IN[17]_BBM_BAS_0066, MINECO-FEDER SAF2016-79126-R, and Comunidad de Madrid IMMUNOTHERCAN-CM S2010/BMD-2326 and B2017/BMD-3733 and La Asociación Española contra el Cáncer (to G.S.); EXOHEP-CM S2017/BMD-3727 and the European Cooperation in Science & Technology (COST) Action CA17112 (to F.J.C.); MINECO Retos SAF2016-78711, the AMMF Cholangiocarcinoma Charity 2018/117, Nano-Liver-CM Y2018/NMT-4949, UCM-25-2019, ERAB EA/18-14 (to F.J.C.). F.J.C. is a Gilead Liver Research Scholar. Grant DK R01 DK107220 from the NIH (to R.J.D.); and PI16/00598 from Carlos III Institute of Health, Spain (to J.J.G.M.). The CNIC is supported by the Ministerio de Ciencia, Innovación y Universidades, and the Pro-CNIC Foundation and is a Severo Ochoa Center of Excellence (SEV-2015-0505).es_ES
dc.publisherNational Academy of Sciences es_ES
dc.subject.meshAnimals es_ES
dc.subject.meshBile Acids and Salts es_ES
dc.subject.meshCholangiocarcinoma es_ES
dc.subject.meshHomeostasis es_ES
dc.subject.meshHumans es_ES
dc.subject.meshMale es_ES
dc.subject.meshMice es_ES
dc.subject.meshMice, Inbred C57BL es_ES
dc.subject.meshMice, Knockout es_ES
dc.subject.meshMitogen-Activated Protein Kinase 8 es_ES
dc.subject.meshMitogen-Activated Protein Kinase 9 es_ES
dc.subject.meshPPAR alpha es_ES
dc.titleJNK-mediated disruption of bile acid homeostasis promotes intrahepatic cholangiocarcinoma.es_ES
dc.typejournal articlees_ES
dc.rights.licenseAttribution-NonCommercial-NoDerivatives 4.0 Internacional*
dc.contributor.funderUnión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF) 
dc.contributor.funderUnión Europea. Comisión Europea 
dc.contributor.funderEuropean Research Council 
dc.contributor.funderFundación BBVA 
dc.contributor.funderMinisterio de Ciencia e Innovación (España) 
dc.contributor.funderComunidad de Madrid (España) 
dc.contributor.funderAsociación Española Contra el Cáncer 
dc.contributor.funderInstituto de Salud Carlos III 
dc.contributor.funderFundación ProCNIC 
dc.contributor.funderNational Institutes of Health (Estados Unidos) 
dc.identifier.journalProceedings of the National Academy of Sciences of the United States of Americaes_ES
dc.repisalud.orgCNICCNIC::Grupos de investigación::Papel de las quinasas activadas por el estrés en el desarrollo de enfermedades cardiovasculares, diabetes y cánceres_ES
dc.repisalud.orgCNICCNIC::Unidades técnicas::Bioinformáticaes_ES
dc.rights.accessRightsopen accesses_ES

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Attribution-NonCommercial-NoDerivatives 4.0 Internacional
This item is licensed under a: Attribution-NonCommercial-NoDerivatives 4.0 Internacional