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dc.creatorGárate-Rascón, M. (María)-
dc.creatorRecalde, M. (Miriam)-
dc.creatorJiménez-Andrés, M. (Maddalen)-
dc.creatorElizalde, M. (María)-
dc.creatorAzkona, M.T. (María Teresa)-
dc.creatorUriarte, I. (Iker)-
dc.creatorLatasa, M.U. (María Ujué)-
dc.creatorUrtasun, R. (Raquel)-
dc.creatorBilbao, I. (Idoia)-
dc.creatorSangro, B. (Bruno)-
dc.creatorGarcía-Ruiz, C. (Carmen)-
dc.creatorFernández-Checa, J.C. (José C.)-
dc.creatorCorrales, F.J. (Fernando José)-
dc.creatorEsquivel, A. (Argitxu)-
dc.creatorPineda-Lucena, A. (Antonio)-
dc.creatorGarcía-Fernández-de-Barrena, M. (Maite)-
dc.creatorAvila, M.A. (Matías Antonio)-
dc.creatorArechederra, M. (María)-
dc.creatorBerasain, C. (Carmen)-
dc.date.accessioned2022-02-14T09:44:35Z-
dc.date.available2022-02-14T09:44:35Z-
dc.date.issued2021-
dc.identifier.citationGárate-Rascón, M. (María); Recalde, M. (Miriam); Jiménez-Andrés, M. (Maddalen); et al. "Splicing factor SLU7 prevents oxidative stress-mediated hepatocyte nuclear factor 4α degradation, preserving hepatic differentiation and protecting from liver damage". Hepatology. 74 (5), 2021, 2791 - 2807es
dc.identifier.issn0270-9139-
dc.identifier.urihttps://hdl.handle.net/10171/62913-
dc.description.abstractBackground and aims: Hepatocellular dedifferentiation is emerging as an important determinant in liver disease progression. Preservation of mature hepatocyte identity relies on a set of key genes, predominantly the transcription factor hepatocyte nuclear factor 4α (HNF4α) but also splicing factors like SLU7. How these factors interact and become dysregulated and the impact of their impairment in driving liver disease are not fully understood. Approach and results: Expression of SLU7 and that of the adult and oncofetal isoforms of HNF4α, driven by its promoter 1 (P1) and P2, respectively, was studied in diseased human and mouse livers. Hepatic function and damage response were analyzed in wild-type and Slu7-haploinsufficient/heterozygous (Slu7+/- ) mice undergoing chronic (CCl4 ) and acute (acetaminophen) injury. SLU7 expression was restored in CCl4 -injured mice using SLU7-expressing adeno-associated viruses (AAV-SLU7). The hepatocellular SLU7 interactome was characterized by mass spectrometry. Reduced SLU7 expression in human and mouse diseased livers correlated with a switch in HNF4α P1 to P2 usage. This response was reproduced in Slu7+/- mice, which displayed increased sensitivity to chronic and acute liver injury, enhanced oxidative stress, and marked impairment of hepatic functions. AAV-SLU7 infection prevented liver injury and hepatocellular dedifferentiation. Mechanistically we demonstrate a unique role for SLU7 in the preservation of HNF4α1 protein stability through its capacity to protect the liver against oxidative stress. SLU7 is herein identified as a key component of the stress granule proteome, an essential part of the cell's antioxidant machinery. Conclusions: Our results place SLU7 at the highest level of hepatocellular identity control, identifying SLU7 as a link between stress-protective mechanisms and liver differentiation. These findings emphasize the importance of the preservation of hepatic functions in the protection from liver injury.es_ES
dc.description.sponsorshipSupported by MINECO/AEI/FEDER (UE SAF2016-75972-R, PID2019-104265RB-I00/AEI/10.13039/501100011033, and PID2019-104878RB-100/AEI/10.13039/501100011033), CIBERehd, Fundación La Caixa (HEPACARE), an AECC postdoctoral fellowship (POSTD18014AREC, to M.A.), a Ministerio de Educación FPU fellowship (FPU18/01461, to M.G.R.), a Ministerio de Educación FPI fellowship (BES-2017-079883, to M.R.); a Ramón y Cajal Program contract (RYC2018-024475-1, to M.G.F.B.), the Fundación Eugenio Rodríguez Pascual, the Fundación Mario Losantos, the Fundación M. Torres, and a generous donation from Mr. Eduardo Avila.es_ES
dc.language.isoenges_ES
dc.publisherWileyes_ES
dc.rightsinfo:eu-repo/semantics/openAccesses_ES
dc.subjectMaterias Investigacion::Ciencias de la Saludes_ES
dc.subjectSLU7es_ES
dc.subjectDegradationes_ES
dc.subjectHepatocyte nuclear factores_ES
dc.subjectOxidative stresses_ES
dc.subjectLiveres_ES
dc.titleSplicing factor SLU7 prevents oxidative stress-mediated hepatocyte nuclear factor 4α degradation, preserving hepatic differentiation and protecting from liver damagees_ES
dc.typeinfo:eu-repo/semantics/articlees_ES
dc.description.noteThis is an open access article under the terms of the Creat ive Commo ns Attri butio n- NonCommercial- NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non- commercial and no modif ications or adaptations are madees_ES
dc.identifier.doi10.1002/hep.32029-
dadun.citation.endingPage2807es_ES
dadun.citation.number5es_ES
dadun.citation.publicationNameHepatologyes_ES
dadun.citation.startingPage2791es_ES
dadun.citation.volume74es_ES

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