Splicing factor SLU7 prevents oxidative stress-mediated hepatocyte nuclear factor 4α degradation, preserving hepatic differentiation and protecting from liver damage
Fecha
2021Autor
Versión
Acceso abierto / Sarbide irekia
Tipo
Artículo / Artikulua
Versión
Versión publicada / Argitaratu den bertsioa
Identificador del proyecto
Impacto
|
10.1002/hep.32029
Resumen
Background 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 ...
[++]
Background 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. [--]
Materias
SLU7,
HNF4α,
Liver differentiation,
Liver damage
Editor
Wiley American Asociation for the Study of Liver Diseases
Publicado en
Hepatology vol. 74, no. 5, 2021
Departamento
Universidad Pública de Navarra. Departamento de Ciencias de la Salud /
Nafarroako Unibertsitate Publikoa. Osasun Zientziak Saila
Versión del editor
Entidades Financiadoras
Supported 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.
Aparece en las colecciones
Los documentos de Academica-e están protegidos por derechos de autor con todos los derechos reservados, a no ser que se indique lo contrario.
La licencia del ítem se describe como © 2021 The Authors. This is an open access article under the terms of the Creative Commons Attribution- 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 modifications or adaptations are made.
Ítems relacionados
Mostrando ítems relacionados por Título, autor o materia.
-
Relapse, cognitive reserve and their relationship with cognition in first episode schizophrenia: a 3-year follow-up study
Sánchez Torres, Ana María ; Amoretti, Silvia; Enguita Germán, Mónica; Mezquida, Gisela; Moreno-Izco, Lucía; Panadero-Gómez, Rocío; Rementería, Lide; Toll, Alba; Rodríguez-Jiménez, Roberto; Roldán, Alexandra; Pomarol-Clotet, Edith; Ibáñez, Ángela; Usall, Judith; Contreras, Fernando; Vieta, Eduard; López-Ilundain, José M.; Merchán-Naranjo, Jessica; González Pinto, Ana; Berrocoso, Esther; Bernardo, Miguel; Cuesta, Manuel J.; Forte, María Florencia; González-Díaz, Jairo M.; Parellada, Mara; Abrokwa, Hayford; Segura, María Sans; González, Judtih Selma; Zorrilla, Iñaki; González-Ortega, Itxaso; Legido, Teresa; Mané, Anna; Sanchez-Pastor, Luis; Rentero, David; Sarró, Salvador; García-León, María Ángeles; Butjosa, Anna; Pardo, Marta; Zarzuela, Amalia; Ribeiro Fernández, María; Sáiz-Ruiz, Jerónimo; León-Quismondo, Leticia; Hernández, Miguel; Cámara, Concepción de la; Gutiérrez-Fraile, Miguel; González-Blanco, Leticia (Elsevier, 2023) Artículo / ArtikuluaSchizophrenia is frequently characterized by the presence of multiple relapses. Cognitive impairments are core features of schizophrenia. Cognitive reserve (CR) is the ability of the brain to compensate for damage caused ... -
Adherence to the Mediterranean diet reduces mortality in the Spanish cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Spain)
Buckland, Genevieve; Agudo, Antonio; Travier, Noemie; Huerta, José María; Cirera, Lluís; Tormo, María José; Navarro, Carmen; Chirlaque, María Dolores; Moreno Iribas, C.; Ardanaz, Eva; Barricarte Gurrea, Aurelio ; Etxeberria Andueza, Jaione ; Marín, Pilar; Quirós, J. Ramón; Redondo, María Luisa; Larrañaga, Nerea; Amiano, Pilar; Dorronsoro, Miren; Arriola, Larraitz; Basterretxea, Mikel; Sánchez, María José; Molina, Esther; González, Carlos A. (Cambridge University Press, 2011) Artículo / ArtikuluaEpidemiological studies show that adherence to a Mediterranean diet (MD) increases longevity; however, few studies are restricted to Mediterranean populations or explore the effect of a MD pattern that directly incorporates ... -
Clinical, histopathologic and genetic features of rhabdoid meningiomas
Garrido Ruiz, Patricia Alejandra; González-Tablas, María; Pasco Peña, Alejandro; Zelaya Huerta, María Victoria ; Ortiz, Javier; Otero, Álvaro; Corchete, Luis Antonio; Ludeña, María Dolores; Caballero Martínez, María Cristina; Córdoba Iturriagagoitia, Alicia; Fernández, Inmaculada Catalina; González-Carreró Fojón, Joaquín; Hernández Laín, Aurelio; Orfao, Alberto; Tabernero, María Dolores (MDPI, 2023) Artículo / ArtikuluaRhabdoid meningiomas (RM) shows heterogeneous histological findings, and a wide variety of chromosomal copy number alterations (CNA) are associated with an unpredictable course of the disease. In this study, we analyzed a ...