Defective HNF4alpha-dependent gene expression as a driver of hepatocellular failure in alcoholic hepatitis
Argemi, Josepmaria (Universidad de Navarra)
Latasa, M. U. (Hepatology Program. Center for Applied Medical Research (CIMA). University of Navarra)
Atkinson, Stephen R (Imperial College London)
Blokhin, I. O. (CUniversity of Miami Miller School of Medicine)
Massey, V. (University of North Carolina at Chapel Hill)
Gue, J. P. (University of Pittsburgh Medical Center)
Cabezas González, Joaquín (Hospital Universitario Marqués de Valdecilla (Santander, Cantabria))
Lozano, Juan José (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Van Booven, D. (University of Miami)
Bell, Aaron (University of Pittsburgh School of Medicine)
Cao, S. (Mayo Clinic)
Vernetti, L. A. (University of Pittsburgh)
Arab, J. P. (Pontificia Universidad Católica de Chile)
Ventura-Cots, Meritxell (University of Pittsburgh Medical Center)
Edmunds, L. R. (University of Pittsburgh)
Fondevilla, C. (Hospital Clínic i Provincial de Barcelona)
Stärkel, P. (Université Catholique de Louvain)
Dubuquoy, L. (University of Lille)
Louvet, Alexandre (University of Lille)
Òdena Garcia, Gemma (University of North Carolina at Chapel Hill)
Gomez, J. L. (University of Pittsburgh School of Medicine)
Aragon, T. (Universidad de Navarra)
Altamirano, José (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Caballería, J (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Jurczak, M. J. (University of Pittsburgh)
Taylor, D. L. (University of Pittsburgh)
Berasain, Carmen (Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas)
Wahlestedt, C. (University of Miami Miller School of Medicine)
Monga, S. P. (University of Pittsburgh School of Medicine)
Morgan, M. Y. (University College London)
Sancho-Bru, P. (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Mathurin, Philippe (University of Lille)
Furuya, S. (Texas A&M University)
Lackner, C. (Medical University of Graz)
Rusyn, I. (Texas A&M University)
Shah, V. H. (Mayo Clinic)
Thursz, M. R. (Imperial College London)
Mann, J. (Newcastle University)
Avila, Matias A (Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas)
Bataller, Ramon (University of North Carolina at Chapel Hill)
Universitat Autònoma de Barcelona

Data:	2019
Resum:	Alcoholic hepatitis (AH) is a life-threatening condition characterized by profound hepatocellular dysfunction for which targeted treatments are urgently needed. Identification of molecular drivers is hampered by the lack of suitable animal models. By performing RNA sequencing in livers from patients with different phenotypes of alcohol-related liver disease (ALD), we show that development of AH is characterized by defective activity of liver-enriched transcription factors (LETFs). TGFβ1 is a key upstream transcriptome regulator in AH and induces the use of HNF4α P2 promoter in hepatocytes, which results in defective metabolic and synthetic functions. Gene polymorphisms in LETFs including HNF4α are not associated with the development of AH. In contrast, epigenetic studies show that AH livers have profound changes in DNA methylation state and chromatin remodeling, affecting HNF4α-dependent gene expression. We conclude that targeting TGFβ1 and epigenetic drivers that modulate HNF4α-dependent gene expression could be beneficial to improve hepatocellular function in patients with AH.
Ajuts:	Instituto de Salud Carlos III PI17/00673
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Adult ; Aged ; Animals ; Biopsy ; Chromatin Assembly and Disassembly ; Disease Progression ; DNA Methylation ; Epigenesis, Genetic ; Female ; Gene Expression Profiling ; Gene Expression Regulation ; Hepatitis, Alcoholic ; Hepatocyte Nuclear Factor 4 ; Hepatocytes ; Humans ; Liver ; Male ; Middle Aged ; Polymorphism, Genetic ; Sequence Analysis, RNA ; Transforming Growth Factor beta1
Publicat a:	Nature communications, Vol. 10 Núm. 1 (january 2019) , p. 3126, ISSN 2041-1723

DOI: 10.1038/s41467-019-11004-3
PMID: 31311938

19 p, 2.5 MB

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