Defective HNF4alpha-dependent gene expression as a driver of hepatocellular failure in alcoholic hepatitis

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...

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Autores: Argemi, Josepmaria, Latasa, Maria U.|||0000-0002-0878-1337, Atkinson, Stephen R, Blokhin, Ilya O., Massey, Veronica, Gue, Joel P., Cabezas González, Joaquín|||0000-0003-0012-484X, Lozano, Juan José, Van Booven, Derek, Bell, Aaron|||0000-0001-6648-0834, Cao, Sheng, Vernetti, Lawrence A., Arab, Juan Pablo|||0000-0002-8561-396X, Ventura-Cots, Meritxell|||0000-0001-9513-2855, Edmunds, Lia R., Fondevilla, Constantino, Stärkel, Peter|||0000-0003-2938-4442, Dubuquoy, Laurent|||0000-0003-3596-5497, Louvet, Alexandre|||0000-0002-5293-007X, Òdena Garcia, Gemma, Gomez, Juan L., Aragon, Tomas, Altamirano, José|||0000-0003-1068-4023, Caballería, Juan, Jurczak, Michael J.|||0000-0002-6335-6915, Taylor, D. Lansing, Berasain, Carmen|||0000-0001-7075-2476, Wahlestedt, Claes|||0000-0003-4471-5916, Monga, Satdarshan P.|||0000-0002-8437-3378, Morgan, Marsha Y., Sancho-Bru, Pau|||0000-0001-5569-9259, Mathurin, Philippe|||0000-0003-3447-2025, Furuya, Shinji, Lackner, Carolin, Rusyn, Ivan, Shah, Vijay H., Thursz, Mark R., Mann, Jelena, Avila, Matias A.|||0000-0001-6570-3557, Bataller, Ramon|||0000-0002-1119-7799
Tipo de recurso: artículo
Fecha de publicación:2019
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:223727
Acceso en línea:https://ddd.uab.cat/record/223727
https://dx.doi.org/urn:doi:10.1038/s41467-019-11004-3
Access Level:acceso abierto
Palabra clave: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
Descripción
Sumario: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.

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