Details

Autor(en) / Beteiligte

• Argemi, Josepmaria
• Latasa, Maria U.
• Atkinson, Stephen R.
• Blokhin, Ilya O.
• Massey, Veronica
• Gue, Joel P.
• Cabezas, Joaquin
• Lozano, Juan J.
• Van Booven, Derek
• Bell, Aaron
• Cao, Sheng
• Vernetti, Lawrence A.
• Arab, Juan P.
• Ventura-Cots, Meritxell
• Edmunds, Lia R.
• Fondevila, Constantino
• Stärkel, Peter
• Dubuquoy, Laurent
• Louvet, Alexandre
• Odena, Gemma
• Gomez, Juan L.
• Aragon, Tomas
• Altamirano, Jose
• Caballeria, Juan
• Jurczak, Michael J.
• Taylor, D. Lansing
• Berasain, Carmen
• Wahlestedt, Claes
• Monga, Satdarshan P.
• Morgan, Marsha Y.
• Sancho-Bru, Pau
• Mathurin, Philippe
• Furuya, Shinji
• Lackner, Carolin
• Rusyn, Ivan
• Shah, Vijay H.
• Thursz, Mark R.
• Mann, Jelena
• Avila, Matias A.
• Bataller, Ramon

Titel

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

Ist Teil von

• Nature communications, 2019-07, Vol.10 (1), p.3126-19, Article 3126

Ort / Verlag

London: Nature Publishing Group UK

Erscheinungsjahr

2019

Quelle

EZB-FREE-00999 freely available EZB journals

Beschreibungen/Notizen

• 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). TGF β 1 is a key upstream transcriptome regulator in AH and induces the use of HNF4 α P2 promoter in hepatocytes, which results in defective metabolic and synthetic functions. Gene polymorphisms in LETFs including HNF4 α 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 HNF4 α -dependent gene expression. We conclude that targeting TGF β 1 and epigenetic drivers that modulate HNF4 α -dependent gene expression could be beneficial to improve hepatocellular function in patients with AH. Alcoholic hepatitis, a common cause of liver failure, lacks effective treatment. Here, the authors show altered hepatic HNF4a isoform expression and hypermethylation of its target genes in patients. HNF4a dysregulation is improved in vitro by TGFb or PPARg modulation suggesting potential therapeutic avenues.