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

• Published in: Nature communications Vol. 10; no. 1; pp. 3126 - 19
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16.07.2019; Nature Publishing Group; Nature Portfolio
• Series: Nature Communications
• Subjects: 13/1; 13/109; 13/51; 13/89; 14; 38/15; 38/91; 45/61; 631/114/2114; 692/4020/4021/1607/1608; 692/4020/4021/288/2032; Adult; Aged; Alcoholic beverages; Animal models; Animals; Biopsy; Chromatin Assembly and Disassembly; Chromatin remodeling; Deoxyribonucleic acid; Disease Progression; DNA; DNA Methylation; Epigenesis, Genetic; Epigenetics; Female; Gene expression; Gene Expression Profiling; Gene Expression Regulation; Gene polymorphism; Gene sequencing; Hepatitis; Hepatitis, Alcoholic - genetics; Hepatitis, Alcoholic - pathology; Hepatocyte nuclear factor 4; Hepatocyte Nuclear Factor 4 - genetics; Hepatocyte Nuclear Factor 4 - metabolism; Hepatocytes; Hepatocytes - pathology; Humanities and Social Sciences; Humans; Life Sciences; Liver; Liver - cytology; Liver - pathology; Liver diseases; Male; Middle Aged; multidisciplinary; Phenotypes; Polymorphism, Genetic; Ribonucleic acid; RNA; Science; Sequence Analysis, RNA; Transcription factors; Transcriptomes; Transforming Growth Factor beta1 - genetics; Transforming Growth Factor beta1 - metabolism; Transforming growth factor-b1; Transforming Growth Factor beta1; RNA; Humans; Liver; Middle Aged; Gene Expression Regulation; Chromatin Assembly and Disassembly; Genetic; Male; Gene Expression Profiling; Disease Progression; Hepatitis; DNA Methylation; Animals; Hepatocytes; Biopsy; Alcoholic; Adult; Female; Aged; Epigenesis; Hepatocyte Nuclear Factor 4; Sequence Analysis; Polymorphism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-11004-3

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.