@article{88cf4649e8fd4903bc2f4c88d393768f,
title = "Defective HNF4alpha-dependent gene expression as a driver of hepatocellular failure in alcoholic hepatitis",
abstract = "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.",
author = "Josepmaria Argemi and Latasa, {Maria U.} and Atkinson, {Stephen R.} and Blokhin, {Ilya O.} and Veronica Massey and Gue, {Joel P.} and Joaquin Cabezas and Lozano, {Juan J.} and {Van Booven}, Derek and Aaron Bell and Sheng Cao and Vernetti, {Lawrence A.} and Arab, {Juan P.} and Meritxell Ventura-Cots and Edmunds, {Lia R.} and Constantino Fondevilla and Peter St{\"a}rkel and Laurent Dubuquoy and Alexandre Louvet and Gemma Odena and Gomez, {Juan L.} and Tomas Aragon and Jose Altamirano and Juan Caballeria and Jurczak, {Michael J.} and Taylor, {D. Lansing} and Carmen Berasain and Claes Wahlestedt and Monga, {Satdarshan P.} and Morgan, {Marsha Y.} and Pau Sancho-Bru and Philippe Mathurin and Shinji Furuya and Carolin Lackner and Ivan Rusyn and Shah, {Vijay H.} and Thursz, {Mark R.} and Jelena Mann and Avila, {Matias A.} and Ramon Bataller",
note = "Funding Information: CLC Genomics Workbench Software licensed through the Molecular Biology Information Service of the Health Sciences Library System, University of Pittsburgh was used for data analysis. This work was mainly supported by NIH/NIAAA funded Consortia “Integrated approaches for identifying molecular targets in alcoholic hepatitis” InTEAM (U01AA021908) (R.B., P.M., P.S-B.,I.R.,J.Cbl). This work was supported in part by: NIH /NIAAA (R01AA023781), USA (C.W.); Hepacare Project, Fundaci{\'o}n La Caixa, Spain (M.A.A., C.B. and M.U.L); Fond national de la recherche scientifique (FNRS J.0146.17) and Fond de la recherche scientifique m{\'e}dicale (FRSM T.0217.18), Belgium (P.S.); NIH/ NCATS (UH3TR000503) and EPA (STAR 83573601), USA (D.L.V. and L.A.T.); MRC, UK (MK/K001949/1) and NIH/NIAAA, USA (UO1AA018663) (J.M.); NIH/NIAAA (1U01AA021908-01-33490), Instituto de Salud Carlos III (PI17/00673) and Miguel Servet (CPII16/00041) and “Una manera de hacer Europa” program, European Regional Development Fund (ERDF), EU (P.S-B.); National Institute for Health Research Imperial Biomedical Research Centre and NIHR Health Technology Assessment Grant 08-14-44 (M.R.T.); NIH T32, DK007052, USA (L.R.E.); NIH/NIAAA (1U01AA021908) and AFEF (P.M., L.D.,A.L.). Acronyms: NIH: National Institutes of Health; NIAAA: National Institute of Alcohol Abuse and Alcoholism; MRC: Medical Research Council; NCATS: National Center for Advancing Translational Sciences; EPA: United States Environmental Protection Agency; STAR: Science to Achieve Results; NIHR: National Institute for Health Research; AFEF: Association Fran{\c c}aise Pour l{\textquoteright}Etude du Foie.",
year = "2019",
month = dec,
day = "1",
doi = "10.1038/s41467-019-11004-3",
language = "English (US)",
volume = "10",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}