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

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

doi:10.1038/s41467-019-11004-3

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

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

Gastroenterology and Hepatology

Research output: Contribution to journal › Article › peer-review

22 Scopus citations

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.

Original language	English (US)
Article number	3126
Journal	Nature communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-11004-3
State	Published - Dec 1 2019

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Argemi, J., Latasa, M. U., Atkinson, S. R., Blokhin, I. O., Massey, V., Gue, J. P., Cabezas, J., Lozano, J. J., Van Booven, D., Bell, A., Cao, S., Vernetti, L. A., Arab, J. P., Ventura-Cots, M., Edmunds, L. R., Fondevilla, C., Stärkel, P., Dubuquoy, L., Louvet, A., ... Bataller, R. (2019). Defective HNF4alpha-dependent gene expression as a driver of hepatocellular failure in alcoholic hepatitis. Nature communications, 10(1), Article 3126. https://doi.org/10.1038/s41467-019-11004-3

Argemi, J, Latasa, MU, Atkinson, SR, Blokhin, IO, Massey, V, Gue, JP, Cabezas, J, Lozano, JJ, Van Booven, D, Bell, A, Cao, S, Vernetti, LA, Arab, JP, Ventura-Cots, M, Edmunds, LR, Fondevilla, C, Stärkel, P, Dubuquoy, L, Louvet, A, Odena, G, Gomez, JL, Aragon, T, Altamirano, J, Caballeria, J, Jurczak, MJ, Taylor, DL, Berasain, C, Wahlestedt, C, Monga, SP, Morgan, MY, Sancho-Bru, P, Mathurin, P, Furuya, S, Lackner, C, Rusyn, I, Shah, VH, Thursz, MR, Mann, J, Avila, MA & Bataller, R 2019, 'Defective HNF4alpha-dependent gene expression as a driver of hepatocellular failure in alcoholic hepatitis', Nature communications, vol. 10, no. 1, 3126. https://doi.org/10.1038/s41467-019-11004-3

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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",

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AU - Argemi, Josepmaria

AU - Latasa, Maria U.

AU - Atkinson, Stephen R.

AU - Blokhin, Ilya O.

AU - Massey, Veronica

AU - Gue, Joel P.

AU - Cabezas, Joaquin

AU - Lozano, Juan J.

AU - Van Booven, Derek

AU - Bell, Aaron

AU - Cao, Sheng

AU - Vernetti, Lawrence A.

AU - Arab, Juan P.

AU - Ventura-Cots, Meritxell

AU - Edmunds, Lia R.

AU - Fondevilla, Constantino

AU - Stärkel, Peter

AU - Dubuquoy, Laurent

AU - Louvet, Alexandre

AU - Odena, Gemma

AU - Gomez, Juan L.

AU - Aragon, Tomas

AU - Altamirano, Jose

AU - Caballeria, Juan

AU - Jurczak, Michael J.

AU - Taylor, D. Lansing

AU - Berasain, Carmen

AU - Wahlestedt, Claes

AU - Monga, Satdarshan P.

AU - Morgan, Marsha Y.

AU - Sancho-Bru, Pau

AU - Mathurin, Philippe

AU - Furuya, Shinji

AU - Lackner, Carolin

AU - Rusyn, Ivan

AU - Shah, Vijay H.

AU - Thursz, Mark R.

AU - Mann, Jelena

AU - Avila, Matias A.

AU - Bataller, Ramon

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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.

AB - 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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JO - Nature communications

JF - Nature communications

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M1 - 3126

ER -

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

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