IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v10y2019i1d10.1038_s41467-019-11004-3.html
   My bibliography  Save this article

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

Author

Listed:
  • Josepmaria Argemi

    (University of Pittsburgh Medical Center (UPMC)
    University of Navarra)

  • Maria U. Latasa

    (University of Navarra)

  • Stephen R. Atkinson

    (Imperial College London)

  • Ilya O. Blokhin

    (University of Miami Miller School of Medicine)

  • Veronica Massey

    (University of North Carolina at Chapel Hill)

  • Joel P. Gue

    (University of Pittsburgh Medical Center (UPMC))

  • Joaquin Cabezas

    (University of North Carolina at Chapel Hill
    Marqués de Valdecilla University Hospital)

  • Juan J. Lozano

    (Enfermedades Hepáticas y Digestivas (CIBERehd)
    Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS))

  • Derek Van Booven

    (University of Miami)

  • Aaron Bell

    (University of Pittsburgh School of Medicine)

  • Sheng Cao

    (Mayo Clinic)

  • Lawrence A. Vernetti

    (University of Pittsburgh)

  • Juan P. Arab

    (Mayo Clinic
    Escuela de Medicina, Pontificia Universidad Catolica de Chile)

  • Meritxell Ventura-Cots

    (University of Pittsburgh Medical Center (UPMC))

  • Lia R. Edmunds

    (University of Pittsburgh)

  • Constantino Fondevila

    (University of Barcelona)

  • Peter Stärkel

    (Université Catholique de Louvain)

  • Laurent Dubuquoy

    (University of Lille)

  • Alexandre Louvet

    (University of Lille)

  • Gemma Odena

    (University of North Carolina at Chapel Hill)

  • Juan L. Gomez

    (University of Pittsburgh School of Medicine)

  • Tomas Aragon

    (University of Navarra)

  • Jose Altamirano

    (Hospital Quiron Salud)

  • Juan Caballeria

    (Enfermedades Hepáticas y Digestivas (CIBERehd)
    Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS))

  • Michael J. Jurczak

    (University of Pittsburgh)

  • D. Lansing Taylor

    (University of Pittsburgh)

  • Carmen Berasain

    (University of Navarra
    Enfermedades Hepáticas y Digestivas (CIBERehd))

  • Claes Wahlestedt

    (University of Miami Miller School of Medicine)

  • Satdarshan P. Monga

    (University of Pittsburgh School of Medicine)

  • Marsha Y. Morgan

    (University College London)

  • Pau Sancho-Bru

    (Enfermedades Hepáticas y Digestivas (CIBERehd)
    Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS))

  • Philippe Mathurin

    (University of Lille)

  • Shinji Furuya

    (Texas A&M University)

  • Carolin Lackner

    (Institute of Pathology)

  • Ivan Rusyn

    (Texas A&M University)

  • Vijay H. Shah

    (Mayo Clinic)

  • Mark R. Thursz

    (Imperial College London)

  • Jelena Mann

    (Newcastle University)

  • Matias A. Avila

    (University of Navarra
    Enfermedades Hepáticas y Digestivas (CIBERehd))

  • Ramon Bataller

    (University of Pittsburgh Medical Center (UPMC)
    University of North Carolina at Chapel Hill)

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.

Suggested Citation

  • 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., 2019. "Defective HNF4alpha-dependent gene expression as a driver of hepatocellular failure in alcoholic hepatitis," Nature Communications, Nature, vol. 10(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-11004-3
    DOI: 10.1038/s41467-019-11004-3
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-019-11004-3
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-019-11004-3?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Yi Duan & Huikuan Chu & Katharina Brandl & Lu Jiang & Suling Zeng & Nairika Meshgin & Eleni Papachristoforou & Josepmaria Argemi & Beatriz G. Mendes & Yanhan Wang & Hua Su & Weizhong Sun & Cristina Ll, 2021. "CRIg on liver macrophages clears pathobionts and protects against alcoholic liver disease," Nature Communications, Nature, vol. 12(1), pages 1-11, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-11004-3. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.