IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v12y2021i1d10.1038_s41467-020-20303-z.html
   My bibliography  Save this article

Hepatocyte-specific IL11 cis-signaling drives lipotoxicity and underlies the transition from NAFLD to NASH

Author

Listed:
  • Jinrui Dong

    (Duke-National University of Singapore Medical School)

  • Sivakumar Viswanathan

    (Duke-National University of Singapore Medical School)

  • Eleonora Adami

    (Duke-National University of Singapore Medical School)

  • Brijesh K. Singh

    (Duke-National University of Singapore Medical School)

  • Sonia P. Chothani

    (Duke-National University of Singapore Medical School)

  • Benjamin Ng

    (Duke-National University of Singapore Medical School
    National Heart Research Institute Singapore, National Heart Centre Singapore)

  • Wei Wen Lim

    (National Heart Research Institute Singapore, National Heart Centre Singapore)

  • Jin Zhou

    (Duke-National University of Singapore Medical School)

  • Madhulika Tripathi

    (Duke-National University of Singapore Medical School)

  • Nicole S. J. Ko

    (Duke-National University of Singapore Medical School)

  • Shamini G. Shekeran

    (Duke-National University of Singapore Medical School)

  • Jessie Tan

    (Duke-National University of Singapore Medical School
    National Heart Research Institute Singapore, National Heart Centre Singapore)

  • Sze Yun Lim

    (National Heart Research Institute Singapore, National Heart Centre Singapore)

  • Mao Wang

    (Duke-National University of Singapore Medical School)

  • Pei Min Lio

    (National Heart Research Institute Singapore, National Heart Centre Singapore)

  • Paul M. Yen

    (Duke-National University of Singapore Medical School)

  • Sebastian Schafer

    (Duke-National University of Singapore Medical School
    National Heart Research Institute Singapore, National Heart Centre Singapore)

  • Stuart A. Cook

    (Duke-National University of Singapore Medical School
    National Heart Research Institute Singapore, National Heart Centre Singapore
    National Heart and Lung Institute, Imperial College London
    MRC-London Institute of Medical Sciences, Hammersmith Hospital Campus)

  • Anissa A. Widjaja

    (Duke-National University of Singapore Medical School)

Abstract

IL11 is important for fibrosis in non-alcoholic steatohepatitis (NASH) but its role beyond the stroma in liver disease is unclear. Here, we investigate the role of IL11 in hepatocyte lipotoxicity. Hepatocytes highly express IL11RA and secrete IL11 in response to lipid loading. Autocrine IL11 activity causes hepatocyte death through NOX4-derived ROS, activation of ERK, JNK and caspase-3, impaired mitochondrial function and reduced fatty acid oxidation. Paracrine IL11 activity stimulates hepatic stellate cells and causes fibrosis. In mouse models of NASH, hepatocyte-specific deletion of Il11ra1 protects against liver steatosis, fibrosis and inflammation while reducing serum glucose, cholesterol and triglyceride levels and limiting obesity. In mice deleted for Il11ra1, restoration of IL11 cis-signaling in hepatocytes reconstitutes steatosis and inflammation but not fibrosis. We found no evidence for the existence of IL6 or IL11 trans-signaling in hepatocytes or NASH. These data show that IL11 modulates hepatocyte metabolism and suggests a mechanism for NAFLD to NASH transition.

Suggested Citation

  • Jinrui Dong & Sivakumar Viswanathan & Eleonora Adami & Brijesh K. Singh & Sonia P. Chothani & Benjamin Ng & Wei Wen Lim & Jin Zhou & Madhulika Tripathi & Nicole S. J. Ko & Shamini G. Shekeran & Jessie, 2021. "Hepatocyte-specific IL11 cis-signaling drives lipotoxicity and underlies the transition from NAFLD to NASH," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-020-20303-z
    DOI: 10.1038/s41467-020-20303-z
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-020-20303-z
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-020-20303-z?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
    ---><---

    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:12:y:2021:i:1:d:10.1038_s41467-020-20303-z. 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.