Hepatic NF-kB-inducing kinase (NIK) suppresses mouse liver regeneration in acute and chronic liver disease

  1. Yi Xiong
  2. Adriana Souza Torsoni
  3. Feihua Wu
  4. Hong Shen
  5. Yan Liu
  6. Xiao Zhong
  7. Mark J Canet
  8. Yatrik M Shah
  9. M Bishr Omary
  10. Yong Liu
  11. Liangyou Rui  Is a corresponding author
  1. University of Michigan Medical School, United States
  2. Wuhan University, China

Abstract

Reparative hepatocyte replication is impaired in chronic liver disease, contributing to disease progression; however, the underlying mechanism remains elusive. Here, we identify Map3k14 (also known as NIK) and its substrate Chuk (also called IKKα) as unrecognized suppressors of hepatocyte replication. Chronic liver disease is associated with aberrant activation of hepatic NIK pathways. We found that hepatocyte-specific deletion of Map3k14 or Chuk substantially accelerated mouse hepatocyte proliferation and liver regeneration following partial-hepatectomy. Hepatotoxin treatment or high fat diet feeding inhibited the ability of partial-hepatectomy to stimulate hepatocyte replication; remarkably, inactivation of hepatic NIK markedly increased reparative hepatocyte proliferation under these liver disease conditions. Mechanistically, NIK and IKKα suppressed the mitogenic JAK2/STAT3 pathway, thereby inhibiting cell cycle progression. Our data suggest that hepatic NIK and IKKα act as rheostats for liver regeneration by restraining overgrowth. Pathological activation of hepatic NIK or IKKα likely blocks hepatocyte replication, contributing to liver disease progression.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Yi Xiong

    Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Adriana Souza Torsoni

    Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Feihua Wu

    Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Hong Shen

    Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Yan Liu

    Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Xiao Zhong

    Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Mark J Canet

    Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Yatrik M Shah

    Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. M Bishr Omary

    Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Yong Liu

    The Institute for Advanced Studies, Wuhan University, Wuhan, China
    Competing interests
    The authors declare that no competing interests exist.
  11. Liangyou Rui

    Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States
    For correspondence
    ruily@umich.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8433-8137

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (DK091591)

  • Liangyou Rui

National Institute of Diabetes and Digestive and Kidney Diseases (DK114220)

  • Liangyou Rui

National Institute of Diabetes and Digestive and Kidney Diseases (DK115646)

  • Liangyou Rui

National Institute of Diabetes and Digestive and Kidney Diseases (DK47918)

  • M Bishr Omary

National Natural Science Foundation of China (81420108006)

  • Yong Liu

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (PRO00006638) of the University of Michigan. The protocol was approved by the Committee on the Ethics of Animal Experiments of the University of Michigan.

Reviewing Editor

  1. Hao Zhu, University of Texas Southwestern Medical Center, United States

Publication history

  1. Received: December 6, 2017
  2. Accepted: July 28, 2018
  3. Accepted Manuscript published: August 2, 2018 (version 1)
  4. Version of Record published: August 6, 2018 (version 2)

Copyright

© 2018, Xiong et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Yi Xiong
  2. Adriana Souza Torsoni
  3. Feihua Wu
  4. Hong Shen
  5. Yan Liu
  6. Xiao Zhong
  7. Mark J Canet
  8. Yatrik M Shah
  9. M Bishr Omary
  10. Yong Liu
  11. Liangyou Rui
(2018)
Hepatic NF-kB-inducing kinase (NIK) suppresses mouse liver regeneration in acute and chronic liver disease
eLife 7:e34152.
https://doi.org/10.7554/eLife.34152

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