Hepatic NF-kB-inducing kinase (NIK) suppresses mouse liver regeneration in acute and chronic liver disease
- University of Michigan Medical School, United States
- 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.
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All data generated or analysed during this study are included in the manuscript and supporting files.
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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.
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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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
