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Hepatic NF-kB-inducing kinase (NIK) suppresses mouse liver regeneration in acute and chronic liver diseases
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 replicatio...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6078493/ https://www.ncbi.nlm.nih.gov/pubmed/30070632 http://dx.doi.org/10.7554/eLife.34152 |
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author | Xiong, Yi Torsoni, Adriana Souza Wu, Feihua Shen, Hong Liu, Yan Zhong, Xiao Canet, Mark J Shah, Yatrik M Omary, M Bishr Liu, Yong Rui, Liangyou |
author_facet | Xiong, Yi Torsoni, Adriana Souza Wu, Feihua Shen, Hong Liu, Yan Zhong, Xiao Canet, Mark J Shah, Yatrik M Omary, M Bishr Liu, Yong Rui, Liangyou |
author_sort | Xiong, Yi |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6078493 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-60784932018-08-08 Hepatic NF-kB-inducing kinase (NIK) suppresses mouse liver regeneration in acute and chronic liver diseases Xiong, Yi Torsoni, Adriana Souza Wu, Feihua Shen, Hong Liu, Yan Zhong, Xiao Canet, Mark J Shah, Yatrik M Omary, M Bishr Liu, Yong Rui, Liangyou eLife Cell Biology 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. eLife Sciences Publications, Ltd 2018-08-02 /pmc/articles/PMC6078493/ /pubmed/30070632 http://dx.doi.org/10.7554/eLife.34152 Text en © 2018, Xiong et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Cell Biology Xiong, Yi Torsoni, Adriana Souza Wu, Feihua Shen, Hong Liu, Yan Zhong, Xiao Canet, Mark J Shah, Yatrik M Omary, M Bishr Liu, Yong Rui, Liangyou Hepatic NF-kB-inducing kinase (NIK) suppresses mouse liver regeneration in acute and chronic liver diseases |
title | Hepatic NF-kB-inducing kinase (NIK) suppresses mouse liver regeneration in acute and chronic liver diseases |
title_full | Hepatic NF-kB-inducing kinase (NIK) suppresses mouse liver regeneration in acute and chronic liver diseases |
title_fullStr | Hepatic NF-kB-inducing kinase (NIK) suppresses mouse liver regeneration in acute and chronic liver diseases |
title_full_unstemmed | Hepatic NF-kB-inducing kinase (NIK) suppresses mouse liver regeneration in acute and chronic liver diseases |
title_short | Hepatic NF-kB-inducing kinase (NIK) suppresses mouse liver regeneration in acute and chronic liver diseases |
title_sort | hepatic nf-kb-inducing kinase (nik) suppresses mouse liver regeneration in acute and chronic liver diseases |
topic | Cell Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6078493/ https://www.ncbi.nlm.nih.gov/pubmed/30070632 http://dx.doi.org/10.7554/eLife.34152 |
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