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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2018
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.
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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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