Hepatic NF-kB-inducing kinase (NIK) suppresses mouse liver regeneration in acute and chronic liver diseases
Yi Xiong,
Adriana Souza Torsoni,
Feihua Wu,
Hong Shen,
Yan Liu,
Xiao Zhong,
Mark J Canet,
Yatrik M Shah,
M Bishr Omary,
Yong Liu,
Liangyou Rui
Affiliations
Yi Xiong
Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States
Adriana Souza Torsoni
Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States; Laboratory of Metabolic Disorders, School of Applied Sciences, University of Campinas, Limeira, Brazil
Feihua Wu
Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States; Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Medicine, China Pharmaceutical University, Nanjing, China
Hong Shen
Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States
Yan Liu
Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States
Xiao Zhong
Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States
Mark J Canet
Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States
Yatrik M Shah
Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States
M Bishr Omary
Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States
Yong Liu
College of Life Sciences, Institute for Advanced Studies, Wuhan University, Wuhan, China
Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States; Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States
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.
