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Hepatic NF-kB-inducing Kinase (NIK) Suppresses Liver Regeneration in Chronic Liver Disease

By Yi Xiong, Adriana Souza Torsoni, Feihua Wu, Hong Shen, Yan Liu, Mark J Canet, M. Yatrik Shah, M. Bishr Omary, Yong Liu, Liangyou Rui

Posted 22 Dec 2017
bioRxiv DOI: 10.1101/238717

Hepatocyte replication maintains liver homeostasis and integrity. It is impaired in chronic liver disease, promoting disease progression. Herein, we have identified NF-kB-inducing kinase (NIK) as an unrecognized suppressor of hepatocyte replication. Hepatic NIK was aberrantly activated in chronic liver disease. Hepatocyte-specific deletion of NIK or its downstream mediator IKKα substantially accelerated hepatocyte proliferation and liver regeneration following partial hepatectomy. Mechanistically, NIK and IKKα suppressed the mitogenic JAK2/STAT3 pathway, thereby inhibiting hepatocyte cell cycle progression. Remarkably, inactivation of hepatic NIK largely reversed suppression of the hepatic JAK2/STAT3 pathway, hepatocyte replication, and liver regeneration induced by either chronic liver injury or metabolic stress. Our data suggest that hepatic NIK acts as a rheostat for liver regeneration to restrain liver overgrowth. Pathologic activation of hepatic NIK blocks hepatocyte replication, likely contributing to liver disease progression.

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