Hepatic NF-kB-inducing Kinase (NIK) Suppresses Liver Regeneration in Chronic Liver Disease
| Autor: | Adriana Souza Torsoni, Liangyou Rui, Yan Liu, Yi Xiong, Hong Shen, Bishr M Omary, Yong Liu, Mark J. Canet, Yatrik M. Shah, Feihua Wu |
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| Rok vydání: | 2017 |
| Předmět: |
0303 health sciences
biology Chemistry Kinase Chronic liver disease medicine.disease Liver regeneration 03 medical and health sciences Liver disease 0302 clinical medicine Mediator medicine.anatomical_structure Hepatocyte Cancer research medicine biology.protein 030211 gastroenterology & hepatology STAT3 Homeostasis 030304 developmental biology |
| Popis: | SummaryHepatocyte 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. |
| Databáze: | OpenAIRE |
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