Hepatic NF-kappa B-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 IKK alpha) 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 IKK alpha suppressed the mitogenic JAK2/STAT3 pathway, thereby inhibiting cell cycle progression. Our data suggest that hepatic NIK and IKK alpha act as rheostats for liver regeneration by restraining overgrowth. Pathological activation of hepatic NIK or IKK alpha likely blocks hepatocyte replication, contributing to liver disease progression.