Impaired hepatocyte priming contributes to dysregulated proliferation and leads to death during liver regeneration in conditional NEMO ko mice

IKKγ/NEMO is the regulatory subunit of the IKK complex activating the transcription factor NF-κB. Hepatocyte-specific NEMO knock-out (ko) animals show a complete inhibition of NF-κB signalling in parenchymal cells leading to a severe phenotype. The animals develop spontaneous hepatocyte apoptosis counterbalanced by proliferation, progressing to hepatocellular carcinoma. As NF-κB is involved in early events of hepatocyte proliferation, we studied the impact of hepatocyte-specific NEMO deletion on liver regeneration. �70% partial hepatectomy (PH) was performed on 8 weeks old NEMO^f/f (wt) and NEMO^Δhepa (ko) mice to study liver regeneration. � All wt mice survived the surgery while 50% of ko died during the first days after PH. Serum marker AST was significantly higher in NEMO^Δhepa animals, as well as Caspase 3 activity, revealing higher liver damage in those mice. In this line, we detected massive apoptosis 2 days after PH, the time point where most of the mice died. Nemo ko mice presented a deficient hepatocyte priming, with TNF-α protein level decreasing after surgery, and IL-6 level constantly low in the liver. Moreover, IL-6 signalling pathway was blunted in those mice. IL-6R and GP130 mRNA levels were five times lower in primary hepatocytes ko mice and STAT3 activation was very weak compared to wt mice. These data were further confirmed by strongly reduced SAA mRNA levels, an acute phase protein. Despite the impaired priming, we observed a low, but constant proliferation rate as we could still detect a high number of proliferating cells a week after the surgery.� Our data demonstrate that hepatocyte-specific NEMO deletion leads to a high mortality after PH. This phenotype could be explained by impaired hepatocytes priming and the inability to activate the protective IL-6 signalling pathway. However the surviving NEMO^Δhepa mice can regenerate their liver albeit with a highly dysregulated proliferative pattern.