Hepatocyte-specific NEMO deletion in mice leads to oxidative stress lethality during liver regeneration

NEMO is the regulatory subunit of the IKK complex activating the transcription factor NF-KB. Hepatocyte-specific NEMO knock-out (NEMOΔhepa) animals show a complete inhibition of NF-KB signalling in parenchymal cells leading to a severe phenotype. As NF-KB is involved in early events of hepatocyte proliferation, we studied the impact of hepatocyte-specific NEMO deletion on liver regeneration. All wt animals survived after partial hepatectomy (PH) while we observed a striking 50% lethality occurring in NEMOΔhepa mice after PH. Liver protein extracts revealed impaired priming in ko mice with low level of TNF-α and IL-6 proteins expression after PH. Further analysis confirmed a significant defect in the IL-6/STAT3 pathway in these mice. As a result, a blunted proliferation rate was observed in the surviving animals. Feeding these animals for 4 weeks with an antioxidant diet (Butylated hydroxyanisole, BHA) resulted in a significantly reduced the liver damage, suppression of oxidative stress-induced DNA damage found in non-fed animals, restoration of a normal hepatocytes’ proliferation and ultimately 100% survival after PH. In the contrary, mice treated for 1 week with an oxidative stress inducer (Phenethyl isothiocyanate, PEITC) showed significantly higher proliferation index in non-operated mice compared to untreated ones as well as increased liver stem cell expression. PEITC treatment triggered a strong NOS2 induction before and shortly after PH in both groups followed by a reduced liver weight/body ratio 24h after surgery compared to non-treated animals. Furthermore, massive lethality was observed in treated mice after PH with 100% of the ko mice dying within 3 days, while the wt mice also died, but not as fast in average. Partial hepatectomy is highly challenging for NEMOΔhepa mice. They showed a completely altered regeneration pattern due to an imbalanced redox homeostastis triggering a compensatory liver stem cell proliferation.

Liver regeneration - oxidative stress