Hepatocyte-specific IKKγ/NEMO expression determines the degree of liver injury

Background & Aims: NEMO is the regulatory subunit of the I kappa B kinase (IKK) complex and is involved in controlling nuclear factor kappa B (NF-kappa B) activation. NEMO knockout mice die during embryogenesis due to massive hepatocyte apoptosis. Here we investigated the role of NEMO-dependent signaling in hepatocytes during acute liver injury. Methods: We generated conditional hepatocyte-specific NEMO knockout mice using the loxP system with the Cre recombinase under the control of the albumin promoter (NEMO Delta LPC). In these mice, we studied mechanisms of tumor necrosis factor (TNF)- and ischemia/reperfusion-dependent liver cell damage. Results: In adult NEMO Delta LPC animals, NEMO is specifically deleted in hepatocytes and no differences in survival, growth, and fertility were found when compared with wild-type (NEMOf/f) mice. TNF stimulation of NEMO Delta LPC mice resulted in high serum transaminase levels and massive hepatocyte apoptosis, which were associated with lack of I kappa B alpha degradation, inhibition of NF-kappa B activation, and target gene transcription. Additionally, ischemia/reperfasion resulted in higher non-parenchymal cell-dependent induction of oxidative stress and stronger inflammation in NEMO Delta LPC mice. This led to massive hepatocyte apoptosis and death of the animals, while NEMOf/f mice survived with significantly lesser liver damage, showing mainly necrotic cell death. Thus, complete inhibition of NF-kappa B activation in hepatocytes, in contrast to attenuation in hepatocyte-specific IKK2(-/-) mice, determines the type of liver cell damage during ischemia/reperfusion injury and is associated with a poor prognosis. Conclusions: Our results show that understanding of the fine tuning of NF-kappa B modulation during liver injury is essential to develop new therapeutic strategies.