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

Abstract

Background & aims: NEMO is the regulatory subunit of the I kappa B kinase (IKK) complex and is involved in controlling nuclear factor kappaB (NF-kappaB) 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 (NEMODeltaLPC). In these mice, we studied mechanisms of tumor necrosis factor (TNF)- and ischemia/reperfusion-dependent liver cell damage.

Results: In adult NEMODeltaLPC animals, NEMO is specifically deleted in hepatocytes and no differences in survival, growth, and fertility were found when compared with wild-type (NEMO(f/f)) mice. TNF stimulation of NEMODeltaLPC 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-kappaB activation, and target gene transcription. Additionally, ischemia/reperfusion resulted in higher nonparenchymal cell-dependent induction of oxidative stress and stronger inflammation in NEMODeltaLPC mice. This led to massive hepatocyte apoptosis and death of the animals, while NEMO(f/f) mice survived with significantly lesser liver damage, showing mainly necrotic cell death. Thus, complete inhibition of NF-kappaB 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-kappaB modulation during liver injury is essential to develop new therapeutic strategies.