Beta‐catenin–NF‐κB interactions in murine hepatocytes: A complex to die for

Wnt/β‐catenin signaling plays an important role in hepatic homeostasis, especially in liver development, regeneration, and cancer, and loss of β‐catenin signaling is often associated with increased apoptosis. To elucidate how β‐catenin may be regulating hepatocyte survival, we investigated the susceptibility of β‐catenin conditional knockout (KO) mice and their wild‐type (WT) littermates to Fas and tumor necrosis factor‐α (TNF‐α), two common pathways of hepatocyte apoptosis. While comparable detrimental effects from Fas activation were observed in WT and KO, a paradoxical survival benefit was observed in KO mice challenged with D ‐galactosamine/lipopolysaccharide. KO mice showed significantly lower morbidity and liver injury due to early, robust, and protracted activation of NF‐κB in the absence of β‐catenin. Enhanced NF‐κB activation in KO mice was associated with increased basal inflammation and Toll‐like receptor 4 expression and lack of the p65/β‐catenin complex in hepatocytes. The p65/β‐catenin complex in WT livers underwent temporal dissociation allowing for NF‐κB activation to regulate hepatocyte survival following TNF‐α‐induced hepatic injury. Decrease of total β‐catenin protein but not its inactivation induced p65 activity, whereas β‐catenin stabilization either chemically or due to mutations repressed it in hepatomas in a dose‐dependent manner, whereas β‐catenin stabilization repressed it either chemically or due to mutations. Conclusion: The p65/β‐catenin complex in hepatocytes undergoes dynamic changes during TNF‐α–induced hepatic injury and plays a critical role in NF‐κB activation and cell survival. Modulation of β‐catenin levels is a unique mode of regulating NF‐κB activity and thus may present novel opportunities in devising therapeutics in specific hepatic injuries. (H EPATOLOGY 2013)