All authors edited and reviewed the final article. “
“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. selleck kinase inhibitor 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 Enzalutamide datasheet 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. (HEPATOLOGY PRKACG 2013) Hepatic inflammation is a common cause of hepatic injury and cell death, with etiologies such as viruses and alcohol. The liver is particularly susceptible to apoptosis due to a rich expression of death receptors. Of the six identified death receptors, Fas and tumor necrosis factor-α (TNF-α) are considered to have

major pathologic significance in the liver.1, 2 Activation of the Fas-mediated apoptotic pathway has been linked to liver diseases such as hepatic inflammation, viral hepatitis, alcoholic hepatitis, nonalcoholic steatohepatitis, cholestasis, and Wilson’s disease, while TNF-α mediated activation of apoptosis has been implicated in alcoholic hepatitis, ischemia/reperfusion, and fulminant hepatic failure.1, 2 Fas-mediated cell death, experimentally induced by intravenous injection of Jo-2 antibody, causes activation of Fas receptor and initiation of a downstream cascade that induces massive hepatocyte apoptosis. Treatment with lipopolysaccharide (LPS) also causes hepatotoxicity and lethality, which is primarily mediated by release of TNF-α from macrophages.