Wnt/ß-Catenin Signaling Protects Mouse Liver against Oxidative Stress-induced Apoptosis through the Inhibition of Forkhead Transcription Factor FoxO3. journal of biological chemistry Tao, G., Lehwald, N., Jang, K. Y., Baek, J., Xu, B., Omary, M. B., Sylvester, K. G. 2013; 288 (24): 17214-17224


Numerous liver diseases are associated with extensive oxidative tissue damage. It is well established that Wnt/ß-catenin signaling directs multiple hepatocellular processes, including development, proliferation, regeneration, nutrient homeostasis, and carcinogenesis. It remains unexplored whether Wnt/ß-catenin signaling provides hepatocyte protection against hepatotoxin-induced apoptosis. Conditional, liver-specific ß-catenin knockdown (KD) mice and their wild-type littermates were challenged by feeding with a hepatotoxin 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet to induce chronic oxidative liver injury. Following the DDC diet, mice with ß-catenin-deficient hepatocytes demonstrate increased liver injury, indicating an important role of ß-catenin signaling for liver protection against oxidative stress. This finding was further confirmed in AML12 hepatocytes with ß-catenin signaling manipulation in vitro using paraquat, a known oxidative stress inducer. Immunofluorescence staining revealed an intense nuclear FoxO3 staining in ß-catenin-deficient livers, suggesting active FoxO3 signaling in response to DDC-induced liver injury when compared with wild-type controls. Consistently, FoxO3 target genes p27 and Bim were significantly induced in ß-catenin KD livers. Conversely, SGK1, a ß-catenin target gene, was significantly impaired in ß-catenin KD hepatocytes that failed to inactivate FoxO3. Furthermore, shRNA-mediated deletion of FoxO3 increased hepatocyte resistance to oxidative stress-induced apoptosis, confirming a proapoptotic role of FoxO3 in the stressed liver. Our findings suggest that Wnt/ß-catenin signaling is required for hepatocyte protection against oxidative stress-induced apoptosis. The inhibition of FoxO through its phosphorylation by ß-catenin-induced SGK1 expression reduces the apoptotic function of FoxO3, resulting in increased hepatocyte survival. These findings have relevance for future therapies directed at hepatocyte protection, regeneration, and anti-cancer treatment.

View details for DOI 10.1074/jbc.M112.445965

View details for PubMedID 23620592

View details for PubMedCentralID PMC3682526