title: Wnt/β-catenin signaling protects mouse liver against oxidative stress-induced apoptosis through the inhibition of forkhead transcription factor FoxO3.
abstract: Numerous liver diseases are associated with extensive oxidative tissue damage. It is well established that Wnt/β-catenin signaling directs multiple hepatocellular processes, including development, proliferation, regeneration, nutrient homeostasis, and carcinogenesis. It remains unexplored whether Wnt/β-catenin signaling provides hepatocyte protection against hepatotoxin-induced apoptosis. Conditional, liver-specific β-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 β-catenin-deficient hepatocytes demonstrate increased liver injury, indicating an important role of β-catenin signaling for liver protection against oxidative stress. This finding was further confirmed in AML12 hepatocytes with β-catenin signaling manipulation in vitro using paraquat, a known oxidative stress inducer. Immunofluorescence staining revealed an intense nuclear FoxO3 staining in β-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 β-catenin KD livers. Conversely, SGK1, a β-catenin target gene, was significantly impaired in β-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/β-catenin signaling is required for hepatocyte protection against oxidative stress-induced apoptosis. The inhibition of FoxO through its phosphorylation by β-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.
authors.affiliation: Department of Surgery, Stanford University School of Medicine, Stanford, California 94305-5148, USA.
authors.forename: Guo-Zhong
authors.initials: GZ
authors.lastname: Tao
authors.forename: Nadja
authors.initials: N
authors.lastname: Lehwald
authors.forename: Kyu Yun
authors.initials: KY
authors.lastname: Jang
authors.forename: Joy
authors.initials: J
authors.lastname: Baek
authors.forename: Baohui
authors.initials: B
authors.lastname: Xu
authors.forename: M Bishr
authors.initials: MB
authors.lastname: Omary
authors.forename: Karl G
authors.initials: KG
authors.lastname: Sylvester
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000473:pathology; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D022781:Hepatocytes / Q000187:drug effects / Q000502:physiology*; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D018384:Oxidative Stress; D010269:Paraquat / Q000494:pharmacology; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011725:Pyridines; D034741:RNA, Small Interfering / Q000235:genetics; D060449:Wnt Signaling Pathway; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D051017:Apoptosis Regulatory Proteins; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D017874:Immediate-Early Proteins; D010269:Paraquat; D017346:Protein Serine-Threonine Kinases; D011725:Pyridines; D034741:RNA, Small Interfering; D000099184:Serum-Glucocorticoid Regulated Kinases; C530773:3,5-diethoxycarbonyl-1,4-dihydrocollidine; C474033:FoxO3 protein, mouse
keywords: Cytoprotection; Foxo; Liver Injury; Oxidative Stress; Reactive Oxygen Species (ROS); Wnt Signaling