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2013 ; 288
(24
): 17214-24
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Wnt/?-catenin signaling protects mouse liver against oxidative stress-induced
apoptosis through the inhibition of forkhead transcription factor FoxO3
#MMPMID23620592
Tao GZ
; Lehwald N
; Jang KY
; Baek J
; Xu B
; Omary MB
; Sylvester KG
J Biol Chem
2013[Jun]; 288
(24
): 17214-24
PMID23620592
show ga
Numerous liver diseases are associated with extensive oxidative tissue damage. It
is well established that Wnt/?-catenin signaling directs multiple hepatocellular
processes, including development, proliferation, regeneration, nutrient
homeostasis, and carcinogenesis. It remains unexplored whether Wnt/?-catenin
signaling provides hepatocyte protection against hepatotoxin-induced apoptosis.
Conditional, liver-specific ?-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 ?-catenin-deficient hepatocytes
demonstrate increased liver injury, indicating an important role of ?-catenin
signaling for liver protection against oxidative stress. This finding was further
confirmed in AML12 hepatocytes with ?-catenin signaling manipulation in vitro
using paraquat, a known oxidative stress inducer. Immunofluorescence staining
revealed an intense nuclear FoxO3 staining in ?-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 ?-catenin KD livers. Conversely, SGK1, a ?-catenin
target gene, was significantly impaired in ?-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/?-catenin signaling is required for hepatocyte protection against oxidative
stress-induced apoptosis. The inhibition of FoxO through its phosphorylation by
?-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.