9 and data not shown). These results imply that β-catenin either regulates these genes indirectly or that it binds an enhancer outside the span of DNA targeted in our experiments (see discussion below). Given the growing research interest in the functional role of β-catenin in adult liver homeostasis, we undertook this study to determine whether β-catenin participates in ethanol metabolism and protection
against DNA Damage inhibitor alcohol-mediated liver pathology. β-Catenin is known to associate with FoxO proteins to regulate the expression of SOD and mediates adaptation to oxidative stress. 23, 26 SOD2, which is present in the mitochondria, is critical for protection against oxidative stress. Mice
with homozygous Sod2 disruption exhibit dysfunction in multiple organs and mortality in the perinatal see more or early neonatal period. 27, 28 Heterozygous disruption of Sod2 causes increased oxidative stress and mitochondrial dysfunction. 29 On the other hand, overexpression of SOD2 protects against alcohol-induced liver injury in rodents. 30 Thus, our results show conservation of the β-catenin-FoxO interaction in the mammalian liver and its relevance to hepatic oxidative stress response. It should be noted that the Sod2 gene has multiple levels of transcriptional, epigenetic, and post-translational regulation. 31 Therefore, regulation
by β-catenin represents just one of many inputs of the complex network regulating SOD2 expression. Despite striking liver steatosis, EtOH KO mice had relatively modest increases in oxidative stress and serum ALT/AST levels and exhibited no survival advantage selleck compound with NAC treatment. Though NAC does not prevent liver steatosis, it does prevent alcohol-induced oxidative stress. 32 Therefore, factors other than oxidative-stress–mediated liver injury were likely causing mortality in KO mice. We show here that the absence of hepatic β-catenin affects the expression and activity of ethanol-metabolizing enzymes and results in high blood-alcohol levels. This defect in ethanol metabolism, along with the hyperammonemia in β-catenin KO mice resulting from loss of hepatic glutamine synthetase expression, likely results in the acute sickness and mortality observed soon after exposure to a 5% ethanol diet. 20 Several hypotheses have been proposed for the rate-limiting step of the major pathway of alcohol metabolism. Some investigators have proposed that the rate of ethanol metabolism is regulated by the amount of hepatic alcohol dehydrogenase. 33 Others have suggested that the rate at which NADH is reoxidized to NAD+ represents the rate-limiting step in alcohol metabolism.