Differential Effects of Axin2 Deficiency on the Fibrogenic and Regenerative Response in Livers of Bile Duct-Ligated Mice

Abstract

Background: Wnt signaling is involved in the pathogenesis of liver fibrosis. Axin2 is a negative regulator of the canonical Wnt pathway by promoting β-catenin degradation. β-Catenin-activating and loss-of-function mutations of Axin2 are thought to be functionally relevant for liver diseases and cancer. Thus, we hypothesized that Axin2 deficiency promotes fibrogenesis. Methods: As the functions and mechanisms of how Axin2/β-catenin signaling participates in the progression of liver fibrosis are unclear, we investigated the progression of liver fibrosis in Axin2-deficient mice using Axin2-LacZ reporter mice (Axin2^+/-, Axin2^-/-, and Axin2^+/+) which underwent bile duct ligation (BDL). Results: Here, we show that the expression of Axin2 is downregulated during fibrogenesis in wild-type mice, which is consistent with a decreased expression of the reporter gene LacZ in Axin2^+/- and Axin2^-/- mice. Surprisingly, no alteration in active β-catenin/Wnt signaling occurs in Axin2-deficient mice upon BDL. Despite a less pronounced liver injury, Axin2 deficiency had only minor and no significant effects on the fibrogenic response upon BDL, i.e. slightly reduced hepatic stellate cell activity and collagen mRNA expression. However, livers of Axin2^-/- mice shared a stronger cell proliferation both already at baseline as well as immediately after BDL. Conclusion: Our results strongly suggest, contrary to expectation, that a deficiency in Axin2 is not equivalent to an increase in active β-catenin and target genes, indicating no functional relevance of Axin2-dependent regulation of the canonical Wnt/β-catenin pathway in the progression of cholestatic liver injury. This also suggests that the negligible effects of Axin2 deficiency during fibrogenesis may be related to an alternative pathway.