Inhibiting Wnt Signaling Reduces Cholestatic Injury by Disrupting the Inflammatory Axis
Cellular and Molecular Gastroenterology and Hepatology
Bile Acids, Cholangiocytes, Farnesoid X Receptor, Nuclear Factor Kappa κB, β-catenin
Background & Aims: β-Catenin, the effector molecule of the Wnt signaling pathway, has been shown to play a crucial role in bile acid homeostasis through direct inhibition of farnesoid X receptor (FXR), which has pleiotropic effects on bile acid homeostasis. We hypothesize that simultaneous suppression of β-catenin signaling and activation of FXR in a mouse model of cholestasis will reduce injury and biliary fibrosis through inhibition of bile acid synthesis. Methods: To induce cholestasis, we performed bile duct ligation (BDL) on wild-type male mice. Eight hours after surgery, mice received FXR agonists obeticholic acid, tropifexor, or GW-4064 or Wnt inhibitor Wnt-C59. Severity of cholestatic liver disease and expression of target genes were evaluated after either 5 days or 12 days of treatment. Results: We found that although the FXR agonists worsened BDL-induced injury and necrosis after 5 days, Wnt-C59 did not. After 12 days of BDL, Wnt-C59 treatment, but not GW-4064 treatment, reduced both the number of infarcts and the number of inflammatory cells in liver. RNA sequencing analysis of whole livers revealed a notable suppression of nuclear factor kappa B signaling when Wnt signaling is inhibited. We then analyzed transcriptomic data to identify a cholangiocyte-specific signature in our model and demonstrated that Wnt-C59–treated livers were enriched for genes expressed in quiescent cholangiocytes, whereas genes expressed in activated cholangiocytes were enriched in BDL alone. A similar decrease in biliary injury and inflammation occurred in Mdr2 KO mice treated with Wnt-C59. Conclusions: Inhibiting Wnt signaling suppresses cholangiocyte activation and disrupts the nuclear factor kappa B–dependent inflammatory axis, reducing cholestatic-induced injury.
Ayers, M., Kosar, K., Xue, Y., Goel, C., Carson, M., Lee, E., Liu, S., Brooks, E., Cornuet, P., Oertel, M., Bhushan, B., & Nejak-Bowen, K. (2023). Inhibiting Wnt Signaling Reduces Cholestatic Injury by Disrupting the Inflammatory Axis. Cellular and Molecular Gastroenterology and Hepatology, 16 (6), 895-921. https://doi.org/10.1016/j.jcmgh.2023.08.004