Zhang R, Nakao T, Luo J, Xue Y, Cornuet P, Oertel M, Kosar K, Singh S, Nejak-Bowen K. Activation of WNT/Beta-Catenin Signaling and Regulation of the Farnesoid X Receptor/Beta-Catenin Complex After Murine Bile Duct Ligation. Hepatol Commun. 2019 Oct 14;3(12):1642-1655. doi: 10.1002/hep4.1430. eCollection 2019 Dec. PubMed PMID: 31832572; PubMed Central PMCID: PMC6887668.
We have recently shown that loss of Î²-catenin prevents the development of cholestatic liver injury and fibrosis after bile duct ligation (BDL) due to loss of the inhibitory farnesoid X receptor (FXR)/Î²-catenin complex, which results in decreased hepatic bile acids (BAs) through activation of FXR. To further understand the role of Wnt/Î²-catenin signaling in regulating BA metabolism and cholestasis, we performed BDL on mice in which hepatocyte Wnt signaling is deficient but Î²-catenin is intact (low-density lipoprotein receptor-related protein [LRP]5/6 knockout [DKO]) as well as mice that have enhanced hepatocyte Î²-catenin expression (serine 45 mutated to aspartic acid [S45D] transgenic [TG] mice). Despite decreased biliary injury after BDL, hepatic injury, fibrosis, and inflammation were comparable in DKO and wild-type (WT) mice. Notably, the FXR/Î²-catenin complex was maintained in DKO livers after BDL, coincident with significantly elevated hepatic BA levels. Similarly, TG mice did not display accelerated injury or increased mortality despite overexpression of Î²-catenin. There was no augmentation of FXR/Î²-catenin association in TG livers; this resulted in equivalent hepatic BAs in WT and TG mice after BDL. Finally, we analyzed the effect of BDL on Î²-catenin activity and identified an increase in periportal cytoplasmic stabilization and association with T-cell factor 4 that correlated with increased expression of distinct downstream target genes. Conclusion: Localization of Î²-catenin and expression of Wnt-regulated genes were altered in liver after BDL; however, neither elimination of Wnt/Î²-catenin signaling nor overexpression of Î²-catenin in hepatocytes significantly impacted the phenotype or progression of BA-driven cholestatic injury.
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