Activation of WNT/Beta‐Catenin Signaling and Regulation of the Farnesoid X Receptor/Beta‐Catenin Complex After Murine Bile Duct Ligation

Abstract

We have recently shown that loss of β‐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)/β‐catenin complex, which results in decreased hepatic bile acids (BAs) through activation of FXR. To further understand the role of Wnt/β‐catenin signaling in regulating BA metabolism and cholestasis, we performed BDL on mice in which hepatocyte Wnt signaling is deficient but β‐catenin is intact (low‐density lipoprotein receptor‐related protein [LRP]5/6 knockout [DKO]) as well as mice that have enhanced hepatocyte β‐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/β‐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 β‐catenin. There was no augmentation of FXR/β‐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 β‐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 β‐catenin and expression of Wnt‐regulated genes were altered in liver after BDL; however, neither elimination of Wnt/β‐catenin signaling nor overexpression of β‐catenin in hepatocytes significantly impacted the phenotype or progression of BA‐driven cholestatic injury.

Effects and mechanism of the bile acid (farnesoid X) receptor on the Wnt/β‑catenin signaling pathway in colon cancer

“…Mutations in the Wnt/β-catenin signaling pathway have been detected in >90% of colon carcinogenesis cases (24). A close association was recently revealed between FXR and Wnt/β-catenin signaling (25)(26)(27). FXR knockdown in a chronic colitis mouse model resulted in greater susceptibility to tumorigenesis and increased tumor progression (28).…”

Inhibition of CBP/β‐catenin signaling ameliorated fibrosis in cholestatic liver disease

“…[ 27 ] Knockdown of β‐catenin prevented BDL‐induced liver fibrosis due to loss of the FXR/β‐catenin complex, which resulted in FXR activation and reduced BA levels. [ 11 ]…”

“…[ 9 ] Studies using hepatocyte‐specific β‐catenin gene KO in mice revealed dual roles of β‐catenin signaling: Deletion of β‐catenin increased liver injury and fibrosis induced by cholestasis in Mdr2 ‐KO mice, whereas it suppressed liver injury and fibrosis due to cholestasis in bile duct–ligated (BDL) mice. [ 10,11 ]…”

Role and Regulation of Wnt/β-Catenin in Hepatic Perivenous Zonation and Physiological Homeostasis

“…63 Subsequent studies suggested that CYP7A1 is also either a direct or an indirect target of Wnt signaling as CYP7A1 is suppressed basally in both b-catenin KO and LRP5/6 KO. 64,65 Interestingly, b-catenin can also impact bile acid metabolism through its physical interaction with farnesoid X receptor(FXR), a nuclear receptor that regulates expression of bile acid efflux transporters and represses CYP7A1 expression through activation of small heterodimer partner(SHP). Lack of b-catenin eliminates FXR sequestration, leading to increased availability of FXR to decrease bile acid biosynthesis and stimulate its elimination, with the result that b-catenin KO have less liver injury, fibrosis, and atypical ductular proliferation after experimental cholestasis.…”

“…Lack of b-catenin eliminates FXR sequestration, leading to increased availability of FXR to decrease bile acid biosynthesis and stimulate its elimination, with the result that b-catenin KO have less liver injury, fibrosis, and atypical ductular proliferation after experimental cholestasis. 64,65 Overexpression of oncogenic b-catenin in mice leads to cholestatic liver disease, whereas in humans, hepatocellular carcinoma with b-catenin gene mutations also exhibits intratumoral cholestasis. 66,67 Because both CYP27 and CYP7A1 are expressed in the perivenous zone along with b-catenin, it is possible that excess b-catenin activates these two bile acid synthesis enzymes either directly or indirectly through inhibition of FXR around the central vein.…”