Wnt/β-catenin reduces fibrosis and enhances hepatocyte reprogramming during cholestasis independent of Yap signaling.

Cholestatic liver diseases are characterized by impaired bile flow. Repairing damage and reestablishing biliary function may slow disease progression and reduce complications. The Wnt/β-catenin pathway can facilitate biliary repair during cholestasis through multiple mechanisms. The impact of constitutive Wnt/β-catenin signaling during cholestasis was analyzed using S45D transgenic (TG) mice, which express non-degradable β-catenin. Compared to WT, TG mice had increased inflammation and decreased fibrosis during prolonged cholestasis. Furthermore, TG mice had increased ductular reaction and hepatocyte reprogramming, which may alleviate injury. Since both Wnt/β-catenin and Yap pathways are implicated in cell plasticity, whether β-catenin works in concordance with or independent of Yap was investigated. In vitro studies demonstrated that Yap was not required for Wnt-mediated hepatocyte reprogramming. Spatial transcriptomics demonstrated suppression of Wnt/β-catenin activity in pericentral hepatocytes, while periportal Yap activation increased in early cholestasis. A dual reporter mouse model showed enhanced Wnt activation in both pericentral and periportal TG HC compared to WT, while Yap activation was equivalent in WT and TG. Transcriptomic analysis of human livers demonstrated that Wnt/β-catenin and Yap target genes also map to distinct cell compartments in cholestatic patients. These findings suggest that enhanced Wnt/β-catenin activation in TG mice accelerates compensatory responses and attenuates disease progression. Activation of Wnt/β-catenin and Yap in different cell types indicates that β-catenin functions independently of Yap.