β-catenin regulation of farnesoid X receptor signaling and bile acid metabolism during murine cholestasis

ABSTRACT

Cholestatic liver diseases result from impaired bile flow and are characterized by inflammation, atypical ductular proliferation (ADP), and fibrosis. The Wnt/β-catenin pathway plays a role in bile duct development, yet its role in cholestatic injury remains indeterminate. Liver-specific β-catenin knockout (KO) mice and wild-type (WT) littermates were subjected to cholestatic injury via bile duct ligation or short-term exposure to 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet. Intriguingly, KO exhibit a dramatic protection from liver injury, fibrosis, and ADP, which coincided with significantly decreased total hepatic bile acids (BA). This led to the discovery of a novel role for β-catenin in regulating BA synthesis and transport through regulation of farnesoid X receptor (FXR) activation. We show that β-catenin functions as both an inhibitor of nuclear translocation and as a nuclear co-repressor through formation of a physical complex with FXR. Loss of β-catenin expedited FXR nuclear localization and FXR/RXRα association, culminating in small heterodimer protein (SHP) promoter occupancy and activation in response to BA or FXR agonist. Conversely, accumulation of β-catenin sequesters FXR, thus inhibiting its activation. Finally, exogenous suppression of β-catenin expression during cholestatic injury reduces β-catenin/FXR complex, activates FXR to decrease total BA and alleviates hepatic injury. Conclusion: We have identified a novel FXR/β-catenin interaction whose modulation via β-catenin suppression promotes FXR activation and decreases hepatic BA, which may provide unique therapeutic opportunities in cholestatic liver diseases. This article is protected by copyright. All rights reserved.

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