Figure 7.

The β-catenin–γ-catenin–transforming growth factor (TGF)-β–hepatocyte nuclear factor 4α (HNF4α) nexus promotes hepatocyte polarization. Schematic diagram depicting the mechanism of cholestasis injury in double knockout (DKO) through regulation of hepatocyte polarity. In a control liver, adherens junction (AJ) proteins β-catenin (and in its absence γ-catenin) maintain hepatocyte polarity by inhibiting TGF-β activation and maintaining HNF4α activation. Hepatocyte-specific dual loss of β-catenin and γ-catenin induces TGF-β signaling in the liver, which leads to down-regulation of HNFα activity and expression of epithelial-mesenchymal transition (EMT) inducers snail, slug, and twist, which collectively lead to loss of hepatocyte polarity, thus contributing to the pathology of cholestatic liver disease. BC, biliary canaliculi; TJ, tight junction; WT, wild type.