Dual β-catenin and γ-catenin loss in hepatocytes impacts their polarity through altered transforming growth factor beta and hepatocyte nuclear factor 4 alpha signaling.

Abstract Hepatocytes are highly polarized epithelia. Loss of hepatocyte polarity is associated with various liver diseases, including cholestasis. However, the molecular underpinnings of hepatocyte polarization remain poorly understood. Previously, we have shown that loss of β-catenin at adherens junctions (AJs) is compensated by γ-catenin and dual loss of both catenins in dual knockouts (DKO) in mice liver leads to progressive intrahepatic cholestasis. However, the clinical relevance of this observation, and further phenotypic characterization of the phenotype, is important. Here, we identify simultaneous loss of β- and γ-catenin in a subset of liver samples from patients of progressive familial intrahepatic cholestasis and primary sclerosing cholangitis. Hepatocytes in DKO mice exhibited defect in apical-basolateral localization of polarity proteins, impaired bile canaliculi formation, and loss of microvilli. Loss of polarity in DKO livers manifested as epithelial-to-mesenchymal transition, increased hepatocyte proliferation, and suppression of hepatocyte differentiation, which was associated with up-regulation of TGFβ signaling and repression of Hnf4α expression and activity. In conclusion, concomitant loss of the two catenins in the liver may be playing a pathogenic role in subsets of cholangiopathies. Our findings also support a previously unknown role β- and γ-catenin in the maintenance of hepatocyte polarity. Improved understanding of the regulation of hepatocyte polarization processes by β and γ-catenin could potentially benefit development of new therapies for cholestasis.