Hepatocyte specific ablation of β and γ‐catenin leads to altered hepatocyte polarity and EMT induction

Abstract

A hallmark of epithelial cells is polarization. Like any other epithelial cell, hepatocytes in the liver show a unique polarity by forming several apical and basolateral poles within a cell. Polarization of hepatocytes is necessary for many functions and requires carefully orchestrated cooperation between cell adhesion molecules, extracellular matrix, cell junctions, cytoskeleton, and intracellular trafficking machinery. Loss of hepatocyte polarity is associated with various liver diseases including cholestasis.Previously, we discovered that simultaneous deletion of adherens junction protein β and γ catenin in the mice liver led to cholestasis (Hepatology, 2017). However, the molecular mechanism that led to cholestasis in the absence of β‐ γ‐catenin remained unclear. To address this, we have developed a hepatocyte specific β and γ catenin conditional double‐knockout mice. Electron microscopy revealed dilation of bile canaliculi with significant reduction in microvilli in the liver of double knock out mice. IHC, protein and RT‐PCR analysis revealed loss of several hepatocyte polarity markers including CD10, ZO‐2, BSEP, and MRP2, increased fibrosis and epithelial‐mesenchymal transition in the liver. Remarkably, RNA‐seq analysis revealed over activation of TGFβ pathway in double knock out liver and blocking TGFβ pathway led to partial rescue of tight‐junctional proteins and cholestasis. Taken together, our findings suggest that β; γ‐catenin are critical to the maintenance of hepatocyte polarity and cholestasis development by regulating TGFβ signaling in hepatocytes. Profound understanding of the regulation of hepatocyte polarity by both β ‐and γ‐ catenin will be useful not only in understanding cholestasis but also in the context of liver development and pathophysiology.