Hepatocyte specific ablation of β‐ and γ‐catenin contributes to loss of hepatocyte polarity and EMT induction by activation of the TGFβ pathway

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 in the double knockouts (DKO). However, the molecular mechanisms that led to cholestasis in DKO were only partially elucidated. Here, we characterize the phenotype further. Electron microscopy revealed dilation of bile canaliculi with significant reduction in microvilli in the DKO livers. 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.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.