Beta‐catenin dependent Wnt signaling promotes hepatocyte‐to‐cholangiocyte transdifferentiation

Abstract

The Wnt/β‐catenin pathway has been identified as a critical regulator of liver development and physiology, and is involved in wide variety of liver pathologies, including atypical ductular proliferation during hepatobiliary injury. Previously, we published mice expressing a mutated non‐degradable form of β‐catenin (S45D) in liver have a significant number of hepatocytes expressing cholangiocyte markers after long‐term exposure to 0.1% 3,5‐ diethoxycarbonyl‐1,4‐dihydro‐collidine (DDC) compared to wild‐type (WT) littermates. There was also marked improvement in intrahepatic cholestasis and an upregulation of Wnt7A, ‐7B, and ‐10A in the portal triad of DDC‐fed mice. Due to these findings we hypothesize that β‐catenin dependent signaling induced hepatocyte‐to‐cholangiocyte transdifferentiation, which may alleviate some of the complications caused by cholangiopathies. To study this we exposed Mdr2 knockout (KO) mice, a murine model for chronic periductular inflammation and cholestatic liver disease, to GC‐1 diet, an analog of the T3 thyroid hormone that activates β‐catenin. We determined Mdr2 KO mice on GC‐1 diet had decreased bilirubin, liver to body weight ratios, fibrosis, and total β‐catenin compared to Mdr2 KO mice on normal diet. The ratio of non‐phosphorylated, active β‐catenin to total β‐catenin was significantly increased in Mdr2 KO mice on GC‐1 diet compared to both the Mdr2 KO and WT mice on normal diet. Surprisingly, however, there was no increase in either ductular proliferation or Sox‐9 expressing transdifferentiating hepatocytes in Mdr2 KO on GC‐1 diet, indicating the activation of an alternative pathway downstream of β‐catenin that we did not initially anticipate. Thus, we demonstrate that the protective effect of b‐catenin activation in a mouse model of cholestasis, albeit through an as‐yet unknown mechanism that will be elucidated in future studies.Support or Funding InformationNational Institute of Biomedical Imaging and Bioengineering of the National Institute of Health under Award Number T32EB0010216UPP Academic Foundation Award 1R01DK103775