This was due to the fact that β-catenin-positive hepatocytes were indeed more apt at expansion and survival in the adverse milieu of chronic DDC exposure exhibited in enhanced atypical ductular reaction and fibrosis. It was interesting to note that hepatic regeneration reflected by hepatocyte proliferation was ongoing in both WT and KO livers at 80 and 150 days when

the hepatocytes lacked terminal differentiation as reflected by decreased expression of HNF4α, C/EBPα, and others. The lack of maturation may be due to ongoing proliferation of the hepatocytes or additional unknown factors due to chronic DDC injury and will need further evaluation. Intriguingly, no atypical ductular proliferation, oval cells, or cholangiocytes were positive for β-catenin in the KO livers at baseline or at the time of initiation of their expansion. The first time when β-catenin-positive cholangiocytes were observed in KO AZD5363 livers was at 80 and 150 days after being on the DDC diet, suggesting that some of these cells may have been derived from β-catenin-positive hepatocytes. Transdifferentiation of hepatocytes to biliary epithelial cells has been demonstrated before and might be

an attempt at repairing biliary damage brought about by DDC.22 Does lack of β-catenin in HER2 inhibitor cholangiocytes as well as atypical ductules in KO liver after chronic DDC administration impede optimal bile duct organization, thus also contributing to intrahepatic cholestasis? A role of β-catenin in biliary specification of the hepatoblasts is known.23-26 Furthermore, β-catenin is important in oval cell proliferation in rats and mice, and its role has recently been shown in differentiation of oval cells to hepatocytes.6, 7, 27 β-Catenin may also

have an important role in bile duct homeostasis. Indeed, in a recent collaborative study we have shown an important 上海皓元医药股份有限公司 role of β-catenin in regulating bile duct morphology.28 Overall, the above findings demonstrate a lack of an optimal reparative response in the absence of β-catenin to DDC-induced chronic liver injury, which is observed as increased atypical ductular proliferation resulting in greater hepatic fibrosis and development of intrahepatic cholestasis. This occurs despite repopulation of the livers with β-catenin-positive hepatocytes, which, however, does improve hepatocyte function in the KO when compared to the WT. These finding support an important role of Wnt/β-catenin signaling in bile duct homeostasis and reiterate its prosurvival and proproliferative role in hepatocyte biology. Additional Supporting Information may be found in the online version of this article. “
“Obesity and associated metabolic disorders have been implicated in liver carcinogenesis; however, there are little data on the role of obesity-related biomarkers on liver cancer risk.