Disparate cellular basis of improved liver repair in beta-catenin-overexpressing mice after long-term exposure to 3,5-diethoxycarbonyl-1,4-dihydrocollidine.
Administration of a hepatotoxic diet containing 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) induces biliary damage followed by hepatocyte injury, which is repaired through atypical ductular proliferation and oval cells and their subsequent differentiation to bile duct cells and hepatocytes. In this study, we examine whether excess β-catenin in transgenic (TG) mice would provide any reparative advantage in response to DDC. No differences in appearance or numbers of total A6-positive oval cells were observed after DDC administration. However, an increase in A6-positive "atypical hepatocytes" in the TG livers was observed after 14 and 28 days, coinciding with an increase in proliferating cell nuclear antigen-positive hepatocytes. Intriguingly, after chronic DDC administration for 150 days, a further increase in atypical hepatocytes was evident in TG mice, with higher numbers of proliferating cell nuclear antigen-positive hepatocytes exhibiting cytoplasmic/nuclear β-catenin and α-fetoprotein but not CK19, HNF1β, or Trop-2. Coincidently, we observed an improvement in intrahepatic cholestasis as seen by decreases in both serum bilirubin and alkaline phosphatase levels in TG mice, indicating an overall improvement in hepatic repair. TG mice exposed to DDC for 4 weeks followed by 2 days of normal chow showed decreases in alkaline phosphatase, atypical ductular proliferation, and periportal inflammation compared with wild-type animals, verifying improved biliary repair in TG livers. Thus, we report a potential role of β-catenin in liver repair, especially in enhancing the resolution of intrahepatic cholestasis after DDC injury.
Thompson
Michael D
MD
Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania 15216, USA.
Awuah
Prince
P
Singh
Sucha
S
Monga
Satdarshan P S
SP
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003997:Dicarbethoxydihydrocollidine / Q000633:toxicity*; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D008099:Liver / Q000187:drug effects* / Q000293:injuries / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D051176:beta Catenin / Q000502:physiology*
D051176:beta Catenin; D003997:Dicarbethoxydihydrocollidine
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