β‐Catenin is essential in normal liver growth, regeneration and function

Abstract

Wnt/β-catenin pathway has shown to be important in embryogenesis and carcinogenesis. In liver, it has been shown to play a role in development, growth and regeneration. The aim of the present study was to conditionally knockout β-catenin, a key component of the Wnt pathway. Floxed β-catenin mice (Ex2–6) were intercrossed with Albumin-Cre recombinase transgenic mice to knockout β-catenin in hepatocytes, which was obvious at 15-30 days after birth by western blot analysis and immunohistochemistry (IHC). While these mice were viable, there was a significant decrease in liver weight/body weight (LW/BW) ratio by 14% at 1 month and 28–35% by 2–6 months of age. There was an accompanying decrease in basal hepatocyte proliferation exhibited by Ki-67 staining. Additional analysis revealed several genes to be downregulated in these mice that play a role in normal liver homeostasis such as those involved in urea cycle, xenobiotic metabolism such as cytochrome P450 and glutathione transferases. When subjected to two-third partial hepatectomy, the Ctnnb1loxp/loxp; Alb-Cre+/− mice appeared lethargic and sicker especially during the first few days. These mice at 40 hours displayed a 3-fold decrease in the number of Ki-67-positive cells and PCNA at the time of peak hepatocyte proliferation in the wild-type mice. This was secondary to decreased expression of various cyclins including A, B, D, E, K and T, demonstrating a compromise in cell cycle. At 14 days after hepatectomy there was still double the number of Ki-67 positive hepatocytes in the knockout mice as compared to the wild-type indicating some continued regeneration. Thus β-catenin plays an important role in normal liver growth and development. In addition, loss of β-catenin blunts and compromises normal liver regeneration. (Supported by RSG-03-141-CNE and NIH-1RO1DK62277 to SPSM)