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β‐Catenin is essential in normal liver growth, regeneration and function
Author(s) -
Tan Xinping,
Monga Satdarshan P. S.
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a1090-a
Subject(s) - liver regeneration , wnt signaling pathway , biology , medicine , endocrinology , hepatocyte , andrology , proliferating cell nuclear antigen , cell growth , regeneration (biology) , microbiology and biotechnology , signal transduction , biochemistry , in vitro
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 Ctnnb1 loxp/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)