Liver-specific loss of β-catenin results in delayed hepatocyte proliferation after partial hepatectomy

Authors

  • Shigeki Sekine,

    1. Diabetes Center, Department of Medicine, Division of Transplantation, University of California San Francisco, San Francisco, CA 94143
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  • Pedro J. A. Gutiérrez,

    1. Diabetes Center, Department of Medicine, Division of Transplantation, University of California San Francisco, San Francisco, CA 94143
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  • Billy Yu-Ang Lan,

    1. Department of Surgery, Division of Transplantation, University of California San Francisco, San Francisco, CA 94143
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  • Sandy Feng,

    1. Department of Surgery, Division of Transplantation, University of California San Francisco, San Francisco, CA 94143
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  • Matthias Hebrok

    Corresponding author
    1. Diabetes Center, Department of Medicine, Division of Transplantation, University of California San Francisco, San Francisco, CA 94143
    • Diabetes Center, Department of Medicine, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143-0573
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    • fax: 415-564-5813.


  • Potential conflict of interest: Nothing to report.

Abstract

Recent studies have suggested that β-catenin is involved in the regulation of hepatocyte proliferation in multiple contexts, including organ development and tumorigenesis. We explored the role of β-catenin during liver regeneration using T cell factor/lymphoid enhancer factor (TCF/LEF)-reporter mice (TOPGal mice) and liver-specific β-catenin knockout mice. Liver-specific β-catenin knockout mice showed a delayed onset of DNA synthesis after hepatectomy, whereas recovery of liver mass was not affected. Among putative β-catenin target genes examined, the induction of Ccnd1 expression was reduced, whereas the expression of Myc and Egfr was unaffected. Furthermore, cyclin D1 protein levels were not induced, and the expression of cyclins A, E, and proliferating cell nuclear antigen was delayed. Intriguingly, the analysis of TOPGal mice showed that hepatocytes with active TCF/LEF transcription are confined to the pericentral zone and are not increased in number during regeneration, indicating an uncoupling between β-catenin/TCF signaling activity and hepatocyte proliferation. Conclusion: Our results indicate that β-catenin is critical for the proper regulation of hepatocyte proliferation during liver regeneration; however, the activity of β-catenin/TCF signaling does not correlate with hepatocyte proliferation, suggesting that this regulation might be indirect/secondary. (HEPATOLOGY 2007;45:361–368.)

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