Tri-iodothyronine induces hepatocyte proliferation by protein kinase a-dependent β-catenin activation in rodents

Authors

  • Maura Fanti,

    1. Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA
    2. Department of Biomedical Sciences, University of Cagliari, Italy
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  • Sucha Singh,

    1. Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA
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  • Giovanna M. Ledda-Columbano,

    1. Department of Biomedical Sciences, University of Cagliari, Italy
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  • Amedeo Columbano,

    Corresponding author
    1. Department of Biomedical Sciences, University of Cagliari, Italy
    • Address reprint requests to: Satdarshan Pal Singh Monga, M.D., Endowed Chair, Vice Chair and Division Director of Experimental Pathology (EP), Professor of Pathology (EP) & Medicine (GI, Hepatology & Nutrition), University of Pittsburgh School of Medicine, 200 Lothrop Street S-422 BST, Pittsburgh, PA 15261. E-mail: smonga@pitt.edu; fax: 412-648-1916; or Amedeo Columbano, Ph.D., Department of Biomedical Sciences, Unit of Oncology and Molecular Pathology, University of Cagliari, Via Porcell 4, 09124 Cagliari, Italy. E-mail: columbano@unica.it; fax: +39-070-666062.

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  • Satdarshan P. Monga

    Corresponding author
    1. Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA
    • Address reprint requests to: Satdarshan Pal Singh Monga, M.D., Endowed Chair, Vice Chair and Division Director of Experimental Pathology (EP), Professor of Pathology (EP) & Medicine (GI, Hepatology & Nutrition), University of Pittsburgh School of Medicine, 200 Lothrop Street S-422 BST, Pittsburgh, PA 15261. E-mail: smonga@pitt.edu; fax: 412-648-1916; or Amedeo Columbano, Ph.D., Department of Biomedical Sciences, Unit of Oncology and Molecular Pathology, University of Cagliari, Via Porcell 4, 09124 Cagliari, Italy. E-mail: columbano@unica.it; fax: +39-070-666062.

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  • See Editorial on Page 2074

  • Potential conflict of interest: SPSM is a consultant for PhaseRx and Merck Pharmaceuticals.

  • This study was funded by NIH grants 1R01DK62277 and Endowed Chair for Experimental Pathology to SPSM; by Associazione Italiana Ricerca sul Cancro (IG-11821), Ministero Università e Ricerca Scientifica (PRIN 2010LC747T), and Regione Autonoma Sardegna (RAS 2012) to AC.

Abstract

Thyroid hormone (T3), like many other ligands of the steroid/thyroid hormone nuclear receptor superfamily, is a strong inducer of liver cell proliferation in rats and mice. However, the molecular basis of its mitogenic activity, which is currently unknown, must be elucidated if its use in hepatic regenerative medicine is to be considered. F-344 rats or C57BL/6 mice were fed a diet containing T3 for 2-7 days. In rats, administration of T3 led to an increased cytoplasmic stabilization and nuclear translocation of β-catenin in pericentral hepatocytes with a concomitant increase in cyclin-D1 expression. T3 administration to wild-type (WT) mice resulted in increased hepatocyte proliferation; however, no mitogenic response in hepatocytes to T3 was evident in the hepatocyte-specific β-catenin knockout mice (KO). In fact, T3 induced β-catenin-TCF4 reporter activity both in vitro and in vivo. Livers from T3-treated mice demonstrated no changes in Ctnnb1 expression, activity of glycogen synthase kinase-3β, known to phosphorylate and eventually promote β-catenin degradation, or E-cadherin-β-catenin association. However, T3 treatment increased β-catenin phosphorylation at Ser675, an event downstream of protein kinase A (PKA). Administration of PKA inhibitor during T3 treatment of mice and rats as well as in cell culture abrogated Ser675-β-catenin and simultaneously decreased cyclin-D1 expression to block hepatocyte proliferation. Conclusion: We have identified T3-induced hepatocyte mitogenic response to be mediated by PKA-dependent β-catenin activation. Thus, T3 may be of therapeutic relevance to stimulate β-catenin signaling to in turn induce regeneration in selected cases of hepatic insufficiency. (Hepatology 2014;59:2309–2320)

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