See Editorial on Page 2074
Tri-iodothyronine induces hepatocyte proliferation by protein kinase a-dependent β-catenin activation in rodents
Article first published online: 14 APR 2014
© 2014 by the American Association for the Study of Liver Diseases
Volume 59, Issue 6, pages 2309–2320, June 2014
How to Cite
Fanti, M., Singh, S., Ledda-Columbano, G. M., Columbano, A. and Monga, S. P. (2014), Tri-iodothyronine induces hepatocyte proliferation by protein kinase a-dependent β-catenin activation in rodents. Hepatology, 59: 2309–2320. doi: 10.1002/hep.26775
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.
- Issue published online: 28 MAY 2014
- Article first published online: 14 APR 2014
- Accepted manuscript online: 7 OCT 2013 03:57PM EST
- Manuscript Accepted: 25 SEP 2013
- Manuscript Received: 2 AUG 2013
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)