| First Author | Fanti M | Year | 2014 |
| Journal | Hepatology | Volume | 59 |
| Issue | 6 | Pages | 2309-20 |
| PubMed ID | 24122933 | Mgi Jnum | J:318235 |
| Mgi Id | MGI:6858879 | Doi | 10.1002/hep.26775 |
| Citation | Fanti M, et al. (2014) Tri-iodothyronine induces hepatocyte proliferation by protein kinase A-dependent beta-catenin activation in rodents. Hepatology 59(6):2309-20 |
| abstractText | UNLABELLED: 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 beta-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 beta-catenin knockout mice (KO). In fact, T3 induced beta-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-3beta, known to phosphorylate and eventually promote beta-catenin degradation, or E-cadherin-beta-catenin association. However, T3 treatment increased beta-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-beta-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 beta-catenin activation. Thus, T3 may be of therapeutic relevance to stimulate beta-catenin signaling to in turn induce regeneration in selected cases of hepatic insufficiency. |
