2026-09-24T02:10:33Zhttps://iris.unica.it/oai/request

oai:iris.unica.it:11584/2664462022-10-15T19:59:27Zcom_11584_207615com_11584_111066col_11584_265854

T3-induced hepatocyte proliferation requires β-catenin and is protein kinase A dependent FANTI, MAURA PKA T3 liver liver regeneration β-catenin Settore MED/04 - Patologia Generale 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 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-mediated 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. 2014-04-15 info:eu-repo/semantics/doctoralThesis http://hdl.handle.net/11584/266446 eng numberofpages:93 info:eu-repo/semantics/openAccess Università degli Studi di Cagliari license:Non specificato