title: Tri-iodothyronine induces hepatocyte proliferation by protein kinase A-dependent β-catenin activation in rodents.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA; Department of Biomedical Sciences, University of Cagliari, Italy.
authors.forename: Maura
authors.initials: M
authors.lastname: Fanti
authors.forename: Sucha
authors.initials: S
authors.lastname: Singh
authors.forename: Giovanna M
authors.initials: GM
authors.lastname: Ledda-Columbano
authors.forename: Amedeo
authors.initials: A
authors.lastname: Columbano
authors.forename: Satdarshan P
authors.initials: SP
authors.lastname: Monga
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology*; D019938:Cyclin D1 / Q000378:metabolism; D048550:Hepatic Insufficiency / Q000188:drug therapy / Q000473:pathology; D022781:Hepatocytes / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D008115:Liver Regeneration / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051381:Rats; D011916:Rats, Inbred F344; D015398:Signal Transduction / Q000502:physiology; D014284:Triiodothyronine / Q000502:physiology* / Q000627:therapeutic use; D051176:beta Catenin / Q000378:metabolism* / Q000502:physiology
chemical_list: D051176:beta Catenin; D014284:Triiodothyronine; D019938:Cyclin D1; D017868:Cyclic AMP-Dependent Protein Kinases