title: Thyroid Hormone Receptor β Agonist Induces β-Catenin-Dependent Hepatocyte Proliferation in Mice: Implications in Hepatic Regeneration.
abstract: Triiodothyronine (T3) induces hepatocyte proliferation in rodents. Recent work has shown molecular mechanism for T3's mitogenic effect to be through activation of β-catenin signaling. Since systemic side effects of T3 may preclude its clinical use, and hepatocytes mostly express T3 hormone receptor β (TRβ), we investigated if selective TRβ agonists like GC-1 may also have β-catenin-dependent hepatocyte mitogenic effects. Here we studied the effect of GC-1 and T3 in conditional knockouts of various Wnt pathway components. We also assessed any regenerative advantage of T3 or GC-1 when given prior to partial hepatectomy in mice. Mice administered GC-1 showed increased pSer675-β-catenin, cyclin D1, BrdU incorporation, and PCNA. No abnormalities in liver function tests were noted. GC-1-injected liver-specific β-catenin knockouts (β-catenin LKO) showed decreased proliferation when compared to wild-type littermates. To address if Wnt signaling was required for T3- or GC-1-mediated hepatocyte proliferation, we used LRP5-6-LKO, which lacks the two redundant Wnt coreceptors. Surprisingly, decreased hepatocyte proliferation was also evident in LRP5-6-LKO in response to T3 and GC-1, despite increased pSer675-β-catenin. Further, increased levels of active β-catenin (hypophosphorylated at Ser33, Ser37, and Thr41) were evident after T3 and GC-1 treatment. Finally, mice pretreated with T3 or GC-1 for 7 days followed by partial hepatectomy showed a significant increase in hepatocyte proliferation both at the time (T0) and 24 h after surgery. In conclusion, like T3, TRβ-selective agonists induce hepatocyte proliferation through β-catenin activation via both PKA- and Wnt-dependent mechanisms and confer a regenerative advantage following surgical resection. Hence, these agents may be useful regenerative therapies in liver transplantation or other surgical settings.
authors.affiliation: Division of Gastroenterology, Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA.
authors.forename: Tamara Feliciano
authors.initials: TF
authors.lastname: Alvarado
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Puliga
authors.forename: Morgan
authors.initials: M
authors.lastname: Preziosi
authors.forename: Minakshi
authors.initials: M
authors.lastname: Poddar
authors.forename: Sucha
authors.initials: S
authors.lastname: Singh
authors.forename: Amedeo
authors.initials: A
authors.lastname: Columbano
authors.forename: Kari
authors.initials: K
authors.lastname: Nejak-Bowen
authors.forename: Satdarshan P S
authors.initials: SP
authors.lastname: Monga
mesh_terms: D000085:Acetates / Q000494:pharmacology*; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D006498:Hepatectomy / Q000379:methods; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008115:Liver Regeneration / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010636:Phenols / Q000494:pharmacology*; D037042:Thyroid Hormone Receptors beta / Q000819:agonists* / Q000378:metabolism; D014284:Triiodothyronine / Q000494:pharmacology*; D060449:Wnt Signaling Pathway / Q000187:drug effects; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D000085:Acetates; C413355:GC 1 compound; D010636:Phenols; D037042:Thyroid Hormone Receptors beta; D051176:beta Catenin; D014284:Triiodothyronine; D017868:Cyclic AMP-Dependent Protein Kinases