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 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.

P2Y2 purinergic receptor activation is essential for efficient hepatocyte proliferation in response to partial hepatectomy

“…Key molecular mediators of upstream of ␤-catenin activation in regenerating livers are not well understood; however, both Wnt-dependent and Wnt-independent activation have been implicated (49). Recent studies have identified that growth factor-mediated activation of receptor tyrosine kinases (HGF, EGF) and activation of protein kinase A (thyroid hormone) regulate ␤-catenin activation via phosphorylation at specific residues (21,49,75).…”

Liver regeneration — mechanisms and models to clinical application

“…The mechanism of this effect was not established, although the study authors specu lated that GCSF might improve neutrophil function, which is commonly diminished in the setting of chronic liver disease. Thyroid hormone (T 3 ) has been demon strated to be a strong inducer of liver cell proliferation in rats and mice 10 , and studies have shown that the hepato cyte mitogenic response is mediated by PKAdependent βcatenin activation 129 . Enthusiasm for T 3 is reinforced by the observation that its administration helps inhibit and/or reverse NAFLD 130 and reduces the risk of hepatic tumour development in rat models 131 .…”

β-Catenin Signaling and Roles in Liver Homeostasis, Injury, and Tumorigenesis

“…39 PKA activation was required for triiodothyronine-induced activation of β -catenin, expression of cyclin D1, and proliferation of hepatocytes. 40 Recently, phosphorylation of β -catenin at S675 was shown to mediate fibrocystin-defective congenital hepatic fibrosis in mice. 41 …”