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.

Potential role of two novel agonists of thyroid hormone receptor‐β on liver regeneration

“…Our present data demonstrating a strong hepatomitogenic effect of IS25 and TG68 suggest that these compounds could be useful in regenerative medicine to manage conditions whereby a rapid liver regeneration is required, such as in the living‐related transplantation, or in the elderly status that is characterized by an impaired liver regenerative capacity 38,39 . Indeed, previous studies have shown that T3 and GC‐1 improved the regenerative response of rodent livers after 70% or 90% hepatectomy and stimulated liver cell proliferation in aged rats when given prior to—or after 70% PH 29,40‐42 …”

“…Our previous findings showed that T3 and two other analogues—Sobetirome and Eprotirome—exert a powerful mitogenic effect in the liver, suggesting their possible use in regenerative medicine 29,30 . Therefore, we investigated whether TG68 and IS25 could elicit a proliferative response in this organ as well.…”

Update on the Mechanisms of Liver Regeneration

“…Indeed, agents such as triiodothyronine or thyroid receptor-β agonists like GC-1 may have clinical applications in settings of hepatic insufficiency. 84–86 …”

Hepatoprotective effect of opioid peptides in stress

“…It is known that the process of liver regeneration after PHE is controlled by a whole cascade of growth factors, cytokines, transcription factors; however, the most important of them are hepatocyte growth factor (HGF), epidermal growth factor, transforming growth factor alpha, and angiogenic factors (Alvarado et al 2016, Beier et al 2016, Ibis et al 2017, Kirschbaum et al 2017, Lisman and Porte 2016. Hepatocyte growth factor plays a key role because it induces the transition of hepatocytes to the mitotic phase.…”