Thyroid Hormone Receptor β Agonist Induces β-Catenin-Dependent Hepatocyte Proliferation in Mice: Implications in Hepatic Regeneration.
Thyroid Hormone Receptor β Agonist Induces β-Catenin-Dependent Hepatocyte Proliferation in Mice: Implications in Hepatic Regeneration.
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DOI：
10.3727/105221616x691631
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发表时间：
2016
期刊：
影响因子：
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通讯作者：
Monga SP
中科院分区：
文献类型：
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作者：
Alvarado TF;Puliga E;Preziosi M;Poddar M;Singh S;Columbano A;Nejak-Bowen K;Monga SP
三碘甲状腺原氨酸（T3）诱导啮齿动物肝细胞增殖。最近的研究表明，T3的有丝分裂作用的分子机制是通过激活β-catenin信号传导。由于T3的全身副作用可能阻碍其临床应用，并且肝细胞主要表达T3激素受体β (TRβ)，我们研究了选择性TRβ激动剂如GC-1是否也可能具有β-连环蛋白依赖的肝细胞有丝分裂作用。在这里，我们研究了GC-1和T3在条件敲除各种Wnt通路成分中的作用。我们还评估了在小鼠部分肝切除术前给予T3或GC-1的任何再生优势。给予GC-1的小鼠显示pSer675-β-catenin， cyclin D1， BrdU掺入和PCNA增加。肝功能检查未见异常。gc -1注射的肝脏特异性β-catenin敲除（β-catenin LKO）与野生型幼崽相比，增殖减少。为了确定T3或gc -1介导的肝细胞增殖是否需要Wnt信号，我们使用了缺乏两个冗余Wnt辅助受体的LRP5-6-LKO。令人惊讶的是，尽管pSer675-β-catenin增加，但在T3和GC-1的作用下，LRP5-6-LKO中肝细胞增殖也明显减少。此外，在T3和GC-1治疗后，活性β-catenin （Ser33、Ser37和Thr41处低磷酸化）水平明显升高。最后，用T3或GC-1预处理7天后进行部分肝切除术的小鼠，在手术时（T0）和术后24小时，肝细胞增殖均显著增加。总之，与T3一样，tr β选择性激动剂通过PKA-和wnt依赖机制通过β-catenin激活诱导肝细胞增殖，并赋予手术切除后的再生优势。因此，这些药物可能是肝移植或其他手术环境中有用的再生疗法。
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.