TAZ inhibits glucocorticoid receptor and coordinates hepatic glucose homeostasis in normal physiological states.
TAZ inhibits glucocorticoid receptor and coordinates hepatic glucose homeostasis in normal physiological states.
复制标题
TAZ 抑制糖皮质激素受体并协调正常生理状态下的肝脏葡萄糖稳态。
作者：
Xu S;Liu Y;Hu R;Wang M;Stöhr O;Xiong Y;Chen L;Kang H;Zheng L;Cai S;He L;Wang C;Copps KD;White MF;Miao J
阐明肝脏维持葡萄糖稳态的机制对于理解生理和病理状态至关重要。在这里，我们显示了一个新的作用，肝脏转录辅激活剂与PDZ结合基序（TAZ）在抑制糖皮质激素受体（GR）。TAZ在中央周围肝细胞中大量表达，并且其表达通过禁食显著降低。TAZ通过其WW结构域与GR的配体结合结构域相互作用，以限制GR与致突变基因启动子中的GR反应元件的结合。因此，肝脏特异性TAZ敲除小鼠显示葡萄糖产生和血糖浓度增加。相反，TAZ在小鼠肝脏中的过表达减少了GR与致炎基因启动子的结合和葡萄糖的产生。因此，我们的研究结果表明，肝TAZ抑制GR反式激活的促性腺激素基因和协调促性腺激素在响应生理禁食和喂养。
The elucidation of the mechanisms whereby the liver maintains glucose homeostasis is crucial for the understanding of physiological and pathological states. Here, we show a novel role of hepatic transcriptional co-activator with PDZ-binding motif (TAZ) in the inhibition of glucocorticoid receptor (GR). TAZ is abundantly expressed in pericentral hepatocytes and its expression is markedly reduced by fasting. TAZ interacts via its WW domain with the ligand-binding domain of GR to limit the binding of GR to the GR response element in gluconeogenic gene promoters. Therefore, liver-specific TAZ knockout mice show increases in glucose production and blood glucose concentration. Conversely, the overexpression of TAZ in mouse liver reduces the binding of GR to gluconeogenic gene promoters and glucose production. Thus, our findings demonstrate that hepatic TAZ inhibits GR transactivation of gluconeogenic genes and coordinates gluconeogenesis in response to physiological fasting and feeding.