Department of Medicine, Columbia University, New York, New York 10032, USA.
J Biol Chem. 2010 Nov 12;285(46):35245-8. doi: 10.1074/jbc.C110.175851. Epub 2010 Sep 29.
Hepatic glucose production (HGP) plays a vital role in maintaining the supply of glucose to the body, and transcription factor FoxO1 is known to confer hormone responsiveness onto HGP. Mice with a liver-specific FoxO1 deletion (L-FoxO1) show reduced HGP and reduced expression of glucose production genes. To determine the contribution of additional transcription factors to HGP, we created double and triple liver-specific knock-outs lacking FoxO1, FoxO3, and FoxO4 or the related protein FoxA2. We show that, when compared with single knock-out of FoxO1, triple ablation of FoxO genes causes more pronounced fasting hypoglycemia, increased glucose tolerance, and enhanced insulin sensitivity, with decreased plasma insulin levels. In contrast, combined ablation of FoxO1 and FoxA2 phenocopied the single knock-out of FoxO1. These data indicate that FoxOs work in concert to regulate multiple aspects of hepatic glucose metabolism.
肝脏葡萄糖生成 (HGP) 在维持身体葡萄糖供应方面发挥着至关重要的作用，已知转录因子 FoxO1 可使 HGP 对激素产生反应。肝脏特异性 FoxO1 缺失 (L-FoxO1) 的小鼠表现出 HGP 降低和葡萄糖生成基因表达降低。为了确定其他转录因子对 HGP 的贡献，我们创建了缺乏 FoxO1、FoxO3 和 FoxO4 或相关蛋白 FoxA2 的双重和三重肝脏特异性敲除小鼠。我们发现，与 FoxO1 的单一敲除相比，FoxO 基因的三重缺失导致更明显的空腹低血糖、葡萄糖耐量增加和胰岛素敏感性增强，同时血浆胰岛素水平降低。相比之下，FoxO1 和 FoxA2 的联合缺失模拟了 FoxO1 的单一敲除。这些数据表明 FoxOs 协同作用以调节肝脏葡萄糖代谢的多个方面。
