GATA助手蛋白2（FOG2）对胰岛素敏感性和肝脏脂质代谢的调节作用

Type 2 diabetes (T2D) and nonalcoholic fatty liver disease (NAFLD) threaten human life more and more these days. Although many factors are reported to induce insulin resistance and lipid dysregulation, such as genetic factors and lifestyle changes, the underlying mechanisms of T2D and NAFLD are still unknown. Friend of GATA 2 (FOG2) is a transcriptional factor regulator, playing an important role in maintaining cardiac function and coronary vasculature. However, the function of FOG2 in the regulation of insulin sensitivity and lipid metabolism remains largely unknown. Our preliminary results showed that FOG2 regulates insulin sensitivity in vitro. Meanwhile, over-expression of FOG2 in mice via tail vein injection induces insulin resistance and reduces lipid accumulation. Therefore, we suspect that FOG2 plays an important role in the regulation of insulin sensitivity and lipid metabolism. In our current project, we will explore the role of FOG2 in regulating insulin sensitivity and lipid metabolism by using adenovirus over-expressing or knocking down FOG2, as well as FOG2 liver specific knock out mice. The molecular mechanisms underlying FOG2 regulated insulin sensitivity and lipid metabolism will be further delineated basing on our mature experimental methods. Except for that, we will also examine the potential possibility of FOG2 in the prevention and treatment of T2D and NAFLD. The results of this project will reveal a novel function of FOG2, and provide new insight in the study of insulin sensitivity and lipid metabolism.

2型糖尿病和非酒精性脂肪肝严重危害人类健康，其发生与遗传因素和生活方式密切相关，阐明其发病机制是亟需解决的科学问题。GATA助手蛋白2（Friend of GATA 2, FOG2）是一类转录因子调节因子，主要在维持心脏功能及冠状动脉发生方面起重要作用，在胰岛素敏感性及肝脏脂质代谢方面的作用尚无报道。申请人前期结果表明FOG2在细胞水平可以调节胰岛素敏感性，并且在野生型小鼠中过表达FOG2会引起胰岛素抵抗，减少脂滴聚集，故推测FOG2是调节机体胰岛素敏感性与脂代谢的重要因子。本项目将利用腺病毒表达系统和FOG2肝脏特异性敲除小鼠结合成熟的胰岛敏感性和脂质代谢技术平台，对FOG2在胰岛素敏感性和脂质代谢方面的的作用及分子机制进行研究，并探究FOG2作为防治2型糖尿病和非酒精性脂肪肝靶标的潜在应用价值。其成果将丰富人们对FOG2生理功能的认识，为研究胰岛素敏感性和脂质代谢提供新的思路和实验依据

FOG2作为转录共调节因子，参与心脏等器官的发育调控，然而其在代谢领域的功能还知之甚少，所以本文研究的主要目的是探索肝脏FOG2在胰岛素敏感性和脂质代谢方面的作用。我们发现，利用腺病毒技术在细胞水平过表达FOG2之后可以显著减弱细胞的胰岛素敏感性。反之，利用干扰腺病毒技术敲低细胞FOG2的表达可以显著提高细胞的胰岛素敏感性。另外，降低胰岛素抵抗db/db小鼠肝脏FOG2的表达可以显著的缓解小鼠的胰岛素抵抗，而向野生型小鼠中注射过表达FOG2腺病毒则可以明显的减弱小鼠的胰岛素敏感性，引起小鼠的胰岛素抵抗现象。除此之外，我们还发现FOG2可以调控肝脏脂质代谢，具体表现为，不论在饥饿还是饱腹状态下，过表达FOG2可以显著的减少小鼠肝脏的脂质积累，而干扰FOG2之后又可以显著的增加小鼠肝脏的脂质积累。进一步的实验发现肝脏FOG2对脂质调控的作用是通过正调控PPARα实现的。在野生型小鼠中过表达PPARα之后可以显著的减弱敲低FOG2所导致的胰岛素敏感性的增强及肝脏脂质积累增多的现象。最后，我们构建了FOG2肝脏特异敲除的小鼠，发现这些小鼠表现出胰岛素敏感性增强和肝脏脂质积累增多的现象，而这些现象同样可以被过表达PPARα所回复。综合来说，我们发现了肝脏FOG2在调控胰岛素敏感性及脂质代谢方面的新功能，而且这种调控作用是依赖于PPARα所介导的。