Guo Yajie, Yu Junjie, Deng Jiali, Liu Bin, Xiao Yuzhong, Li Kai, Xiao Fei, Yuan Feixiang, Liu Yong, Chen Shanghai, Guo Feifan
Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences, Shanghai, China.
Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences, Shanghai, China
Diabetes. 2016 Aug;65(8):2151-63. doi: 10.2337/db15-1565. Epub 2016 May 3.
Friend of GATA 2 (FOG2) is a transcriptional cofactor involved mostly in cardiac function. The aim of this study was to investigate the role of hepatic FOG2 in insulin sensitivity and lipid accumulation. FOG2 overexpression by adenovirus-expressing FOG2 (Ad-FOG2) significantly attenuates insulin signaling in hepatocytes in vitro. Opposite effects were observed when FOG2 was knocked down through adenovirus-expressing small hairpin RNA for FOG2 (Ad-shFOG2). Furthermore, FOG2 knockdown by Ad-shFOG2 ameliorated insulin resistance in leptin receptor-mutated (db/db) mice, and FOG2 overexpression by Ad-FOG2 attenuated insulin sensitivity in C57BL/6J wild-type (WT) mice. In addition, Ad-FOG2 reduced, whereas Ad-shFOG2 promoted, hepatic triglyceride (TG) accumulation in WT mice under fed or fasted conditions, which was associated with increased or decreased hepatic peroxisome proliferator-activated receptor α (PPARα) expression, respectively. Moreover, the improved insulin sensitivity and increased hepatic TG accumulation by Ad-shFOG2 were largely reversed by adenovirus-expressing PPARα (Ad-PPARα) in WT mice. Finally, we generated FOG2 liver-specific knockout mice and found that they exhibit enhanced insulin sensitivity and elevated hepatic TG accumulation, which were also reversed by Ad-PPARα. Taken together, the results demonstrate a novel function of hepatic FOG2 in insulin sensitivity and lipid metabolism through PPARα.
GATA 2之友（FOG2）是一种主要参与心脏功能的转录辅因子。本研究旨在探讨肝脏FOG2在胰岛素敏感性和脂质蓄积中的作用。通过表达FOG2的腺病毒（Ad-FOG2）使FOG2过表达，可显著减弱体外培养的肝细胞中的胰岛素信号传导。当通过表达针对FOG2的小发夹RNA的腺病毒（Ad-shFOG2）敲低FOG2时，观察到相反的效果。此外，Ad-shFOG2敲低FOG2可改善瘦素受体突变（db/db）小鼠的胰岛素抵抗，而Ad-FOG2使FOG2过表达则减弱C57BL/6J野生型（WT）小鼠的胰岛素敏感性。另外，在进食或禁食条件下，Ad-FOG2减少而Ad-shFOG2促进WT小鼠肝脏甘油三酯（TG）蓄积，这分别与肝脏过氧化物酶体增殖物激活受体α（PPARα）表达的减少或增加有关。此外，在WT小鼠中，表达PPARα的腺病毒（Ad-PPARα）在很大程度上逆转了Ad-shFOG2改善的胰岛素敏感性和增加的肝脏TG蓄积。最后，我们构建了肝脏特异性FOG2基因敲除小鼠，发现它们表现出增强的胰岛素敏感性和升高的肝脏TG蓄积，这也被Ad-PPARα逆转。综上所述，结果表明肝脏FOG2通过PPARα在胰岛素敏感性和脂质代谢中具有新功能。
