Department of Endocrinology, Clinical Medical College of Yangzhou University, Yangzhou, China.
Department of Enphrology, Clinical Medical College of Yangzhou University, Yangzhou, China.
Cell Death Dis. 2018 Feb 19;9(3):289. doi: 10.1038/s41419-018-0321-7.
Long non-coding RNA Gomafu is involved in diabetes-related diseases. However, its role in insulin resistance (IR) remains unclear. Our objective is to explore the role of Gomafu in hepatic IR and glucose intolerance. Gomafu expression was determined in livers of ob/ob mice and high-fat diet (HFD) mice. The binding activity of NF-κB on the Gomafu promoter was measured by chromatin immunoprecipitation and quantitative real-time PCR assays. Increased Gomafu expression was observed in the livers of obese mice. Besides, the binding of NF-κB on the Gomafu promoter was also observed in hepatocytes from ob/ob mice. Further study showed that knockdown of NF-κB p65 alleviated the increase in hepatic Gomafu expression in vivo and in vitro. Knockdown of hepatic Gomafu inhibited hepatic glucose production (HGP) and improved insulin sensitivity in obese mice, whereas, overexpression of hepatic Gomafu resulted in an increase in random and fasting blood glucose levels in lean mice. In addition, we demonstrated that Gomafu functioned as miR-139 sponge and led to the de-repression of its target gene Foxo1, which played an important role in gluconeogenesis and HGP in hepatocytes. Finally, silenced Foxo1 expression abolished the effect of Gomafu overexpression on gluconeogenesis and glucose production in hepatocytes. Taken together, our data suggested that the increase in Gomafu expression contributed to hepatic IR in obese mice.
长链非编码 RNA Gomafu 与糖尿病相关疾病有关。然而，其在胰岛素抵抗（IR）中的作用尚不清楚。我们的目的是探讨 Gomafu 在肝 IR 和葡萄糖耐量异常中的作用。测定 ob/ob 小鼠和高脂肪饮食（HFD）小鼠肝脏中的 Gomafu 表达。通过染色质免疫沉淀和实时定量 PCR 测定测定 NF-κB 对 Gomafu 启动子的结合活性。肥胖小鼠肝脏中观察到 Gomafu 表达增加。此外，还观察到 ob/ob 小鼠肝细胞中 NF-κB 结合在 Gomafu 启动子上。进一步的研究表明，NF-κB p65 的敲低减轻了体内和体外肝 Gomafu 表达的增加。肝 Gomafu 的敲低抑制肥胖小鼠的肝葡萄糖生成（HGP）并改善胰岛素敏感性，而肝 Gomafu 的过表达导致瘦小鼠的随机和空腹血糖水平升高。此外，我们证明 Gomafu 作为 miR-139 的海绵，并导致其靶基因 Foxo1 的去抑制，Foxo1 在肝细胞中的糖异生和 HGP 中起重要作用。最后，沉默 Foxo1 表达消除了 Gomafu 过表达对肝细胞中糖异生和葡萄糖生成的影响。总之，我们的数据表明，Gomafu 表达的增加导致肥胖小鼠的肝 IR。
