Tajima-Shirasaki Natsumi, Ishii Kiyo-Aki, Takayama Hiroaki, Shirasaki Takayoshi, Iwama Hisakazu, Chikamoto Keita, Saito Yoshiro, Iwasaki Yasumasa, Teraguchi Atsushi, Lan Fei, Kikuchi Akihiro, Takeshita Yumie, Murao Koji, Matsugo Seiichi, Kaneko Shuichi, Misu Hirofumi, Takamura Toshinari
From the Departments of Endocrinology and Metabolism.
System Biology, and.
J Biol Chem. 2017 Jun 30;292(26):10791-10800. doi: 10.1074/jbc.M116.747006. Epub 2017 May 2.
Selenoprotein P (encoded by in humans, in rat), a liver-derived secretory protein, induces resistance to insulin and vascular endothelial growth factor (VEGF) in type 2 diabetes. Suppression of selenoprotein P may provide a novel therapeutic approach to treating type 2 diabetes; however, few drugs inhibiting expression in hepatocytes have been identified. The present findings demonstrate that eicosapentaenoic acid (EPA) suppresses expression by inactivating sterol regulatory element-binding protein-1c (SREBP-1c, encoded by in rat) in H4IIEC3 hepatocytes. Treatment with EPA caused concentration- and time-dependent reduction in promoter activity. EPA activated AMP-activated protein kinase (AMPK); however, the inhibitory effect of EPA on promoter activity was not canceled with an AMPK inhibitor compound C and dominant-negative AMPK transfection. Deletion mutant promoter assays and computational analysis of transcription factor-binding sites conserved among the species resulted in identification of a sterol regulatory element (SRE)-like site in the promoter. A chromatin immunoprecipitation (ChIP) assay revealed that EPA decreases binding of SREBP-1c to the promoter. Knockdown of resulted in a significant down-regulation of expression. Conversely, SREBP-1c overexpression inhibited the suppressive effect of EPA. These data provide a novel mechanism of action for EPA involving improvement of systemic insulin sensitivity through the regulation of selenoprotein P production independently of the AMPK pathway and suggest an additional approach to developing anti-diabetic drugs.
硒蛋白P（人类中由 编码，大鼠中由 编码）是一种肝脏来源的分泌蛋白，在2型糖尿病中可诱导对胰岛素和血管内皮生长因子（VEGF）的抵抗。抑制硒蛋白P可能为治疗2型糖尿病提供一种新的治疗方法；然而，很少有能抑制肝细胞中 表达的药物被发现。目前的研究结果表明，二十碳五烯酸（EPA）通过使H4IIEC3肝细胞中的固醇调节元件结合蛋白-1c（SREBP-1c，大鼠中由 编码）失活来抑制 表达。用EPA处理导致 启动子活性呈浓度和时间依赖性降低。EPA激活了AMP活化蛋白激酶（AMPK）；然而，EPA对 启动子活性的抑制作用并未被AMPK抑制剂化合物C和显性负性AMPK转染所消除。缺失突变启动子分析以及对物种间保守的转录因子结合位点的计算分析，在 启动子中鉴定出一个类似固醇调节元件（SRE）的位点。染色质免疫沉淀（ChIP）分析表明，EPA减少了SREBP-1c与 启动子的结合。敲低 导致 表达显著下调。相反，SREBP-1c过表达抑制了EPA的抑制作用。这些数据为EPA提供了一种新的作用机制，即通过独立于AMPK途径调节硒蛋白P的产生来改善全身胰岛素敏感性，并提示了一种开发抗糖尿病药物的额外方法。
