Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, Department of Basic Veterinary Medicine, College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, Hubei Province, PR China.
Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, College of Life Science and Technology, Huazhong Agricultural University, Wuhan 430070, Hubei Province, PR China.
Biochim Biophys Acta Mol Cell Biol Lipids. 2018 May;1863(5):538-548. doi: 10.1016/j.bbalip.2018.02.003. Epub 2018 Feb 25.
The fat mass and obesity-associated (FTO) gene is tightly related to body weight and fat mass, and plays a pivotal role in regulating lipid accumulation in hepatocytes. However, the mechanisms underlying its function are poorly understood. Sterol regulatory element binding protein-1c (SREBP1c) is a transcription factor that regulates lipogenesis. Cell death-inducing DFFA (DNA fragmentation factor-α)-like effector c (CIDEC) plays a crucial role in lipid droplets (LDs) size controlling and lipid accumulation. In this report, we first observed that FTO overexpression in HepG2 cells resulted in an increase of lipogenesis and up-regulation of SREBP1c and CIDEC, two key regulatory factors in lipogenesis. In contrast, FTO knockdown in HepG2 cells resulted in a decrease of lipogenesis and down-regulation of SREBP1c and CIDEC expression. Moreover, SREBP1c knockdown resulted in a decrease of lipogenesis in HepG2 cells with FTO overexpression. In addition, FTO demethylation defect mutant presented less transcription of the key genes, and less nuclear translocation and maturation of SREBP1c. Further investigation demonstrated that overexpression of SREBP1c in HepG2 cells also promoted high CIDEC expression. Luciferase reporter assays showed that SREBP1c significantly stimulated CIDEC gene promoter activity. Finally, CIDEC knockdown reduced SREBP1c-induced lipogenesis. In conclusion, our studies suggest that FTO increased the lipid accumulation in hepatocytes by increasing nuclear translocation of SREBP1c and SREBP1c maturation, thus improving the transcriptional activity of LD-associated protein CIDEC. Our studies may provide new mechanistic insight into nonalcoholic fatty liver disease (NAFLD) mediated by FTO.
肥胖相关基因（FTO）与体重和体脂密切相关，在调节肝细胞脂质积累方面发挥着关键作用。然而，其作用机制尚不清楚。固醇调节元件结合蛋白-1c（SREBP1c）是一种调节脂肪生成的转录因子。细胞死亡诱导 DFFA（DNA 片段化因子-α）样效应因子 c（CIDEC）在控制脂滴（LDs）大小和脂质积累方面起着至关重要的作用。在本报告中，我们首先观察到，FTO 在 HepG2 细胞中的过表达导致脂肪生成增加，并上调了 SREBP1c 和 CIDEC，这是脂肪生成的两个关键调节因子。相反，FTO 在 HepG2 细胞中的敲低导致脂肪生成减少和 SREBP1c 和 CIDEC 表达下调。此外，SREBP1c 的敲低导致 FTO 过表达的 HepG2 细胞中的脂肪生成减少。此外，FTO 去甲基化缺陷突变体的关键基因转录减少，SREBP1c 的核易位和成熟减少。进一步的研究表明，SREBP1c 在 HepG2 细胞中的过表达也促进了 CIDEC 的高表达。荧光素酶报告基因分析表明，SREBP1c 显著刺激 CIDEC 基因启动子活性。最后，CIDEC 的敲低减少了 SREBP1c 诱导的脂肪生成。总之，我们的研究表明，FTO 通过增加 SREBP1c 的核易位和成熟来增加肝细胞中的脂质积累，从而提高与 LD 相关的蛋白 CIDEC 的转录活性。我们的研究可能为肥胖相关的非酒精性脂肪性肝病（NAFLD）提供新的机制见解。
