FTO promotes SREBP1c maturation and enhances CIDEC transcription during lipid accumulation in HepG2 cells
FTO promotes SREBP1c maturation and enhances CIDEC transcription during lipid accumulation in HepG2 cells
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FTO 在 HepG2 细胞脂质积累过程中促进 SREBP1c 成熟并增强 CIDEC 转录
DOI：
10.1016/j.bbalip.2018.02.003
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发表时间：
2018-05-01
影响因子：
4.8
通讯作者：
Liu, Guoquan
中科院分区：
文献类型：
--
作者：
Chen, Ao;Chen, Xiaodong;Liu, Guoquan
脂肪量和肥胖相关（FTO）基因与体重和脂肪量密切相关，在调节肝细胞脂质积累中发挥着关键作用。然而，人们对其功能背后的机制知之甚少。甾醇调节元件结合蛋白-1c (SREBP1c) 是调节脂肪生成的转录因子。细胞死亡诱导 DFFA（DNA 碎片因子-α）样效应子 c (CIDEC) 在脂滴 (LD) 大小控制和脂质积累中发挥着至关重要的作用。在本报告中，我们首先观察到 HepG2 细胞中 FTO 过表达导致脂肪生成增加以及 SREBP1c 和 CIDEC（脂肪生成中的两个关键调节因子）的上调。相比之下，HepG2 细胞中的 FTO 敲低导致脂肪生成减少以及 SREBP1c 和 CIDEC 表达下调。此外，SREBP1c 敲低导致 FTO 过表达的 HepG2 细胞脂肪生成减少。此外，FTO去甲基化缺陷突变体的关键基因转录减少，SREBP1c核转位和成熟减少。进一步研究表明，HepG2 细胞中 SREBP1c 的过度表达也促进了 CIDEC 的高表达。荧光素酶报告基因检测显示 SREBP1c 显着刺激 CIDEC 基因启动子活性。最后，CIDEC 敲除减少了 SREBP1c 诱导的脂肪生成。总之，我们的研究表明，FTO 通过增加 SREBP1c 的核转位和 SREBP1c 成熟来增加肝细胞中的脂质积累，从而提高 LD 相关蛋白 CIDEC 的转录活性。我们的研究可能为 FTO 介导的非酒精性脂肪性肝病 (NAFLD) 提供新的机制见解。
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-alpha)-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.