KLF15‐activating Twist2 ameliorated hepatic steatosis by inhibiting inflammation and improving mitochondrial dysfunction via NF‐κB‐FGF21 or SREBP1c‐FGF21 pathway
KLF15‐activating Twist2 ameliorated hepatic steatosis by inhibiting inflammation and improving mitochondrial dysfunction via NF‐κB‐FGF21 or SREBP1c‐FGF21 pathway
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DOI：
10.1096/fj.201901347rr
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发表时间：
2019-10
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影响因子：
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通讯作者：
Lulu Zhou;Qinjin Li;Ao Chen;Na Liu;N. Chen;Xiaojun Chen;Lin Zhu;Benzeng Xia;Yuqing Gong;Xiao-dong Chen
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作者：
Lulu Zhou;Qinjin Li;Ao Chen;Na Liu;N. Chen;Xiaojun Chen;Lin Zhu;Benzeng Xia;Yuqing Gong;Xiao-dong Chen
扭曲相关蛋白 2 (TWIST2) 通过与其他 b-HLH 蛋白二聚化而被鉴定为基本螺旋-环-螺旋 (b-HLH) 转录抑制蛋白。 TWIST2在多种肿瘤中的重要性已被强调；然而，很少有研究报道其在代谢和代谢疾病中的作用。本研究旨在探讨TWIST2在肝脂肪变性中的新作用和调控机制。我们的结果表明，Twist2 敲低导致小鼠肥胖、胰岛素抵抗和肝脂肪变性，并伴有炎症、内质网应激和线粒体功能障碍。在体外，TWIST2 过表达可改善肝细胞脂肪变性，抑制炎症，并以成纤维细胞生长因子 21 (FGF21) 依赖性模式改善线粒体含量和功能。 NF-κB 通过直接结合 FGF21 启动子 DNA 负向调节 FGF21 转录，而 TWIST2 过表达通过抑制 NF-κB 表达和易位至细胞核来消除 FGF21 转录。 TWIST2 过表达降低了细胞内活性氧水平，增加了线粒体 DNA 和生物发生，并增强了 ATP 产生和抗氧化能力。此外，TWIST2 的表达受到胰岛素靶向甾醇调节元件结合蛋白 1c (SREBP1c) 和叉头盒蛋白 O1 的抑制，并被靶向 Krüppel 样因子 15 的地塞米松增强，该因子直接与 Twist2 启动子 DNA 相互作用。总之，我们的研究确定了 TWIST2 通过 NF-κB-FGF21 或 SREBP1c-FGF21 通路改善脂肪变性、炎症和氧化应激来维持肝脏稳态的重要作用和调节机制，这可能为非酒精性脂肪肝疾病提供新的治疗方案。-Zhou, L., Li, Q., Chen, A., Liu, N., Chen, N., Chen, X., Zhu, L., Xia, B.、Gong, Y.、Chen, X. KLF15 激活 Twist2 通过 NF-κB-FGF21 或 SREBP1c-FGF21 途径抑制炎症和改善线粒体功能障碍，从而改善肝脂肪变性。 FASEB J. 33, 14254-14269 (2019)。 www.fasebj.org
Twist‐related protein 2 (TWIST2) is identified as a basic helix‐loop‐helix (b‐HLH) transcription repressor by dimerizing with other b‐HLH proteins. The significance of TWIST2 has been emphasized in various tumors; however, few studies report its functions in metabolism and metabolic diseases. Here we aimed to explore the novel role and regulation mechanism of TWIST2 in hepatic steatosis. Our results showed that Twist2 knockdown caused mice obesity, insulin resistance, and hepatic steatosis, which were accompanied with inflammation, endoplasmic reticulum stress, and mitochondrial dysfunction. In vitro, TWIST2 overexpression ameliorated hepatocellular steatosis, inhibited inflammation, and improved mitochondrial content and function with a fibroblast growth factor 21 (FGF21)‐dependent pattern. NF‐κB negatively regulated FGF21 transcription by directly binding to FGF21 promoter DNA, which was eliminated by TWIST2 overexpression by inhibiting NF‐κB expression and translocation to nucleus. TWIST2 overexpression decreased intracellular reactive oxygen species level, increased mitochondrial DNA and biogenesis, and enhanced ATP production and antioxidation ability. Additionally, TWIST2 expression was repressed by insulin‐targeting sterol regulatory element‐binding protein 1c (SREBP1c) and forkhead box protein O1 and was enhanced by dexamethasone targeting Krüppel‐like factor 15, which directly interacted with Twist2 promoter DNA. Together, our studies identify an important role and regulation mechanism of TWIST2 in maintaining hepatic homeostasis by ameliorating steatosis, inflammation, and oxidative stress via the NF‐κB‐FGF21 or SREBP1c‐FGF21 pathway, which may provide a new therapeutic scheme for nonalcoholic fatty liver disease.—Zhou, L., Li, Q., Chen, A., Liu, N., Chen, N., Chen, X., Zhu, L., Xia, B., Gong, Y., Chen, X. KLF15‐activating Twist2 ameliorated hepatic steatosis by inhibiting inflammation and improving mitochondrial dysfunction via NF‐κB‐FGF21 or SREBP1c‐FGF21 pathway. FASEB J. 33, 14254‐14269 (2019). www.fasebj.org