Baicalein stimulates fibroblast growth factor 21 expression by up-regulating retinoic acid receptor-related orphan receptor α in C2C12 myotubes
Baicalein stimulates fibroblast growth factor 21 expression by up-regulating retinoic acid receptor-related orphan receptor α in C2C12 myotubes
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DOI：
10.1016/j.biopha.2018.10.154
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发表时间：
2019-01-01
影响因子：
7.5
通讯作者：
Inoue, Makoto
中科院分区：
文献类型：
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作者：
Hirai, Takao;Nomura, Kohei;Inoue, Makoto
视黄酸受体相关孤儿受体（ROR） a与多种生理功能有关，包括免疫系统、炎症和昼夜节律。在本研究中，合成的ROR α / γ激动剂SR1078刺激C2C12肌管中成纤维细胞生长因子21 （FGF21）的产生和基因表达。FGF21是FGF家族的一员，在调节外周糖耐量和脂质代谢中发挥重要作用，改善代谢健康。在rora沉默的细胞中，FGF21 mRNA的表达和分泌明显弱于转染非靶向对照siRNA的细胞。SR1078在C2C12肌管中以剂量依赖的方式显著上调内质网应激标志物C/EBP同源蛋白（CHOP），而在rora沉默的C2C12细胞中CHOP表达降低，提示ROR α参与调控FGF21表达，刺激C2C12肌管内质网应激。天然化合物黄芩素上调C2C12肌管中FGF21的表达和分泌。黄芩素处理后，C2C12肌管中CHOP mRNA和蛋白表达上调。此外，在C2C12细胞中，ROR α的下调阻止了黄芩素对FGF21的增强和CHOP的上调。综上所述，这些结果表明黄芩素在C2C12肌管中通过rora依赖机制刺激内质网应激反应和FGF21的表达，并表明黄芩素通过其增强FGF21产生的能力作为一种有效的抗肥胖疗法的潜力。
Retinoic acid receptor-related orphan receptor (ROR) a has been implicated in various physiological functions, including the immune system, inflammation, and circadian rhythms. In the present study, the synthetic ROR alpha/gamma agonist SR1078 stimulated the production and gene expression of fibroblast growth factor 21 (FGF21) in C2C12 myotubes. FGF21, a member of the FGF family, plays important roles in the regulation of peripheral glucose tolerance and lipid metabolism and improves metabolic health. The mRNA expression and secretion of FGF21 was significantly weaker in Rora-silenced cells than in cells transfected with non-targeting control siRNA. SR1078 significantly up-regulated C/EBP homologous protein (CHOP), an established marker of ER stress, in a dose-dependent manner in C2C12 myotubes, while CHOP expression was decreased in Rora-silenced C2C12 cells, suggesting that ROR alpha is involved in the regulation of FGF21 expression and stimulates ER stress in C2C12 myotubes. The naturally occurring compound baicalein up-regulated FGF21 expression and secretion in C2C12 myotubes. Additionally, the up-regulation of CHOP mRNA and protein expression was observed in C2C12 myotubes after the baicalein treatment. Furthermore, the knockdown of ROR alpha prevented the augmentation of FGF21 and up-regulation of CHOP in response to baicalein in C2C12 cells. Collectively, these results suggest that baicalein stimulates the ER stress response and FGF21 expression through an RORa-dependent mechanism in C2C12 myotubes, and indicate the potential of baicalein as an effective anti-obesity therapy via its ability to enhance FGF21 production.