Transmembrane G protein-coupled receptor 5 signaling stimulates fibroblast growth factor 21 expression concomitant with up-regulation of the transcription factor nuclear receptor Nr4a1
Transmembrane G protein-coupled receptor 5 signaling stimulates fibroblast growth factor 21 expression concomitant with up-regulation of the transcription factor nuclear receptor Nr4a1
复制标题
跨膜 G 蛋白偶联受体 5 信号传导刺激成纤维细胞生长因子 21 表达，同时上调转录因子核受体 Nr4a1
DOI：
10.1016/j.biopha.2021.112078
复制
发表时间：
2021
影响因子：
7.5
通讯作者：
Hirai Takao
中科院分区：
文献类型：
--
作者：
Kiyama Genki;Nakashima Ken-ichi;Shimada Kazumasa;Murono Naoko;Kakihana Wataru;Imai Hideki;Inoue Makoto;Hirai Takao
成纤维细胞生长因子21 （Fibroblast growth factor 21, FGF21）是一种内分泌因子，在调节能量稳态、糖脂代谢等方面发挥重要作用。它是由多种代谢和细胞应激引起的，如饥饿和寒冷的挑战，这反过来又促进了对应激环境的适应。FGF21的药理作用受到了广泛关注，因为在啮齿动物模型中，FGF21或其类似物已被证明具有抗肥胖作用。在本研究中，我们发现从连翘（forsythia suspensa）果实中分离的活性成分3- o -乙酰齐墩果酸（3- o - acetyloleolic acid）可以刺激FGF21的产生，同时上调C2C12肌管中核受体Nr4a1的转录因子。此外，在过表达TGR5受体的C2C12细胞中，3- o -乙酰齐墩果酸处理显著增加了mfgf21启动子活性。用p38 MAPK抑制剂SB203580治疗可有效抑制3- o -乙酰齐墩果酸的这些刺激作用。3- o -乙酰齐墩果酸刺激后，SB203580预处理也显著抑制了C2C12肌管中fgf21mrna的丰度和FGF21的分泌，这表明配体激活的TGR5在C2C12肌管中诱导FGF21需要激活p38。这些发现共同表明，TGR5受体信号通过p38激活驱动FGF21表达，至少部分通过介导Nr4a1表达。因此，3- o -乙酰齐墩果酸作为抗肥胖药物的新生物学功能可能是通过激活TGR5受体介导的。
Fibroblast growth factor 21 (FGF21) acts as an endocrine factor, playing important roles in the regulation of energy homeostasis, glucose and lipid metabolism. It is induced by diverse metabolic and cellular stresses, such as starvation and cold challenge, which in turn facilitate adaptation to the stress environment. The pharmacological action of FGF21 has received much attention, because the administration of FGF21 or its analogs has been shown to have an anti-obesity effect in rodent models. In the present study, we found that 3-O-acetyloleanolic acid, an active constituent isolated from the fruits ofForsythia suspensa, stimulated FGF21 production concomitant with the up-regulation of a transcription factor, nuclear receptor Nr4a1, in C2C12 myotubes. Additionally, significant increases inmFgf21promoter activity were observed in C2C12 cells overexpressing TGR5 receptor in response to 3-O-acetyloleanolic acid treatment. Treatment with the p38 MAPK inhibitor SB203580 was effective at suppressing these stimulatory effects of 3-O-acetyloleanolic acid. Pretreatment with SB203580 also significantly repressedFGF21mRNA abundance and FGF21 secretion in C2C12 myotubes after 3-O-acetyloleanolic acid stimulation, suggesting that p38 activation is required for the induction of FGF21 by ligand-activated TGR5 in C2C12 myotubes. These findings collectively indicated that TGR5 receptor signaling drives FGF21 expression via p38 activation, at least partly, by mediating Nr4a1 expression. Thus, the novel biological function of 3-O-acetyloleanolic acid as an agent having anti-obesity effects is likely to be mediated through the activation of TGR5 receptors.