FSH mediates estradiol synthesis in hypoxic granulosa cells by activating glycolytic metabolism through the HIF-1 alpha-AMPK-GLUT1 signaling pathway

文献类型： 外文期刊

第一作者： Wu, Gang

作者： Wu, Gang;Li, Chengyu;Tao, Jingli;Liu, Zhaojun;Li, Xiaoxuan;Zang, Ziyu;Fu, Chen;Wei, Jiayuan;Yang, Yaxing;Zhu, Qian;Shen, Ming;Liu, Honglin;Zhang, Jia-Qing

作者机构：

期刊名称：JOURNAL OF BIOLOGICAL CHEMISTRY （ 影响因子：5.486； 五年影响因子：5.295 ）

ISSN：

年卷期： 2022 年 298 卷 5 期

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收录情况： SCI

摘要： Owing to the avascular environment within ovarian follicles, granulosa cells (GCs) are believed to live in a hypoxic niche. Follicle-stimulating hormone (FSH)-mediated steroidogenesis is crucial for normal growth and maturation of ovarian follicles, but it remains unclear how FSH stimulates estradiol (E2) synthesis under hypoxic conditions. Here, we aimed to explore whether FSH affects the ATP production required for estrogen synthesis from the perspective of glucose metabolism. It was observed that the levels of both E2 and HIF-1 alpha were markedly increased in a dose-dependent manner in mouse ovarian GCs after the injection of FSH in vivo, indicating that hypoxia/HIF1 alpha may be relevant to FSH-induced E2 synthesis. By treating hypoxic GCs with FSH in vitro, we further revealed that the activation of the AMP-activated protein kinase (AMPK)- GLUT1 pathway, which in turn stimulates ATP generation, may be essential for FSH-mediated E2 production during hypoxia. In contrast, inhibition of AMPK or GLUT1 with siRNAs/antagonist both repressed glycolysis, ATP production, and E2 synthesis despite FSH treatment. Moreover, blocking HIF-1 alpha activity using siRNAs/PX-478 suppressed AMPK activation, GLUT1 expression, and E2 levels in FSH-treated GCs. Finally, the in vitro findings were verified in vivo, which showed markedly increased AMPK activity, GLUT1 expression, glycolytic flux, ATP levels, and E2 concentrations in ovarian GCs following FSH injection. Taken together, these findings uncovered a novel mechanism for FSH-regulating E2 synthesis in hypoxic GCs by activating glycolytic metabolism through the HIF-1 alpha-AMPK-GLUT1 pathway.

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