Department of Obstetrics and Gynecology, The First Affiliated Hospital of the Fourth Military Medical University, Xi'an, China.
Department of Obstetrics and Gynecology, The First Affiliated Hospital of the Fourth Military Medical University, Xi'an, China.
Mol Cell Endocrinol. 2024 Dec 1;594:112381. doi: 10.1016/j.mce.2024.112381. Epub 2024 Sep 26.
This study aimed to elucidate the role of TP53-induced glycolysis and apoptosis regulator (TIGAR) in polycystic ovary syndrome (PCOS). A rat model PCOS was constructed by subcutaneous injection with dehydroepiandrosterone (DHEA). Follicular atresia and reduced granular cells (GCs) in ovaries suggested successful modeling. The low expression of TIGAR was observed in ovarian tissue of PCOS rat. To explore the role of TIGAR in PCOS, lentivirus carrying the TIGAR were used to up-regulate TIGAR expression. TIGAR overexpression reduced the DHEA-induced increase of ovarian weight, the levels of estradiol (E2), and the ratio of luteinizing hormone/follicle-stimulating hormone (LH/FSH) in the serum, as well as improved the morphology of the follicle, especially increased the thickness of the GC layer, which attributed to the inhibition of apoptosis by TIGAR. In addition, high expression of TIGAR inhibited oxidative stress in ovaries of PCOS rat, as evidenced by decreased level of malondialdehyde (MDA), and reactive oxygen species (ROS), and enhanced activity of glutathione peroxidase (GPX) and superoxide dismutase (SOD). Mechanically, Nrf2/OH-1 signal pathway was activated by TIGAR. The effect of TIGAR on PCOS were verified in the primary rat GCs treated with dihydrotestosterone, but also the rescue experiment was performed. Downregulation of Nrf2 reversed the effects of TIGAR, indicating that TIGAR suppressed oxidative stress and GC apoptosis by activating Nrf2/OH-1 pathway in PCOS. Finally, non-targeted metabolomics revealed that TIGAR might affect the energy metabolic pathway, thereby altering the metabolic profile of primary rat GCs. This study provided new insights into the prevention and treatment of PCOS.
本研究旨在阐明 TP53 诱导的糖酵解和凋亡调节剂（TIGAR）在多囊卵巢综合征（PCOS）中的作用。通过皮下注射脱氢表雄酮（DHEA）构建大鼠 PCOS 模型。卵巢中卵泡闭锁和颗粒细胞（GC）减少表明模型构建成功。在 PCOS 大鼠的卵巢组织中观察到 TIGAR 的低表达。为了探讨 TIGAR 在 PCOS 中的作用，使用携带 TIGAR 的慢病毒上调 TIGAR 表达。TIGAR 过表达降低了 DHEA 诱导的卵巢重量增加、血清中雌二醇（E2）水平和黄体生成素/卵泡刺激素（LH/FSH）比值，以及改善了卵泡形态，特别是增加了 GC 层的厚度，这归因于 TIGAR 抑制细胞凋亡。此外，TIGAR 的高表达抑制了 PCOS 大鼠卵巢中的氧化应激，表现为丙二醛（MDA）和活性氧（ROS）水平降低，谷胱甘肽过氧化物酶（GPX）和超氧化物歧化酶（SOD）活性增强。机制上，TIGAR 激活了 Nrf2/OH-1 信号通路。在经二氢睾酮处理的原代大鼠 GCs 中验证了 TIGAR 对 PCOS 的作用，也进行了挽救实验。下调 Nrf2 逆转了 TIGAR 的作用，表明 TIGAR 通过激活 Nrf2/OH-1 通路抑制 PCOS 中的氧化应激和 GC 凋亡。最后，非靶向代谢组学揭示 TIGAR 可能影响能量代谢途径，从而改变原代大鼠 GCs 的代谢谱。本研究为 PCOS 的防治提供了新的见解。
