Przygrodzka Emilia, Bhinderwala Fatema, Powers Robert, McFee Renee M, Cupp Andrea S, Wood Jennifer R, Davis John S
Olson Center for Women's Health, Department of Obstetrics and Gynecology, University of Nebraska Medical Center, Omaha, Nebraska, USA.
Department of Chemistry, University of Nebraska-Lincoln, Lincoln, Nebraska, USA.
J Biol Chem. 2025 Jan;301(1):108042. doi: 10.1016/j.jbc.2024.108042. Epub 2024 Nov 29.
The pituitary gonadotropin luteinizing hormone (LH) is the primary stimulus for ovulation, luteal formation, and progesterone synthesis, regardless of species. Despite increased awareness of intracellular signaling events initiating the massive production of progesterone during the reproductive cycle and pregnancy, critical gaps exist in our knowledge of the metabolic and lipidomic pathways required for initiating and maintaining luteal progesterone synthesis. Using untargeted metabolomics and metabolic flux analysis in primary steroidogenic luteal cells, evidence is provided for rapid LHCGR-stimulation of metabolic pathways leading to increased glycolysis and oxygen consumption. Treatment with LH stimulated posttranslational modifications of enzymes involved in de novo lipogenesis. Mechanistic studies implicated a crucial role for de novo fatty acid synthesis and fatty acid oxidation in energy homeostasis, LHCGR/PKA signaling, and, consequently, progesterone production. These findings reveal novel hormone-sensitive metabolic pathways essential for maintaining LHCGR/PKA signaling and steroidogenesis. Understanding hormonal control of metabolic pathways in steroidogenic cells may help elucidate approaches for improving ovarian function and successful reproduction or identifying metabolic targets for developing nonhormonal contraceptives.
无论物种如何，垂体促性腺激素促黄体生成素（LH）都是排卵、黄体形成和孕酮合成的主要刺激因素。尽管人们越来越意识到在生殖周期和怀孕期间启动大量孕酮产生的细胞内信号事件，但我们对启动和维持黄体孕酮合成所需的代谢和脂质组学途径的了解仍存在关键空白。通过在原代类固醇生成黄体细胞中使用非靶向代谢组学和代谢通量分析，为LH对导致糖酵解增加和氧消耗增加的代谢途径的快速刺激提供了证据。LH处理刺激了参与从头脂肪生成的酶的翻译后修饰。机制研究表明，从头脂肪酸合成和脂肪酸氧化在能量稳态、LHCGR/PKA信号传导以及因此的孕酮产生中起着关键作用。这些发现揭示了维持LHCGR/PKA信号传导和类固醇生成所必需的新型激素敏感代谢途径。了解类固醇生成细胞中代谢途径的激素控制可能有助于阐明改善卵巢功能和成功繁殖的方法，或确定开发非激素避孕药的代谢靶点。
