Wu Gang, Pan Yitong, Chen Min, Liu Zhaojun, Li Chengyu, Sheng Yanan, Li Hongmin, Shen Ming, Liu Honglin
College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China.
College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China.
Int J Biol Macromol. 2024 Nov;280(Pt 4):135580. doi: 10.1016/j.ijbiomac.2024.135580. Epub 2024 Sep 23.
Hypoxia that occurs during the luteinization process of granulosa cells (GC) contributes to the formation of lactate in follicles. Lysine lactylation (Kla), a post-translational modification directly regulated by lactate levels, is a metabolic sensor that converts metabolic information into gene expression patterns. In this study, we employed human chorionic gonadotropin (hCG) to induce GCs luteinization and discovered that hypoxia enhances hCG-mediated GCs luteinization by stimulating lactate production/lactylation. The elevated levels of luteinization markers (including progesterone synthesis, expression of CYP11A1 and STAR) were accompanied by increased lactate production as well as enhanced lactylation in mouse ovarian GCs after the injection of hCG in vivo. By treating GCs with hypoxia in vitro, we found that hypoxia accelerated hCG-induced GCs luteinization, which was inhibited after blocking lactate production/lactylation. Further investigations revealed that H3K18la might contribute to hCG-induced luteinization in hypoxic GCs by upregulating CYP11A1 and STAR transcription. Additionally, we identified that CREB K136la is also required for hCG-induced GCs luteinization under hypoxia. Finally, the in vitro findings were verified in vivo, which showed impaired GCs luteinization and corpus luteum formation after blocking the lactate/lactylation by intraperitoneal injection of oxamate/C646 in mice. Taken together, this study uncovered a novel role of protein lactylation in the regulation of GCs luteinization.
颗粒细胞（GC）黄体化过程中出现的缺氧有助于卵泡中乳酸的形成。赖氨酸乳酰化（Kla）是一种直接受乳酸水平调控的翻译后修饰，是一种将代谢信息转化为基因表达模式的代谢传感器。在本研究中，我们使用人绒毛膜促性腺激素（hCG）诱导GC黄体化，并发现缺氧通过刺激乳酸产生/乳酰化增强hCG介导的GC黄体化。在体内注射hCG后，小鼠卵巢GC中黄体化标志物（包括孕酮合成、CYP11A1和STAR的表达）水平升高，同时乳酸产生增加以及乳酰化增强。通过在体外对GC进行缺氧处理，我们发现缺氧加速了hCG诱导的GC黄体化，在阻断乳酸产生/乳酰化后受到抑制。进一步研究表明，H3K18la可能通过上调CYP11A1和STAR转录促进缺氧GC中hCG诱导的黄体化。此外，我们还确定在缺氧条件下，CREB K136la也是hCG诱导GC黄体化所必需 的。最后，体外研究结果在体内得到验证，在小鼠腹腔注射草氨酸/ C646阻断乳酸/乳酰化后，GC黄体化和黄体形成受损。综上所述，本研究揭示了蛋白质乳酰化在GC黄体化调控中的新作用。
