饱和脂肪酸—内质网应激—FOXC1在高脂饮食诱导的雄性小鼠生精细胞增殖减低中的作用及机制研究

Obesity is a common metabolic disease in modern society, and significantly elevated rate of infertility was observed in obese people. Meanwhile, obese people are often accompanied by changes in the composition and content of free fatty acids in the body, and the increased saturated fatty acids is reported closely related to the occurrence and development of a variety of diseases such as diabetes and fatty liver etc. Our previous studies have shown that damage of testicular Sertoli cells was induced by high concentrations of saturated fatty acids. Whether spermatogenic cells would be affected by elevated saturated fatty acids has not been reported. We found that the content of testicular local free fatty acids was significantly increased in high-fat diet mice in the preliminary study, while the sperm count in the epididymis was significantly reduced, and the spermatogenic epithelium was significantly thinned and the proliferation ability of germ cells was decreased, suggesting that the increased free fatty acids may be involved in the decline of spermatogenic function induced by high-fat diet. In recent years, the role of transcription factor FOXC1 in the proliferation and migration of tumor cells has attracted extensive attention. Whether it is involved in the decreased spermatogenic function of testis induced by saturated fatty acids was still unknown. The aim of this study was to provide clinical guidance via investigating the effect of free saturated fatty acids on germ cell proliferation and the role of transcription factor FOXC1 in this process.

肥胖是现代社会常见代谢性疾病，肥胖人群中男性不育率显著增加。与此同时肥胖人群往往伴有体内游离脂肪酸的组分及含量的变化，饱和脂肪酸的升高与多种疾病如糖尿病、脂肪肝等的发生发展密切相关。我们前期的研究表明，高浓度的饱和脂肪酸可诱导氧化应激引发睾丸睾丸支持细胞的损伤。那么升高的饱和脂肪酸是否会影响生精细胞而导致生精功能低下尚未有研究报道。通过构建高脂喂食小鼠模型，我们发现高脂小鼠睾丸局部游离脂肪酸含量明显增加，同时小鼠附睾精子计数明显减少，生精上皮明显变薄，增殖减低，这提示升高的游离脂肪酸可能参与了高脂诱导的小鼠生精功能下降。近年来，转录因子FOXC1对肿瘤细胞的增殖，迁移的调控已引起广泛关注，它是否参与饱和脂肪酸诱导的睾丸生精功能低下仍未可知。本研究旨在探究游离脂肪酸对生精细胞增殖能力的影响以及转录因FOXC1在其中扮演的作用，以期为临床提供指导。

肥胖是现代社会常见代谢性疾病，肥胖人群中男性不育率显著增加。这类人群往往伴有体内游离脂肪酸的组分及含量的变化，体内饱和脂肪酸的升高与多种疾病如糖尿病、脂肪肝等的发生发展密切相关。已有研究表明，高浓度的饱和脂肪酸可以诱导睾丸间质细胞和睾丸支持细胞的损伤。饱和脂肪酸是否会影响生精细胞而导致生精功能低下尚未有研究报道。近年来，转录因子FOXC1对肿瘤细胞的增殖，迁移的调控已引起广泛关注，它是否参与饱和脂肪酸诱导的睾丸生精功能低下仍未可知。本研究项目通过成功构建高饱和脂肪酸喂食小鼠模型，发现其对生殖细胞的损伤，并在体外研究中利用油红染色，流式细胞周期检测，Qpcr, Western Blot，siRNA干扰实验等分子生物学手段发现饱和脂肪酸可直接进入精原细胞细胞系GC-2，并在生精细胞内堆积诱导GC2细胞的增殖减少，凋亡增加。罗格列酮的的应用可显著逆转饱和脂肪酸诱导的脂类堆积和细胞增殖能力下降。进一步研究发现饱和脂肪酸在GC2细胞内的堆积可诱导FOXC1及细胞周期蛋白Cyclin D1的表达下降，进而引起细胞增殖减低。通过本研究的开展证实饱和脂肪酸这一重要代谢物质对生精细胞的毒性影响,可在一定程度说明肥胖对男性生育力影响的可能机制，并证实FOXC1在饱和脂肪酸的生殖毒性中扮演的重要作用。本研究为临床男性不育患者的诊治提供了新的思路和方向。