Arias Andreina, Quiroz Alonso, Santander Nicolás, Morselli Eugenia, Busso Dolores
Laboratory of Nutrition, Metabolism and Reproduction, Research and Innovation Center, Program of Reproductive Biology, Universidad de Los Andes, Santiago, Chile.
Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile.
Front Cell Dev Biol. 2022 Sep 14;10:941539. doi: 10.3389/fcell.2022.941539. eCollection 2022.
Cholesterol is an essential component of animal cells. Different regulatory mechanisms converge to maintain adequate levels of this lipid because both its deficiency and excess are unfavorable. Low cell cholesterol content promotes its synthesis and uptake from circulating lipoproteins. In contrast, its excess induces the efflux to high-density lipoproteins (HDL) and their transport to the liver for excretion, a process known as reverse cholesterol transport. Different studies suggest that an abnormal HDL metabolism hinders female fertility. HDL are the only lipoproteins detected in substantial amounts in follicular fluid (FF), and their size and composition correlate with embryo quality. Oocytes obtain cholesterol from cumulus cells gap junctions because they cannot synthesize cholesterol and lack HDL receptors. Recent evidence has supported the possibility that FF HDL play a major role in taking up excess unesterified cholesterol (UC) from the oocyte. Indeed, genetically modified mouse models with disruptions in reverse cholesterol transport, some of which show excessive circulating UC levels, exhibit female infertility. Cholesterol accumulation can affect the egg´s viability, as reported in other cell types, and activate the plasma membrane structure and activity of membrane proteins. Indeed, in mice deficient for the HDL receptor Scavenger Class B Type I (SR-B1), excess circulating HDL cholesterol and UC accumulation in oocytes impairs meiosis arrest and hinders the developmental capacity of the egg. In other cells, the addition of cholesterol activates calcium channels and dysregulates cell death/survival signaling pathways, suggesting that these mechanisms may link altered HDL cholesterol metabolism and infertility. Although cholesterol, and lipids in general, are usually not evaluated in infertile patients, one study reported high circulating UC levels in women showing longer time to pregnancy as an outcome of fertility. Based on the evidence described above, we propose the existence of a well-regulated and largely unexplored system of cholesterol homeostasis controlling traffic between FF HDL and oocytes, with significant implications for female fertility.
胆固醇是动物细胞的重要组成部分。不同的调节机制共同作用以维持这种脂质的适当水平，因为其缺乏和过量都不利。细胞胆固醇含量低会促进其合成以及从循环脂蛋白的摄取。相反，其过量会诱导胆固醇外流至高密度脂蛋白（HDL），并将其转运至肝脏进行排泄，这一过程称为胆固醇逆向转运。不同研究表明，HDL代谢异常会阻碍女性生育能力。HDL是卵泡液（FF）中大量检测到的唯一脂蛋白，其大小和组成与胚胎质量相关。卵母细胞通过卵丘细胞间隙连接获取胆固醇，因为它们无法合成胆固醇且缺乏HDL受体。最近的证据支持了FF HDL在从卵母细胞摄取过量未酯化胆固醇（UC）中起主要作用的可能性。事实上，逆向胆固醇转运受到破坏的转基因小鼠模型，其中一些显示循环UC水平过高，表现出雌性不育。正如在其他细胞类型中所报道的，胆固醇积累会影响卵子的活力，并激活质膜结构和膜蛋白的活性。确实，在缺乏HDL受体清道夫B类I型（SR-B1）的小鼠中，卵母细胞中循环HDL胆固醇过量和UC积累会损害减数分裂停滞，并阻碍卵子的发育能力。在其他细胞中，添加胆固醇会激活钙通道并失调细胞死亡/存活信号通路，这表明这些机制可能将HDL胆固醇代谢改变与不育联系起来。尽管通常不育患者不评估胆固醇和一般脂质，但一项研究报告称，作为生育结果，怀孕时间较长的女性循环UC水平较高。基于上述证据，我们提出存在一个调节良好且很大程度上未被探索的胆固醇稳态系统，该系统控制着FF HDL与卵母细胞之间的物质交换，对女性生育能力具有重要影响。
