Division of Reproductive and Developmental Sciences, Oregon National Primate Research Center, Oregon Health & Science University West Campus, Beaverton, Oregon 97006, USA.
Biol Reprod. 2012 Mar 30;86(3):89. doi: 10.1095/biolreprod.111.096347. Print 2012 Mar.
The expressions of genes involved in cholesterol efflux increase, whereas those involved in extracellular cholesterol uptake decrease, during spontaneous functional regression of the primate corpus luteum (CL). This may result from liver x receptor (LXR) alpha (official symbol NR1H3) and/or beta (official symbol NR1H2) control of luteal gene transcription, because these nuclear receptor superfamily members are key regulators of cellular cholesterol homeostasis. Therefore, studies were conducted to assess endogenous LXR ligands in the primate CL through the luteal phase, and to determine the effect of synthetic or natural LXR ligands on cholesterol efflux and uptake in functional primate luteal cells. Using high-performance liquid chromatography tandem mass spectrometry, three LXR ligands were identified and quantified in the rhesus macaque CL, including 22R-hydroxycholesterol (22ROH), 27-hydroxycholesterol (27OH), and desmosterol. Levels of 22ROH paralleled serum progesterone concentrations, whereas mean levels of 27OH tended to be higher following the loss of progesterone synthesis. Desmosterol was present throughout the luteal phase. Functional macaque luteal cells treated with the synthetic LXR agonist T0901317 or physiologically relevant concentrations of the endogenous luteal ligands 22ROH, 27OH, and desmosterol had increased expression of various known LXR target genes and greater cholesterol efflux. Additionally, T0901317 reduced low-density lipoprotein receptor protein and extracellular low-density lipoprotein uptake, whereas 27OH decreased low-density lipoprotein receptor protein, most likely via a posttranslational mechanism. Collectively, these data support the hypothesis that LXR activation causes increased cholesterol efflux and decreased extracellular cholesterol uptake. In theory, these effects could deplete the primate CL of cholesterol needed for steroidogenesis, ultimately contributing to functional regression.
在灵长类动物黄体（CL）自发功能退化过程中，涉及胆固醇外排的基因表达增加，而涉及细胞外胆固醇摄取的基因表达减少。这可能是由于肝 X 受体（LXR）α（官方符号 NR1H3）和/或β（官方符号 NR1H2）控制黄体基因转录所致，因为这些核受体超家族成员是细胞胆固醇稳态的关键调节因子。因此，进行了研究以评估灵长类 CL 中的内源性 LXR 配体在黄体期的情况，并确定合成或天然 LXR 配体对功能性灵长类黄体细胞中胆固醇外排和摄取的影响。使用高效液相色谱串联质谱法，在恒河猴 CL 中鉴定和定量了三种 LXR 配体，包括 22R-羟胆固醇（22ROH）、27-羟胆固醇（27OH）和去甲固醇。22ROH 水平与血清孕激素浓度平行，而在孕激素合成丧失后，27OH 的平均水平趋于更高。去甲固醇在黄体期一直存在。用合成 LXR 激动剂 T0901317或生理相关浓度的内源性黄体配体 22ROH、27OH 和去甲固醇处理功能性猕猴黄体细胞，增加了各种已知的 LXR 靶基因的表达和胆固醇外排。此外，T0901317 降低了低密度脂蛋白受体蛋白和细胞外低密度脂蛋白摄取，而 27OH 降低了低密度脂蛋白受体蛋白，这很可能是通过翻译后机制。总的来说，这些数据支持 LXR 激活导致胆固醇外排增加和细胞外胆固醇摄取减少的假设。从理论上讲，这些作用可能会耗尽灵长类 CL 中用于甾体生成的胆固醇，最终导致功能退化。
