REGULATION OF INTRACELLULAR CHOLESTEROL LEVELS DURING PRIMATE LUTEAL REGRESSION

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 孕激素（P）是由黄体（CL）产生的，并且是维持灵长类动物早期妊娠所必需的。在非妊娠周期中，CL的P分泌必须停止（功能退化），以允许下一个卵巢周期的开始。 通过低密度脂蛋白受体和清道夫受体B1在CL内发生高速率的胆固醇摄取，以适应其显著水平的P产生（每天约40 mg）。这种高摄取率必须与外排（也称为胆固醇逆向转运）密切平衡，以确保不发生过量胆固醇的细胞毒性作用。 胆固醇流出是由于细胞内胆固醇经由ATP结合盒亚家族成员A1（ABCA 1）和G1（ABCG 1）转移至细胞外受体载脂蛋白而发生的，这进而导致高密度脂蛋白颗粒的形成。 编码参与胆固醇摄取和流出的蛋白质的基因的表达受到称为肝X受体（LXR）α和β的核激素受体的严格控制。 两种LXR亚型在结合各种氧化固醇（胆固醇代谢物，其用作细胞内胆固醇水平的指示剂）后被激活。 因此，LXR充当胆固醇传感器，在胆固醇过量的情况下刺激胆固醇流出。 本项目的目的是评估内源性LXR配体的水平，氧固醇，在猕猴CL的过程中的功能退化，并确定是否黄体细胞LXR激活影响胆固醇的摄取和流出，从而导致P输出的变化。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Progesterone (P) is produced by the corpus luteum (CL) and is absolutely required to maintain early pregnancy in primates. In non-conception cycles, P secretion from the CL must cease (functional regression) to allow for the initiation of the next ovarian cycle. A high rate of cholesterol uptake within the CL occurs via low density lipoprotein receptor and scavenger receptor B1 to accommodate its significant level of P production (~40 mg daily). This high rate of uptake has to be closely balanced with efflux (also known as reverse cholesterol transport) to ensure that the cytotoxic effects of excessive cholesterol do not occur. Cholesterol efflux occurs as a result of the transfer of intracellular cholesterol via the ATP-binding cassette subfamily members A1 (ABCA1) and G1 (ABCG1) to extracellular acceptor apolipoproteins, which in turn, leads to the formation of high density lipoprotein particles. The expression of genes encoding proteins involved in cholesterol uptake and efflux are tightly controlled by the nuclear hormone receptors known as liver X receptors (LXR) alpha and beta. Both LXR isoforms are activated upon binding various oxysterols, cholesterol metabolites that serve as indicators of intracellular cholesterol levels. Thus, LXRs serve as cholesterol sensors that stimulate cholesterol efflux in cases of cholesterol excess. The objective of this project is to assess the level of endogenous LXR ligands, the oxysterols, within the rhesus macaque CL during the course of functional regression, and to determine whether luteal cell LXR activation affects cholesterol uptake and efflux, thereby leading to changes in P output.