REGULATION OF INTRACELLULAR CHOLESTREROL LEVELS DURING PRIMATE LUTEAL REGRESSION

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 孕酮(P)是由黄体(CL)产生的，是维持灵长类动物早期妊娠所必需的。在非受孕周期中，CL的P分泌必须停止(称为功能退化)，以便启动下一个卵巢周期。CL内的高胆固醇摄取率通过低密度脂蛋白受体和清道夫受体B1类发生，以适应其显著的P产生水平(~40毫克/天)。这种高摄取率必须与外流(也称为反向胆固醇运输)密切平衡，以确保不会发生过量胆固醇的细胞毒性影响。胆固醇外流是细胞内胆固醇通过三磷酸腺苷结合盒亚家族成员A1(ABCA1)和G1(Abcg1)转移到细胞外受体载脂蛋白，进而导致高密度脂蛋白颗粒形成的结果。参与胆固醇摄取和外流的编码蛋白的基因表达受到被称为肝X受体(LXR)的核激素受体的严格控制。这两种LXR亚型都是在结合各种氧化甾醇时被激活的，氧化甾醇是胆固醇代谢产物，用作细胞内胆固醇水平的指示器。因此，LXRs作为胆固醇传感器，在胆固醇过剩的情况下刺激胆固醇外流。本项目的目的是评估恒河猴CL在功能退化过程中内源性LXR配体-氧固醇的水平，并确定黄体细胞LXR的激活是否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 (termed 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 class 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.