Decreased Cholesterol Uptake and Increased Liver X Receptor-Mediated Cholesterol Efflux Pathways During Prostaglandin F2 Alpha-Induced and Spontaneous Luteolysis in Sheep
Decreased Cholesterol Uptake and Increased Liver X Receptor-Mediated Cholesterol Efflux Pathways During Prostaglandin F2 Alpha-Induced and Spontaneous Luteolysis in Sheep
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DOI：
10.1095/biolreprod.114.124941
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发表时间：
2015-05-01
影响因子：
3.6
通讯作者：
Bogan, Randy L.
中科院分区：
文献类型：
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作者：
Seto, Nickie L.;Bogan, Randy L.
在非灵长类动物中，已经确定前列腺素F2 α（PGF2 α）启动黄体溶解。细胞内胆固醇浓度的变化引起的胆固醇摄取和流出的调制可能介导PGF 2 α诱导的黄体溶解。胆固醇流出和摄取的这些变化部分由肝脏x受体（LXR）α（NR1H3）和β（NR1H2）控制，这些核受体增加胆固醇流出或限制胆固醇摄取所必需的基因表达。因此，我们假设PGF2 α降低胆固醇摄取的表达，增加胆固醇流出基因的表达，部分通过增强LXR活性介导。为了检验这一假设，使用了诱导性黄体溶解模型，其中母羊在黄体中期用盐水或PGF 2 alpha处理，并在12、24或48小时后收集黄体（CL），通过定量实时PCR和蛋白质浓度来测定mRNA和蛋白质浓度。分别进行蛋白质印迹分析。作为一种补充方法，将发生自发性黄体溶解的CL与黄体中期CL进行比较。负责胆固醇摄取的脂蛋白受体在两种黄体溶解模型中均显著降低。LXR靶基因ATP结合盒亚家族A1（ABCA1）的表达，胆固醇流出的重要介质，在两个实验模型中显着增加。染色质免疫沉淀证实，PGF 2 α处理导致增强的NR1H3和NR1H2结合ABCA 1启动子。PGF 2 α给药后还观察到脂滴分布的定性变化。这些数据支持这一假设，即降低胆固醇摄取和增加外排介导绵羊的黄体溶解，这部分是由PGF 2 α刺激LXR活性控制的。
In nonprimate species, it has been well established that prostaglandin F2 alpha (PGF2alpha) initiates luteolysis. Changes in intracellular cholesterol concentrations caused by modulation of cholesterol uptake and efflux may mediate PGF2alpha-induced luteolysis. These changes in cholesterol efflux and uptake are controlled, in part, by the liver x receptors (LXR) alpha (NR1H3) and beta (NR1H2), nuclear receptors that increase expression of genes necessary for cholesterol efflux or limiting cholesterol uptake. Therefore, we hypothesized that PGF2alpha reduces expression of cholesterol uptake and increases expression of cholesterol efflux genes, mediated in part by enhanced LXR activity. To test this hypothesis, an induced luteolysis model was used whereby ewes were treated during their midluteal phase with saline or PGF2alpha and corpora lutea (CL) collected 12, 24, or 48 h later for determination of mRNA and protein concentrations by quantitative real-time PCR and Western blot analysis, respectively. As a complementary approach, CL undergoing spontaneous luteolysis were compared to midluteal phase CL. The lipoprotein receptors responsible for cholesterol uptake were significantly decreased in both luteolysis models. Expression of the LXR target gene ATP binding cassette subfamily A1 (ABCA1), an important mediator of cholesterol efflux, was significantly increased in both experimental models. Chromatin immunoprecipitation confirmed that PGF2alpha treatment resulted in enhanced NR1H3 and NR1H2 binding to the ABCA1 promoter. Qualitative changes in lipid droplet distribution were also observed following PGF2alpha treatment. These data support the hypothesis that reduced cholesterol uptake and increased efflux mediate luteolysis in sheep, which is partially controlled by PGF2alpha stimulation of LXR activity.