Glucocorticoid Receptor and Lipid Homeostasis

脂肪平衡受到荷尔蒙和营养信号的精确控制。糖皮质激素是 类固醇激素在调节脂质动态平衡方面起着关键作用。然而，这些机制 这些糖皮质激素的作用在很大程度上还不清楚。糖皮质激素通过 细胞内糖皮质激素受体(GR)。GR是一种转录因子，当与配体结合时， 可以与基因组糖皮质激素反应元件(GRE)结合来调节 附近的基因。因此，了解糖皮质激素作用的一个关键步骤是直接识别基因。 受GR调节，触发生理反应。我们已经确定了一个GR主要靶基因， 空腹诱导脂肪因子(FIAF，又名血管生成素样蛋白4，ANGPTL4)，编码一种分泌的 抑制脂蛋白脂酶并诱导脂肪组织脂肪分解的蛋白质。这项提议的目标是 探讨其在糖皮质激素调节脂代谢中的作用及机制。 糖皮质激素、胰岛素和AICAR等不同信号对FIAF基因转录的调控 (一种AMP激活的激酶激活剂)。在目标1中，我们将分析糖皮质激素对染色质的影响 FIAF基因的结构、组蛋白乙酰化和甲基化状态。我们还将调查 FOXO1在FIAF基因糖皮质激素和胰岛素反应中的潜在作用此外，我们还将 AMP激酶是否介导AICAR对糖皮质激素激活的FIAF的抑制作用 基因转录。在目标2中，我们将利用缺乏FIAF基因的小鼠来探索FIAF在代谢中的作用 长期糖皮质激素治疗和禁食引起的变化。除了测量新陈代谢 此外，我们还将使用稳定同位素标记技术监测脂质代谢率。 总体而言，这项研究不仅将扩大我们对糖皮质激素潜在机制的理解-- 调节血脂动态平衡，也将提供重要的知识，可应用于开发 针对肥胖症和糖尿病等代谢性疾病的治疗干预。

Lipid homeostasis is exquisitely controlled by hormonal and nutritional signals. Glucocorticoids are steroid hormones that play a critical role in regulating lipid homeostasis. However, the mechanisms underlying these glucocorticoid effects are largely unclear. Glucocorticoids convey their signals through an intracellular glucocorticoid receptor (GR). GR is a transcription factor, which upon binding to ligands, can associate with genomic glucocorticoid response element (GRE) to regulate the transcription of nearby genes. Thus, one critical step to understand glucocorticoid action is to identify genes directly regulated by GR that trigger the physiological response. We have identified a GR primary target gene, fasting-induced adipose factor (FIAF, a.k.a angiopoietin-like 4, ANGPTL4), which encodes a secreted protein that inhibits lipoprotein lipase and induces adipose tissue lipolysis. The goals of this proposal are to examine the role in glucocorticoid-regulated lipid metabolism and to elucidate the mechanisms of transcriptional regulation of FIAF gene by distinct signals that include glucocorticoids, insulin and AICAR (an AMP-activated kinase activator). In Aim 1, we will analyze the effects of glucocorticoids on chromatin structure, and histone acetylation and methylation status of FIAF gene. We will also investigate the potential role of FOXO1 in glucocorticoid and insulin response on FIAF gene. Moreover, we will investigate whether AMP kinase mediates the inhibitory effect of AICAR on glucocorticoid-activated FIAF gene transcription. In Aim 2, we will use mice lacking FIAF gene to explore the role of FIAF in metabolic changes induced by long-term glucocorticoid treatment and fasting. In addition to measure metabolic parameters, we will also monitor the rate of lipid metabolism using stable isotope labeling technique. Overall, this research not only will expand our understanding on mechanisms underlying glucocorticoid- regulate lipid homeostasis, but also will provide important knowledge that can be applied to develop therapeutic interventions against metabolic diseases, such as obesity and diabetes.