Function of the Nuclear Receptor LRH-1

描述(申请人提供)：最近的X射线晶体研究已确定磷脂是潜在的配体，但它们与LRH-1反式激活的相关性尚不清楚。我们发现，具有两个C11：0(二十一酰基；DUPC)或两个C12：0(二月桂酰基；DLPC)脂肪酸侧链的不寻常的磷脂酰胆碱(PC)物种是LRH-1反式激活的有效激活剂。这两种化合物都是激动剂，在体外和细胞内都能增加共激活剂的结合。在初步研究中，用DUPC或DLPC治疗小鼠可诱导胆汁酸生物合成酶的表达，并增加总胆酸池的大小。DLPC治疗还显著改善糖尿病db/db小鼠的血糖稳态。这项提议的目的是验证LRH-1是一种关键的代谢调节剂的假设，它具有激动剂配体，对代谢紊乱有有益的影响。目的：1.明确新型LRH-1激动剂配体对培养的肝细胞和肠道细胞系基因表达和功能的影响。2.明确新型LRH-1激动剂配体对正常小鼠肝脏和肠道基因表达和功能的影响。3.确定新的LRH-1配体对小鼠疾病模型中基因表达和功能的影响，特别是2型糖尿病和炎症性肠病。我们相信，这些研究将对代谢稳态产生新的见解，并有可能开辟一条全新的途径来解决代谢紊乱问题。与公共健康相关：该项目基于一种新的潜在荷尔蒙的发现。这些化合物激活了两个鲜为人知的核激素受体，并改变了肝功能。它们还显示出抗糖尿病的效果，一个特别的目标是探索它们是如何起作用的，以及它们是否具有潜在的治疗效用。

DESCRIPTION (provided by applicant): Recent x-ray crystal studies have identified phospholipids as potential ligands, but their relevance to LRH-1 transactivation has been unclear. We have found that unusual phosphatidylcholine (PC) species with two C11:0 (diundecanoyl; DUPC) or two C12:0 (dilauroyl; DLPC) fatty acid side chains are potent activators of LRH-1 transactivation. Both compounds are agonists that increase coactivator binding both in vitro and in cells. In preliminary studies, treatment of mice with either DUPC or DLPC induces expression of bile acid biosynthetic enzymes and increases overall bile acid pool size. DLPC treatment also markedly improves glucose homeostasis in diabetic db/db mice. The goal of this proposal is to test the hypothesis that LRH-1 is a key metabolic regulator with agonist ligands that have beneficial effects in metabolic disorders. The aims are to: 1. Define the impact of novel LRH-1 agonist ligands on gene expression and function in cultured hepatocytes and intestinal cell lines. 2. Define the impact of novel LRH-1 agonist ligands on gene expression and function in normal mouse liver and intestine. 3. Define the impact of novel LRH-1 ligands on gene expression and function in murine disease models, particularly type 2 diabetes and inflammatory bowel disease. We believe that these studies will produce new insights into metabolic homeostasis, and that they have the potential to open up a completely new avenue to approaching metabolic disorders. PUBLIC HEALTH RELEVANCE: This project is based on the discovery of a new class of potential hormones. These compounds activate two poorly understood nuclear hormone receptors and alter liver functions. They also show antidiabetic effects, and a particular goal is to explore how they work and whether they have potential therapeutic utility.