核受体及其配体对代谢综合征分子调控机制的研究

项目名称： 核受体及其配体对代谢综合征分子调控机制的研究

项目编号： No.30873107

项目类型： 面上项目

立项/批准年度： 2009

项目学科： 轻工业、手工业

项目作者： 郑智慧

作者单位： 河北师范大学

项目金额： 32万元

中文摘要： 核受体（Nuclear receptor,NR）是一类由配体激活的核转录因子，其中PPAR、FXR、LXR和ER在代谢综合征 (metabolic syndrome, MS)中的糖代谢、固醇和脂代谢的紊乱中起关键调节作用。本项目利用GAL4-NR(LBD)嵌合受体、核受体靶基因调控序列以及串联核受体相应元件（Nuclear Response Element， NRE）的三种报告基因方法建立了一个代谢性核受体调节剂的筛选技术平台，并筛选得到20多个新核受体调节剂。利用其中的PPARα#947;双激动剂、非固醇类FXR选择性激动剂、FXR/LXR双激动剂等作为分子探针，采用基因芯片、定量PCR、半定量PCR、Western blot、计算机分子对接等技术，通过研究这些调节剂对代谢调控途径中关键靶基因的表达、药效基团和初步药效等，揭示了这些核受体PPAR、LXR和FXR调节剂在糖代谢、脂代谢、胆固醇代谢以及炎症控制方面的分子作用机制以及潜在药理作用。另外，本研究还揭示了霉酚酸通过激活PPAR途径的一个全新抗肿瘤分子机制。总之， 这些研究为今后以核受体为靶点的药物研发奠定科学理论依据和研究策略。

中文关键词： 核受体；调节剂；代谢综合征；代谢调控；基因表达

英文摘要： Nuclear receptors (NRs) are a superfamily of ligand-activated transcription factors that play critical role in many biological processes. peroxisome proliferator-activated receptors (PPARs), liver X receptors (LXRs) and farnesoid X receptor (FXR) and estrogen receptor (ER) regulate the metabolism of glucose, fat, cholesterol and bile acids, which involved in numerous diseases, including type 2 diabetes, obesity, dyslipidemia, atherosclerosis and metabolic syndrome. In this study, based on mammalian one-hybrid GAL4-NR (LBD) chimare receptor, NR target gene promoter-luc and NRE-luc three cell-based report gene assays, a high throughput screening platform for NR modulars was established and dozens of compounds were discovered as new NRs modulators. The molecular mechanism of PPAR, LXR and FXR on the metabolic regulation were further studied with PPARα#947; dual agonist, selective FXR agonist, and FXR/LXR dual agonist by expression analysis on the key genes in glucose and cholesterol metabolism. The results show that FXR agonist has significant effects on modulating the expression of fat and cholesterol metabolism assoiciated genes. FXR/LXR dual agonist exhibits anti-atherosclerosis effects through upregulating the reverse cholesterol transport genes and downregulating inflammation genes. Partial PPARα#947; dual agonists have regulatory effects on glucose and cholesterol metabolism via regulating the expression of glucose transporter and reversse cholesterol transport associated genes. In addition, a novel anticancer mechanism of Mycophenolic acid through PPARγctivation was revealed by PPAR RNAi and PPAR overexpression in this study.

英文关键词： Nuclear receptors; metabolic syndrome; modulator; agonist；gene expression