项目名称: YY1调节肝脏胆汁酸受体FXR转录机制的研究
项目编号: No.81200636
项目类型: 青年科学基金项目
立项/批准年度: 2013
项目学科: 医学二处
项目作者: 陆炎
作者单位: 上海交通大学
项目金额: 23万元
中文摘要: 非酒精性脂肪肝病(NAFLD)的特征性表现是肝脏内甘油三酯的过量堆积。肥胖是NAFLD的主要危险因素之一,但其内在机制尚不清楚。我们在高脂喂养小鼠和db/db小鼠的肝脏组织中发现YY1表达上调,而FXR明显下调。利用YY1腺病毒转染C57小鼠后,肝脏内甘油三酯沉积增加,FXR的表达下降,甘油三酯合成基因表达上调。表明YY1可能通过下调FXR参与肥胖相关的脂肪肝发生。本项目将在这些重要发现的基础上,运用多种现代生物学方法,进一步开展以下工作:(1)采用shRNA腺病毒,沉默肥胖小鼠肝脏中YY1的表达,观察脂肪肝改善情况及FXR基因表达变化;(2)体外细胞及分子水平研究YY1调控FXR表达的机制;(3)利用FXR基因敲除小鼠,明确YY1和FXR的调控关系;在小鼠肝脏过表达FXR,观察是否可以逆转(Rescue)YY1的作用。通过这些问题的阐释,有望为NAFLD的治疗提供新的理论依据和治疗靶点。
中文关键词: 肥胖;非酒精性脂肪肝病;阴阳因子1;法尼醇X受体;转录调控
英文摘要: Nonalcoholic fatty liver disease (NAFLD) is characterized by accumulation of excessive triglycerides in the liver. Obesity is usually associated with NAFLD through unknown mechanisms. Here, we found that expression level of YY1 was markedly increased while FXR was reduced in livers from high-fat-diet-induced obese mice and db/db mice. In addition, hepatic overexpression of YY1 suppressed FXR expression and promoted triglycerides accumulation in C57 mice,indicating that YY1 might promote liver steatosis through down-regulation of FXR expression. Therefore, using in vivo and in vitro models,our project will further investigate:(1) whether hepatic YY1 knockdown could improve hepatosteatosis and FXR expression in obese mice; (2) the molecular mechanisms of YY1 in the regulation of FXR;(3) the regulation of FXR by YY1 using FXR knockout models; whether FXR overexpression could rescue the hepatosteatosis induced by YY1. Our project will benefit to seek new therapeutic targets for fatty liver diseases and related metabolic disorders.
英文关键词: Obesity;Non-alcoholic fatty liver diseases;Yin Yang 1;Farnesoid X receptor;Transcriptional regulation