caveolin-1在非酒精性脂肪性肝病中的作用和机制研究

Abstract: Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide, and the mechanism of NAFLD has been a topic of intense investigation during recent years. Our previous studies observed that hepatic caveolin-1 expression level correlated with the stage of NAFLD. Current study intends to investigate the role of cavolin-1 in NAFLD. The expression of caveolin-1 will be manipulated in vivo and in vitro, and the functional consequences of these manipulations on the degree of hepatic steatosis, expression level of SR-BI，FASN and COX-2 will be analyzed. As the increasing prevalence of NAFLD, the results of this study will not only expand our understanding of the mechanisms of NAFLD, but also assist in the eventual development of new therapeutic targets for the disease.

非酒精性脂肪性肝病（NAFLD）是一种以肝细胞脂肪贮积和变性为特征的临床综合征。微囊蛋白1（caveolin-1）是一种富集于细胞膜、内质网的多功能信号蛋白。本课题组前期研究发现caveolin-1在高脂饮食NAFLD模型小鼠和胆碱蛋氨酸缺乏饮食NAFLD模型小鼠肝脏中表达均显著上调，提示caveolin-1表达变化可能与NAFLD发病有关，然而具体机制尚不清楚。本研究拟建立NAFLD细胞及小鼠模型并结合caveolin-1 基因敲除小鼠，用siRNA和重组腺病毒技术抑制或增强caveolin-1的表达，观察caveolin-1表达变化对肝细胞脂肪变性的影响，并通过Western blot、Real time RT-PCR等方法检测caveolin-1表达改变对于脂质代谢和炎症反应相关蛋白SR-BI、FASN、COX-2等表达的影响，以揭示caveolin-1在NAFLD中的可能调节机制。

微囊蛋白-1（Caveolin-1）可以参与维持细胞脂质稳态和内吞作用，但其在非酒精性脂肪性肝病发生发展中的作用尚不清楚。本项目旨在研究Caveolin-1在肝脏脂肪变性发病机制中的作用。首先，我们发现Caveolin-1在游离脂肪酸诱导的细胞模型和高脂饮食诱导动物模型中表达显著下降；体外抑制Caveolin-1表达可以加重肝细胞脂质贮积，高表达Caveolin-1则可以减轻肝细胞脂质贮积；体外采用Caveolin-1基因敲除小鼠与野生型喂养高脂饮食4周，结果显示Caveolin-1基因敲除小鼠出现肝脏脂质沉积增加、肝细胞甘油三酯含量升高及肝酶升高。进一步研究发现体内外Caveolin-1基因敲除或抑制可以显著增加脂质合成关键酶SREBP-1表达。本研究阐明了Caveolin-1在非酒精性脂肪性肝病发生发展中可能起着关键的保护作用，Caveolin-1表达下降可以通过升高SREBP-1加重非酒精性脂肪性肝病脂质贮积和肝脏损伤，激活Caveolin-1表达可能成为NAFLD治疗的新的分子靶点。