PPARδ通过调控自噬改善非酒精性脂肪肝病的作用和机制研究

NAFLD严重影响着人类健康。前期工作显示在多种脂肪肝模型中PPARδ与自噬相关蛋白的表达均显著下调。给予脂肪肝动物模型以PPARδ激动剂或在肝脏特异性过表达PPARδ，明显改善模型动物的肝脏脂质沉积，自噬相关蛋白显著增加，肝脏的脂肪酸氧化增加。鉴于自噬在肝脏脂质代谢中的重要作用，在本项研究中，我们将利用多种经典的NAFLD的动物模型，并建立肝脏组织特异性PPARδ敲除小鼠，从体内和体外水平，结合现代细胞生物学和分子生物学技术，详细探究PPARδ与自噬在肝脏脂质沉积的调控作用，这对于从整体水平认识PPARδ的生物学功能至关重要；而且，该研究也将更新和拓展我们对自噬与肝脏脂质代谢的认识，对于预防和治疗代谢性疾病，具有重要的指导意义；尤其需要指出，本研究对于开发以PPARδ为靶标治疗非酒精性脂肪肝药物开发，以及对深入理解NAFLD发病过程中自噬所扮演的关键角色也具有重要的科学影响。

NAFLD have an serious effect on human health . We have done lots of foundational work in dissecting the mechanism of PPARδand autophagy in NAFLD treatment. Our results showed that PPARδand autophagy related proteins displayed the same tendency in different NAFLD mice models, such as high fat diet (HFD)-fed mice, ob/ob and db/db mice. Treating with PPARδagonist or Adeno-Associated Viral mediated PPARδoverexpression could significantly improve the hepatic steatosis, and enhance the expression of autophagy related proteins as well. Considering the central role of the autophagy in regulation of NAFLD, in this project, we will establish liver specific PPAR delta knockout mouse model. In the present study, we will demonstrate the significant role and underlying mechanism of PPAR delta and autophagy in regulating hepatic steatosis in vivo and in vitro by using modern cell biological and molecular biological methods. It will be of importance to reveal further the biological function of PPARδ and to update the knowledge of autophagy in hepatic lipid metabolism theoretically and practically. It should be noted that our project would be of great instructional value in developing more new drugs based on PPARδ, and of great significance in understanding the role of autophagy in the progress of NAFLD.