Sel1L缺失对肝脏线粒体活性氧及脂质代谢平衡的影响研究

项目名称： Sel1L缺失对肝脏线粒体活性氧及脂质代谢平衡的影响研究

项目编号： No.31501154

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 生物科学

项目作者： 潘志雄

作者单位： 苏州大学

项目金额： 20万元

中文摘要： 内质网应激、线粒体内活性氧（ROS）失衡是导致非酒精性脂肪肝炎和肝癌的主要原因。本项目组前期通过组织特异性敲除Sel1L基因发现，Sel1L在维持内质网稳定和生命存活中必不可少，特别是肝脏特异性敲除Sel1L基因（L-Sel1L-/-）小鼠会自发出现非酒精性脂肪肝及肝癌症状，同时伴随着线粒体ROS水平上升和抗氧化酶系统失衡。然而对于ROS上升的原因及其在脂肪肝形成中的作用尚不清楚。本项目以L-Sel1L-/-小鼠模型为平台，通过检测不同日龄小鼠代谢能、肝脏病理变化、脂代谢及ROS平衡通路相关基因的变化，系统研究L-Sel1L-/-小鼠ROS动态变化规律及其对肝病发生影响；同时通过饲喂ROS清除剂N-乙酰半胱氨酸（NAC）来验证ROS在L-Sel1L-/-小鼠肝病发生中的作用。以期为阐明非酒精性脂肪肝的形成机制提供依据，并为非酒精性脂肪肝、肝癌的预防和治疗提供新的策略。

中文关键词： 活性氧（ROS）；Sel1L；内质网应激；非酒精性脂肪肝；脂质代谢

英文摘要： Dysfunction and failure of mitochondria reactive oxygen species (ROS) homeostasis and endoplasmic reticulum (ER) stress have been shown to be responsible for the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and hepatocarcinoma (HCC). Through conditional gene-targeting in mice, we have previously show that Sel1L is indispensable for ER homeostasis and survival, and liver-Sel1L knockout (L-Sel1L-/-) mice developed NAFLD with dysfunction ROS homeostasis and antioxidants system, and developed HCC in one year old. The underlying molecular mechanisms of dysfunction ROS and formation NAFLD, however, are incompletely understood. In this application, base on L-Sel1L-/- mice ER-stress model, by studying the ROS and lipid homeostasis variation of liver tissue and exploring the relationship between ROS levels and the activity of antioxidant system at different developmental stages of liver disease. The novel insight from the proposed research is expected to significantly advance our understanding of the molecular underlying NAFLD and HCC. Consequently, the new knowledge is highly expected to lead to novel and more effective therapeutic strategies for the prevention and treatment of NAFLD and HCC.

英文关键词： reactive oxygen species;Sel1L;ER-stress;NAFLD;lipid metabolism