非酒精性脂肪性肝病已成为严重威胁人类健康的全球重要公共卫生问题。肝脏X受体(LXR)在维持肝脏乃至全身脂代谢稳态平衡中起到十分关键的作用。本课题组前期研究利用免疫沉淀-质谱分析方法，首次发现Leupaxin（LPXN）是LXR的相互作用蛋白，并初步证实LPXN是LXR的辅激活因子，调控肝脏脂代谢。本项目拟进一步开展以下工作:（1）采用shRNA腺病毒，沉默脂肪肝小鼠肝脏中LPXN的表达，观察脂肪肝改善情况及脂质合成基因表达变化；（2）体外细胞及分子水平探讨LPXN调控LXR转录活性的机制；（3）利用LXR基因敲除小鼠，明确LPXN和LXR的调控关系；(4)在已建立的人群随访队列中，检验LPXN基因多态性与脂肪肝的遗传关联性。从而系统地探讨LPXN通过LXR调控肝脏脂代谢的作用与机制。这些问题的阐释，不仅有助于阐明脂肪肝发生机制，而且为今后针对LXR信号通路进行药物开发提供新的理论依据。

Non-alcoholic fatty liver disease has become an important public health problem globally. Liver X receptor (LXR) plays a crucial role in maintaining hepatic and circulating lipid metabolism. Our previous study, using immunoprecipitation and mass spectrometry, firstly discovered that Leupaxin (LPXN) interacted with LXR, and we further confirmed that LPXN could regulate hepatic lipid metabolism as a co-activator of LXR. Thus, in this project we will further investigate: (1) whether hepatic LPXN knockdown could improve hepatosteatosis and expression of genes involved in lipogenesis in NAFLD mice models; (2) the molecular mechanisms of LPXN regulating LXR transcription in cell models; (3) the regulation of LXR by LPXN using LXR knockout models; whether LXR knockout could rescue the hepatosteatosis induced by Leupaxin; (4) the genetic relevance between LPXN gene polymorphism and lipid metabolism in the established NAFLD cohort. Our project will benefit to clarify the mechanism of NAFLD, and provide new theoretical basis for future drug development targeting LXR signaling pathway.