肝细胞内HMGB1经ATF6/PPARα/CPT-Iα信号通路改善非酒精性脂肪肝脂质沉积的保护机制研究

非酒精性脂肪性肝病（NAFLD）以肝细胞脂质沉积为特征，临床疗效欠佳。亟需明确该病的发病机制从而优化其治疗策略。高迁移率族蛋白B1（HMGB1）是脂肪肝领域的新兴研究热点，其生物学功能与细胞定位密切相关。已知细胞外HMGB1在NAFLD中通过炎症机制作为“行凶者”加速疾病进展，但细胞内HMGB1在该病发生发展中的作用尚未清楚。申请人立足于前期观察到的肝细胞内HMGB1改善NAFLD脂质沉积的现象，结合生物信息学预测结果，推测肝细胞内HMGB1可能通过ATF6/PPARα/CPT-Iα信号通路增强脂肪酸β氧化从而抑制脂质沉积。本项目拟采用重组质粒与腺病毒、染色质免疫共沉淀、凝胶迁移、分子克隆、荧光素酶报告基因检测等方法验证上述假说，以证实细胞内HMGB1在NAFLD发病中的“保护者”角色。预期结果将在理论上深化对NAFLD疾病成因的认识，同时也有望为该病的精准治疗提供新的潜在靶点。

The hallmark of nonalcoholic fatty liver disease (NAFLD) is abnormal lipid accumulation in the liver. Although much attention has focused on NAFLD in recent decades, its pathogenesis remains largely obscure. Recently, extracellular high mobility group box 1 (HMGB1) has been identified as a potent inflammatory mediator in the development of NAFLD. However, intracellular functions of HMGB1 in the pathogenesis of NAFLD are unexplored. Our previous work using hepatocyte-specific HMGB1 knockout mice has indicated the protective role of intracellular HMGB1 in ameliorating hepatic steatosis in the early stage of NAFLD. Intracellular HMGB1-mediated ATF6/PPARα/CPT-Iα pathway has been proposed based on bioinformatic analysis. In order to further explore the anti-steatotic effects of intracellular HMGB1, recombinant plasmid, recombinant adenovirus, CHIP、EMSA、molecular cloning and luciferase reporter gene assay will be applied to illustrate relationships among HMGB1, ATF6 and PPARα in the hepatocyte. Our research will provide a new insight into the pathogenesis of NAFLD and therefore contribute to developing new therapeutic strategies for NAFLD.