PGC1α-NAD+-NLRP3炎性小体通路在NAFLD发病中的作用及其分子机制

非酒精性脂肪性肝病（NAFLD）是高发慢性肝病，其发病机制尚未完全明确。近年文献报道，PGC1α与NAFLD发病密切相关。我们前期研究发现，NAFLD小鼠及细胞模型肝细胞中PGC1α表达水平均显著下降，肝脏特异性高表达PGC1α显著增加NAD+合成并减轻肝细胞脂变，提示PGC1α是调节NAFLD的关键分子，但具体调节机制尚不清楚。本项目拟采用激光共聚焦显微镜、流式细胞术、靶基因过表达与siRNA沉默等技术以及NAFLD细胞模型、肝脏特异性高表达PGC1α小鼠和NAFLD小鼠模型，探讨并确定PGC1α促进NAD+的生物合成，升高的NAD+下调ROS含量从而抑制NLRP3炎性小体的表达，继而抑制调控脂质合成酶类表达的转录因子SREBP-1C、激活调控脂肪酸β氧化的关键蛋白PPARα、抑制嗜中性粒细浸润途径参与NAFLD发病的作用及分子机制，为NAFLD临床治疗及新药研发提供新思路。

Nonalcoholic fatty liver disease (NAFLD) is one of the chronic liver diseases with high morbility, but its pathogenesis is poorly understood. Recent studies found that the PGC1α is closely linked to the pathgenesis of NAFLD. Our previous studies revealed that the expression of PGC1α were significantly decreased in cellular and mouse models of NAFLD. By using a hepatocyte-specific PGC1α overexpression (LivPGC1α) mouse model, we demonstrated that PGC1α increased the NAD+ level and ameliorated hepatic steatosis. It indicated that PGC1α is a key molecule in NAFLD. However, the pathogenic mechanism of PGC1α-NAD+ in the pathogenesis of NAFLD remains unknown. In this research project, by using laser confocal microscopy, flow cytometry, target gene overexpression and siRNA-dependent silence as well as or NAFLD cell models or LivPGC1α mouse model and NAFLD mouse models, we try to research and determine the roles and mechanisms the PGC1α regulating NAD+ biosynthesis to reduce ROS level, and futher inhibit the NLRP3 inflammasome expression, the suppressed NLRP3 inflammasome down-regulating the expression of SREBP-1C, the transcription factors for regulation of fatty synthetic enzymes, and acvitating the key protein of regulating fatty acid beta oxidation, and inhibiting the neutrophil infiltration pathways, which involved in the pathogenesis of NAFLD. The findings of this project will provide new ideas of clinical treatment and drug research of NAFLD.