NLRP3炎症小体调控脂联素/AMPK/PPAR-α/脂肪酸氧化通路在非酒精性脂肪性肝炎中的作用机制

Nonalcoholic fatty steatohepatitis (NASH) is increasing year by year. However, there are no currently effective drugs for the treatment of NASH. NLRP3 inflammasome is a hotspot of research in recent years, which has been confirmed to be closely related to NASH. However, the specific regulatory mechanism of NLRP3 inflammasome during the development of NASH remained to be unknown. Recent studies have shown that adiponectin/AMPK/PPAR-α/fatty acid oxidation pathway was also involved in the pathogenesis of NASH. Our preliminary work has found that NLRP3 inflammasome related protein significantly increased in mouse model, while mRNA of PPAR-α significantly decreased. The levels of IL-18, IL-1β in NASH patients were also elevated. Therefore, we assume that activated NLRP3 inflammasome inhibits the secretion of adiponectin and the combination of adiponectin to its receptors, AdipoR1 and AdipoR2, leading to the inhibition of AMPK activation and decreased activity of PPAR-α, respectively, resulting in fatty acid oxidation disorder and the deposition of hepatic triglyceride. Our research would observe how NLRP3 inflammasome regulate adiponectin/AMPK/PPAR-α/fatty acid oxidation pathway from three aspects including cell experiments, animal experiments and clinical specimens. The present study aims to explore the role of NLRP3 inflammasome involved in the mechanism of NASH, which is of great significance to provide new strategies for prevention and treatment of NASH.

非酒精性脂肪性肝炎（NASH）的发病率逐年递增，目前缺乏有效的治疗药物。NLRP3炎症小体已被证实与NASH密切相关，然而相关的作用机制不明。新近的研究表明脂联素/AMPK/PPAR-α/脂肪酸氧化通路也参与了NASH的发病过程。本前期工作发现NASH小鼠模型中，NLRP3炎症小体相关的蛋白表达明显升高，而脂肪酸氧化相关的基因PPAR-α的表达则明显降低，而NASH患者的NLRP3炎症小体的效应分子IL-1β、IL-18也显著升高。为此我们设想：NLRP3炎症小体可抑制脂联素的产生及其与受体的结合，进而抑制AMPK磷酸化，降低PPAR-α的活性，导致脂肪酸氧化障碍及甘油三酯沉积。本课题拟从体内、体外及临床标本三个方面观察NLPR3炎症小体对脂联素/AMPK/PPAR-α/脂肪酸氧化通路的调控机理，对于探索NLRP3炎症小体在NASH中的作用机制具有重要意义，以期为NASH的防治提供新策略。

非酒精性脂肪性肝病（NAFLD）的发病率逐年递增，目前缺乏有效的治疗药物。既往的研究表明NLRP3炎症小体促进了胰岛素抵抗和非酒精性脂肪性肝病（NAFLD）的发生及发展，然而相关的作用机制不明。本项目经过调整后主要从两个方面展开了工作，第一部分从细胞、动物、临床标本三个方面观察了各种内外源性的信号分子激活NLRP3炎症小体后，导致其下游细胞因子IL-1β、IL-18的释放，促进脂肪酸氧化障碍及肝脏甘油三酯沉积，进而促进了胰岛素抵抗及NASH的发生。第二部分是观察袖状胃成型术及NLRP3炎症小体特异性抑制剂CY-09对于非酒精性脂肪肝小鼠模型的治疗作用。主要研究结果如下：①内源及外源性因素刺激肝细胞后，可以导致脂滴在肝细胞质中大量沉积，亦可以通过线粒体和NOX4途径导致肝细胞氧化应激反应，最终促进NLRP3炎症小体的激活和下游细胞因子IL-18、IL-1β的分泌。②NAFLD 患者血浆血管紧张素II（AngII）水平明显升高，AngII是NAFLD一个独立的危险因素，AngII 可能通过激活 NLRP3 炎症小体及其下游细胞因子促进肝细胞炎症反应及 NAFLD/NASH 的发生。未来在临床中可能会为NAFLD的血清学生物标志物检测提供新的思路。③袖状胃成型术联合NLRP3炎症小体特异性抑制剂CY-09可以改善胰岛素抵抗，减轻小鼠脂肪肝变性程度，这种联合治疗可能会成为临床上治疗NAFLD的新方法。.我们发现AngII是NAFLD一个独立的危险因素，AngII 可能通过激活 NLRP3 炎症小体及其下游细胞因子促进肝细胞炎症反应及 NAFLD/NASH 的发生。为NAFLD的血清学生物标志物检测提供了新的思路，AngII未来在临床中可能成为NAFLD的一个血清标志物。另外，本项目发现：袖状胃成型术联合NLRP3炎症小体特异性抑制剂CY-09可以改善胰岛素抵抗，减轻小鼠脂肪肝变性程度，未来拟进行大动物实验和人体试验，一步一步将该联合治疗的方法推向临床应用，或许可以为NAFLD临床治疗提供新手段。在本项目的资助下目前已发表SCI论文2篇，另有1篇在审稿，获得了2项专利。