脂联素调控炎症小体NLRP3在非酒精性脂肪性肝炎中的作用及机制研究

The mechanism on the development of non-alcoholic steatohepatitis remains unkown. We found that in high fat diet (HFD)-induced NASH mice model, the gene expression of inflammasome NLRP3 / ASC / caspase1 and associated inflammatory factors IL1β mRNA significantly increased in adiponectin knockout mice comparing to wide type mice. In vitro study showed that adiponectin suppressed free fatty acid-mediated NLRP3 activation in primary hepatocyte. Therefore, we proposed that “adiponectin, a protective adipokine, may alleviate the development of NASH via negatively regulating inflammasome NLRP3 activation ” . In in vitro study, primary hepatocyte will be isolated from C57BL/6 and treated with palmitate to investigate the underlying molecular mechanism on adiponectin-modulated NLRP3 activity. In in vivo study, high fat diet-induced NASH model in adiponect knock out mice(APNKO) and C57BL/6 will be used to examine that the impact of adiponectin-NLRP3 on the progress of NASH. Adiponectin, NLRP3 and other inflammatory factors will be analyzed in liver tissue and serum sample from NASH patients and healthy control. This study may provide an insight into new immunotherapeutic strategies for NASH treatment

非酒精性脂肪性肝炎(NASH)进展的机制尚不清楚。我们发现在高脂饮食诱导的NASH模型中，脂联素基因敲除（APNKO）小鼠肝组织内炎症小体成分NLRP3,ASC,Caspase1,IL1β 基因的表达较野生型小鼠明显升高， 体外研究显示脂联素抑制了棕榈酸介导的肝细胞内炎症小体NLRP3活化。因此我们推测“脂联素作为一种保护性脂肪细胞因子，可能通过负性调控炎症小体NLRP3延缓了NASH疾病进展”。本研究拟采用脂联素联合棕榈酸处理鼠原代肝细胞，体外研究脂联素调控炎症小体NLRP3活化的分子机制；拟采用高脂饲料喂养C57BL/6及APNKO小鼠诱导NASH模型，从不同时间节点探讨脂联素对NLRP3的调控作用及对NASH进展的影响；采用NASH患者和健康对照肝组织及血清标本，分析NASH发展过程中脂联素、NLRP3及相关炎症因子的关系，为NASH的发展机制提供新的理论基础，为其防治提供新的策略。