α1-抗胰蛋白酶作为NAFLD进展生物标志物有效性及机制研究

临床上尚无特异性和敏感性良好的生物标记物用于监测非酒精性脂肪肝（NAFLD）的发展和临床疗效评估。α1-抗胰蛋白酶（AAT）由肝脏分泌，通过抑制中性粒细胞弹性蛋白酶发挥抗炎等作用，已有三项全基因组关联性分析发现与NAFLD进展相关，但尚未有临床验证的研究报道。申请人最近发现NAFLD动物模型中可见AAT的同源蛋白Serpina1a表达降低，并可能与肝脏内质网应激相关。本项目拟用采用2个临床NAFLD队列和3种NAFLD、脂肪性肝炎（NASH）动物模型，验证AAT作为NAFLD进展的生物标志物的有效性，并在NASH动物模型评估其潜在新的干预靶点和相关机制。本项目将加深对NAFLD发生进展的机制认识，并有可能提供新的NAFLD发生发展生物标志物。

Until now, there are no specific and sensitive biomarkers for monitoring the development and clinical efficacy of nonalcoholic fatty liver disease (NAFLD). The α-1-antitrypsin (AAT) is secreted by the liver and has an anti-inflammatory effect by inhibiting neutrophil elastase. According to the three genome-wide association analyses, AAT was related to NAFLD's progress, while no clinical studies have been reported yet. Recently, we found that the expression of AAT homologous protein Serpina1a was decreased in the NAFLD animal model, which might be related to liver endoplasmic reticulum stress. Therefore, we tend to establish two clinical NAFLD cohorts and three animal models of NAFLD and steatohepatitis (NASH) to explore whether the AAT can be used as a biomarker of NAFLD progression and to explore its potential new intervention targets and related mechanisms in NASH animal model. We hope that this project will help us further understand the mechanism of NAFLD's occurrence and progress and may provide new biomarkers of the event and development of NAFLD.