FGF4及其非促分裂改构体对非酒精性脂肪肝作用及分子机制研究

非酒精性脂肪性肝病（Nonalcoholic fatty liver disease, NAFLD）是当前严重威胁人类健康的慢性疾病，患者数量庞大、致病机制复杂且缺乏有效的治疗手段。新近研究表明，肝脏组织易感基因在NAFLD/NASH发生发展中起着重要作用，已成为脂肪肝疾病治疗的关键靶点。本课题前期基于临床研究发现了一种NAFLD/NASH新型疾病响应因子——成纤维细胞生长因子FGF4，且外周注射FGF4蛋白能显著改善2型糖尿病脂肪肝的脂肪变性，提示内源性FGF4可能是NAFLD/NASH的新易感基因。本课题首次拟通过构建肝脏组织特异性Fgf4基因敲除鼠验证这一假设；进一步通过分子改良构建非促分裂的FGF4改构体，并利用该分子深入开展对NAFLD/NASH的治疗作用和分子机制研究。通过本课题的实施，有望为日益严峻的NAFLD/NASH新治疗靶点的发现和新药物的开发提供关键理论支撑。

Nonalcoholic fatty liver disease (NAFLD) is a chronic disease that currently poses a serious threat to human health, with up to 300 million patients, about 20% of which have evolved into end-stage liver diseases such as liver fibrosis and cirrhosis. It has a large number of patients, complicated pathogenic mechanisms, and lacks effective treatments. Recent studies have shown that liver tissue susceptibility genes play an important role in the occurrence and development of NAFLD / NASH, and constitute a key target for the treatment of fatty liver disease. Based on clinical research, we found that fibroblast growth factor FGF4 is a new disease response factor for NAFLD/NASH, and peripheral injection of FGF4 protein can significantly ameliorate steatosis of fatty liver in type 2 diabetes, suggesting that endogenous FGF4 may be a new susceptibility gene of NAFLD/NASH. This project is the first to verify this hypothesis by constructing liver tissue-specific Fgf4 knockout mice. And use this molecule to carry out in-depth research on the therapeutic effect and molecular mechanism of NAFLD/NASH. Through the implementation of this project, it is expected to provide key theoretical basis for the discovery of new treatment targets for NAFLD/NASH and the development of new drugs.