药物诱导的胆汁淤积中FABP4通过SphK-S1P信号通路对肝细胞损伤及适应性保护的作用及分子机制研究

药物性肝损伤（DILI）备受关注，其中药物诱导的胆汁淤积（DIC）易导致慢性肝病及恶性结局。高浓度胆汁酸（BAs）蓄积是DIC病理过程的重要事件，常导致肝细胞损伤的恶性反应及伴随下调BAs的适应性保护反应。脂代谢异常与DILI的损伤类型和转归密切相关，其机制尚不清楚。我们前期工作发现脂肪酸结合蛋白4（FABP4）在DIC患者血清、DIC小鼠肝组织中显著上调；敲除FABP4可改善DIC小鼠肝损伤，改变BAs合成及组成，抑制肝组织SphK-S1P信号通路，其中机制亟需进一步研究。本项目拟以脂代谢异常的脂肪因子为切入点，系统性研究和明确FABP4调节肝细胞恶性反应和适应性反应在DIC中的致病作用和机制，揭示FABP4调控SphK-S1P信号通路的规律，评估FABP4作为临床DILI及DIC严重程度和预后预测价值，明晰靶向干预FABP4对治疗DIC的潜在价值，为形成DILI诊疗新策略奠定基础。

Drug-induced liver injury (DILI) has attracted much attention, and drug-induced cholestasis (DIC) is prone to cause chronic liver disease and malignant outcomes. Excessive high concentration of bile acids (BAs) accumulation is an indispensable event in DIC, which often leads to the deteriorative response of hepatocyte injury and the adaptive response for down-regulation of BAs to protect liver. Previous studies have found that abnormal lipid metabolism is significantly related to injury types and clinical outcomes of DILI. We found that fatty acid binding protein 4（FABP4）was significantly increased in serum of DIC patients and liver tissue of DIC mice; knocking out FABP4 could improve liver damage in DIC mice, down-regulate BAs synthesis, change BAs composition, and inhibit SphK-S1P signaling pathway. However, the underlying mechanism remains unclear. Taking adipocytokines in abnormal lipid metabolism as an entry point, the aim of this project is to investigate the pathogenic role and mechanism of FABP4 in regulating the hepatocellular deteriorative response and adaptive response in DIC, to reveal the regulatory mechanism of SphK-S1P signaling pathway by FABP4, to evaluate the predictive value of FABP4 in prognosis of DILI and DIC, and to clarify the therapeutic potential of FABP4 in DIC.