Fasiglifam (TAK-875), a G protein-coupled receptor 40 (GPR40) agonist, was a drug candidate for type 2 diabetes. However, its development was terminated in phase 3 trials due to liver safety concerns. Although TAK-875 was reported to inhibit hepatobiliary transporters and disturb bile acid disposition, pathogenic mechanisms of TAK-875-induced liver injury are not fully understood. In this study, we sought to identify the mechanisms with a hepatic genome-wide transcriptomic analysis in a murine model. We demonstrated that, among the three GPR40 agonists, TAK-875, AMG-837, and TUG-770, only TAK-875 induced acute liver injury in mice. Transcriptome profiles of TAK-875-exposed liver was compared with those of non-hepatotoxic analogues AMG-837 and TUG-770 as negative controls and those of classical hepatotoxicants concanavalin A and carbon tetrachloride as positive controls. The comparative hepatic transcriptome analyses revealed the enrichment of genes involved in inflammation, endoplasmic reticulum (ER) stress, apoptosis, and hepatic lipid accumulation, suggesting that these events play pathophysiologic roles in the development of TAK-875-induced liver injury. These results were validated by quantitative PCR with significant changes in chemokines, danger signals, ER stress mediators, proapoptotic factors, and hepatic steatosis markers only in TAK-875-exposed liver. Pretreatment of TAK-875-administered mice with an ER stress inhibitor 4-phenylbutyric acid (4-PBA) alleviated the liver injury. Consistent with the in vivo study, pretreatment of HepG2 cells with 4-PBA significantly improved the decrease of cell viability induced by TAK-875. In conclusion, by a comprehensive transcriptomic analysis, we found multiple possible processes that contribute to TAK-875-induced acute liver injury in mice.

Fasiglifam（TAK-875）是一种G蛋白偶联受体40（GPR40）激动剂，是2型糖尿病的候选药物。但是，由于对肝脏安全的担忧，该药的开发已在3期试验中终止。尽管据报道TAK-875抑制肝胆转运蛋白并干扰胆汁酸的分布，但TAK-875诱导的肝损伤的致病机制尚不完全清楚。在这项研究中，我们试图通过在小鼠模型中进行全肝基因组转录组分析来确定机制。我们证明，在三种GPR40激动剂TAK-875，AMG-837和TUG-770中，只有TAK-875诱导了小鼠的急性肝损伤。将TAK-875暴露的肝脏的转录组图谱与非肝毒性类似物AMG-837和TUG-770的转录组图谱作阴性对照，比较经典肝毒性伴刀豆球蛋白A和四氯化碳的转录组图谱作为阳性对照。肝转录组比较分析显示，涉及炎症，内质网（ER）应激，细胞凋亡和肝脂质蓄积的基因富集，表明这些事件在TAK-875诱导的肝损伤的发生中起病理生理作用。这些结果通过定量PCR进行了验证，只有在暴露于TAK-875的肝脏中，趋化因子，危险信号，内质网应激介质，促凋亡因子和肝脂肪变性标志物才发生明显变化。用ER应激抑制剂4-苯基丁酸（4-PBA）预处理TAK-875给药的小鼠可减轻肝脏损伤。符合在体内研究中，用4-PBA预处理HepG2细胞可显着改善TAK-875诱导的细胞活力的降低。总之，通过全面的转录组分析，我们发现了多种可能的过程，这些过程可能导致TAK-875诱导的小鼠急性肝损伤。