Transcriptomic analysis of a mouse model of Acetaminophen-induced hepatitis

Acetaminophen (APAP) is a widely used analgesic and antipyretic drug recognized as one of the major causes of liver disease. While safe at recommend doses, APAP overdose might cause acute liver failure, representing the first cause for liver transplantation in several Western countries. GPBAR1, also known as TGR5, is a steroid-activated G protein-coupled receptor (GPCRs), activated by secondary bile acids. GPBAR1 is not expressed by hepatocytes, but is highly represented by Kupffer cells, monocytes and macrophages, NKT cells and liver sinusoidal cells. Previous studies have shown that GPBAR1 activation regulates these cells of innate immunity, contributing to maintenance of a tolerogenic state by intestinal and liver macrophages. Here, we investigated the role of GPBAR1 in a mouse model of APAP-induced hepatitis. To gain insights on the pathogenesis and on the therapeutic role of GPBAR1 agonism in this model, mice were administered with APAP (500 mg/kg), alone or in combination with a GPBAR1 agonist, known as BAR501 (30 mg/kg). Total RNA extracted from the livers of each group of mice were subjected to RNAseq analysis performed on Ion S5 Sequencer with Torrent Suite Software v6.对乙酰氨基酚（Acetaminophen, APAP）是临床广泛应用的镇痛解热药物，同时也是引发肝脏疾病的主要诱因之一。按推荐剂量使用时安全性良好，但APAP过量可诱发急性肝衰竭，在多个西方国家中已成为肝移植的首要病因。GPBAR1（亦称TGR5）是一类可被次级胆汁酸激活的类固醇类G蛋白偶联受体（G protein-coupled receptors, GPCRs）。该受体并不表达于肝细胞，而在库普弗细胞、单核细胞、巨噬细胞、自然杀伤T细胞（NKT cells）及肝窦状细胞中高表达。既往研究表明，GPBAR1激活可调控上述固有免疫细胞，通过肠道与肝脏巨噬细胞维持免疫耐受状态。本研究旨在探究GPBAR1在APAP诱导性肝炎小鼠模型中的作用。为深入解析该模型的发病机制以及GPBAR1激动的治疗作用，研究人员对小鼠单独给予APAP（500 mg/kg），或联合给予GPBAR1激动剂BAR501（30 mg/kg）。随后提取各组小鼠肝脏的总RNA，采用Ion S5测序仪结合Torrent Suite软件v6开展RNA测序分析。