G protein-coupled bile acids receptor 1 (GPBAR1 or TGR5) has been widely studied as a metabolic regulator involved in bile acids synthesis, glucose metabolism and energy homeostasis. Several recent studies have shown that mammalian GPBAR1 is also involved in antiviral innate immune responses. However, the functions of piscine GPBAR1 in antibacterial or antiviral immune responses and lipid metabolism remain unclear. In the present study, we report the functional characterization of zebrafish gpbar1. Similar to mammalian GPBAR1, zebrafish gpbar1 contains similar domain composition, shows a dose-dependent activation by bile acids including INT777, LCA, DCA, CDCA and CA, and can be induced by viral infection. Compared with corresponding control groups, a significant antiviral activity against spring viremia of carp virus (SVCV) infection was observed in ZF4 cells overexpressing zebrafish gpbar1 with INT777 treatment, but not in ZF4 cells overexpressing zebrafish gpbar1 without INT777 treatment. The activation of zebrafish gpbar1 had no significant antibacterial effect against Edwardsiella piscicida infection in ZF4 cells in vitro. Transcriptome analysis revealed that zebrafish gpbar1 activation played a crucial role in activating RLR signaling pathway and inducing the production of ISGs, but not for bile acid biosynthesis and transportation. The co-occurrence analysis for antiviral-related and bile acids metabolism-related DEGs suggested a strong interaction among 2 bile acid receptors (gpbar1 and nr1h4), slco2b1 and the antiviral DEGs. The lipidomic analysis showed that zebrafish gpbar1 activation in ZF4 cells resulted a change of glycerophospholipids, but none of bile acids nor their derivatives, which were different from mammalian GPBAR1. All together, these results firstly demonstrate the conserved antiviral role of gpbar1 and its function in regulating glycerophospholipids metabolism in teleost.

G 蛋白偶联胆汁酸受体 1（GPBAR1 或 TGR5）已被广泛研究为参与胆汁酸合成、葡萄糖代谢和能量稳态的代谢调节剂。最近的几项研究表明，哺乳动物 GPBAR1 也参与抗病毒先天免疫反应。然而，鱼GPBAR1在抗菌或抗病毒免疫反应和脂质代谢中的作用仍不清楚。在本研究中，我们报告了斑马鱼gpbar1的功能特征。类似于哺乳动物GPBAR1、斑马鱼gpbar1包含相似的结构域组成，显示出由包括 INT777、LCA、DCA、CDCA 和 CA 在内的胆汁酸引起的剂量依赖性激活，并且可以由病毒感染诱导。与相应的对照组相比，在用INT777处理过表达斑马鱼gpbar1的ZF4细胞中观察到对鲤鱼病毒血症（SVCV）感染的显着抗病毒活性，但在没有INT777处理的过表达斑马鱼gpbar1的ZF4细胞中没有观察到。斑马鱼gpbar1的激活对ZF4细胞体外感染爱德华氏菌没有明显的抗菌作用。转录组分析显示斑马鱼gpbar1活化在激活 RLR 信号通路和诱导 ISG 的产生中起关键作用，但对胆汁酸的生物合成和运输不重要。抗病毒相关和胆汁酸代谢相关 DEG 的共现分析表明 2 种胆汁酸受体（gpbar1和nr1h4）、slco2b1和抗病毒 DEG 之间存在强烈的相互作用。脂质组学分析表明，ZF4 细胞中斑马鱼gpbar1的激活导致甘油磷脂的变化，但胆汁酸及其衍生物均与哺乳动物 GPBAR1 不同。总之，这些结果首先证明了gpbar1的保守抗病毒作用及其在硬骨鱼甘油磷脂代谢中的调节作用。