College of Pharmacy, Pusan National University, Busan 609-735, Republic of Korea.
College of Pharmacy, Pusan National University, Busan 609-735, Republic of Korea.
Cell Signal. 2019 Jan;53:190-200. doi: 10.1016/j.cellsig.2018.10.001. Epub 2018 Oct 7.
Although GPR35 is an orphan G protein-coupled receptor, synthetic agonists and antagonists have been developed. Recently, cromolyn, a mast cell stabilizer, was reported as an agonist of GPR35 and was shown to exhibit antifibrotic effects through its actions on hepatocytes and stellate cells. In this study, the role of GPR35 in hepatic steatosis was investigated using an in vitro model of liver X receptor (LXR)-mediated hepatocellular steatosis and an in vivo model of high fat diet-induced liver steatosis. GPR35 was expressed in Hep3B human hepatoma cells and mouse primary hepatocytes. A specific LXR activator, T0901317, induced lipid accumulation in Hep3B cells. Lodoxamide, the most potent agonist of GPR35, inhibited lipid accumulation in a concentration-dependent manner. The protective effect of lodoxamide was inhibited by a specific GPR35 antagonist, CID2745687, and by siRNA-mediated knockdown of GPR35. The expression of SREBP-1c, a key transcription factor for lipid synthesis, was induced by T0901317 and the induction was inhibited by lodoxamide. Through the use of specific inhibitors of cellular signaling components, the lodoxamide-induced inhibition of lipid accumulation was found to be mediated through p38 MAPKs and JNK, but not through G proteins and ERKs. Furthermore, the protective effect of lodoxamide was confirmed in mouse primary hepatocytes. Lodoxamide suppressed high fat diet-induced fatty liver development, which suggested the protective function of GPR35 in liver steatosis. Therefore, the present data suggest that GPR35 may function to protect against fatty liver development.
虽然 GPR35 是一种孤儿 G 蛋白偶联受体，但已经开发出了它的合成激动剂和拮抗剂。最近，肥大细胞稳定剂 cromolyn 被报道为 GPR35 的激动剂，并被证明通过其对肝细胞和星状细胞的作用发挥抗纤维化作用。在这项研究中，使用肝 X 受体 (LXR) 介导的肝细胞脂肪变性的体外模型和高脂肪饮食诱导的肝脂肪变性的体内模型研究了 GPR35 在肝脂肪变性中的作用。GPR35 在 Hep3B 人肝癌细胞和小鼠原代肝细胞中表达。一种特定的 LXR 激活剂 T0901317 诱导 Hep3B 细胞内脂质积累。GPR35 的最有效激动剂 lodoxamide 以浓度依赖的方式抑制脂质积累。特异性 GPR35 拮抗剂 CID2745687 和 GPR35 的 siRNA 介导的敲低抑制了 lodoxamide 的保护作用。脂质合成的关键转录因子 SREBP-1c 的表达被 T0901317 诱导，而 lodoxamide 抑制了这种诱导。通过使用细胞信号转导成分的特异性抑制剂，发现 lodoxamide 诱导的脂质积累抑制是通过 p38 MAPKs 和 JNK 介导的，而不是通过 G 蛋白和 ERKs 介导的。此外，在小鼠原代肝细胞中证实了 lodoxamide 的保护作用。Lodoxamide 抑制高脂肪饮食诱导的脂肪肝发展，这表明 GPR35 在肝脂肪变性中具有保护作用。因此，目前的数据表明 GPR35 可能具有预防脂肪肝发展的作用。
