Du Jianlong, Zhang Junzhi, Xiang Xiaojun, Xu Dan, Cui Kun, Mai Kangsen, Ai Qinghui
Key Laboratory of Aquaculture Nutrition and Feed (Ministry of Agriculture and Rural Affairs), The Key Laboratory of Mariculture (Ministry of Education), Ocean University of China, Qingdao, China.
Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China.
Front Nutr. 2022 Nov 24;9:1024631. doi: 10.3389/fnut.2022.1024631. eCollection 2022.
Unfolded protein responses from endoplasmic reticulum (ER) stress have been implicated in inflammatory signaling. The vicious cycle of ER stress and inflammation makes regulation even more difficult. This study examined effects of farnesoid X receptor (FXR) in ER-stress regulation in large yellow croakers. The soybean-oil-diet-induced expression of ER stress markers was decreased in fish with FXR activated. In croaker macrophages, FXR activation or overexpression significantly reduced inflammation and ER stress caused by tunicamycin (TM), which was exacerbated by FXR knockdown. Further investigation showed that the TM-induced phosphorylation of PERK and EIF2α was inhibited by the overexpression of croaker FXR, and it was increased by FXR knockdown. Croaker NCK1 was then confirmed to be a regulator of PERK, and its expression in macrophages is increased by FXR overexpression and decreased by FXR knockdown. The promoter activity of croaker NCK1 was inhibited by yin-yang 1 (YY1). Furthermore, the results show that croaker FXR overexpression could suppress the P65-induced promoter activity of YY1 in HEK293t cells and decrease the TM-induced expression of in macrophages. These results indicate that FXR could suppress P65-induced expression and then increase NCK1 expression, thereby inhibiting the PERK pathway. This study may benefit the understanding of ER stress regulation in fish, demonstrating that FXR can be used in large yellow croakers as an effective target for regulating ER stress and inflammation.
内质网（ER）应激引发的未折叠蛋白反应与炎症信号传导有关。ER应激和炎症的恶性循环使得调节变得更加困难。本研究检测了法尼醇X受体（FXR）对大黄鱼ER应激调节的影响。在FXR激活的鱼类中，大豆油饮食诱导的ER应激标志物表达降低。在大黄鱼巨噬细胞中，FXR激活或过表达显著减轻了衣霉素（TM）引起的炎症和ER应激，而FXR敲低则加剧了这种炎症和应激。进一步研究表明，大黄鱼FXR的过表达抑制了TM诱导的PERK和EIF2α磷酸化，而FXR敲低则使其增加。随后证实大黄鱼NCK1是PERK的调节因子，其在巨噬细胞中的表达因FXR过表达而增加，因FXR敲低而降低。阴阳1（YY1）抑制了大黄鱼NCK1的启动子活性。此外，结果表明，大黄鱼FXR过表达可抑制HEK293t细胞中P65诱导的YY1启动子活性，并降低巨噬细胞中TM诱导的YY1表达。这些结果表明，FXR可抑制P65诱导的YY1表达，进而增加NCK1表达，从而抑制PERK途径。本研究可能有助于理解鱼类中的ER应激调节，表明FXR可作为调节大黄鱼ER应激和炎症的有效靶点。
