Key Laboratory of Aquaculture Nutrition and Feed, Ministry of Agriculture & Key Laboratory of Mariculture, Ministry of Education, College of Fisheries, Ocean University of China, Qingdao, China.
State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China.
FASEB J. 2022 May;36(5):e22330. doi: 10.1096/fj.202200334RR.
1,25-dihydroxyvitamin D [1,25(OH) D ], the most active vitamin D (VD) metabolite, is a steroid hormone playing an important role in many physiological functions in addition to maintaining mineral homeostasis. In this study, we explored the mechanism that the VD regulated insulin pathway and glucose metabolism in zebrafish in vitro and in vivo. Our results show that 1,25(OH) D significantly enhances the expression of insulin receptor a (insra), insulin receptor substrate 1 (irs1) and glucose transporter 2 (glut2), and promotes glycolysis and glycogenesis, while suppressing gluconeogenesis in zebrafish liver cell line (ZFL) under the condition of high glucose (20 mM), instead of the normal glucose (10 mM). Moreover, consistent results were obtained from the zebrafish fed with VD -deficient diet, as well as the cyp2r1 zebrafish, in which endogenous VD metabolism is blocked. Furthermore, results from dual-luciferase reporting system exhibited that 1,25(OH) D directly activated the transcription of insra, rather than insrb in zebrafish by binding to vitamin D response element (VDRE) located at -181 to -167 bp in the promoter region of insra. Importantly, the 1,25(OH) D treatment significantly alleviated the symptoms of hyperglycemia in diabetic zebrafish. In conclusion, our study demonstrated that VD activates VDRE located in the promoter area of insra in zebrafish to promote insulin/insra signaling pathway, thereby contributing to the maintenance of glucose homeostasis.
1,25-二羟维生素 D [1,25(OH) D ]，是维生素 D（VD）的最活跃代谢物，是一种甾体激素，除了维持矿物质稳态外，在许多生理功能中也发挥着重要作用。在这项研究中，我们探讨了 VD 在体外和体内调节斑马鱼胰岛素通路和葡萄糖代谢的机制。我们的结果表明，1,25(OH) D 可显著增强胰岛素受体 a（insra）、胰岛素受体底物 1（irs1）和葡萄糖转运蛋白 2（glut2）的表达，并促进糖酵解和糖异生，同时抑制高糖（20 mM）条件下斑马鱼肝细胞系（ZFL）的糖异生，而不是正常葡萄糖（10 mM）。此外，从喂食缺乏 VD 饮食的斑马鱼以及内源性 VD 代谢受阻的 cyp2r1 斑马鱼中也得到了一致的结果。此外，双荧光素酶报告系统的结果表明，1,25(OH) D 通过与 insra 启动子区域 -181 至 -167 bp 处的维生素 D 反应元件（VDRE）结合，直接激活了斑马鱼 insra 的转录，而不是 insrb。重要的是，1,25(OH) D 处理显著缓解了糖尿病斑马鱼的高血糖症状。总之，我们的研究表明，VD 通过激活位于 insra 启动子区域的 VDRE，在斑马鱼中激活胰岛素/insra 信号通路，从而有助于维持葡萄糖稳态。
