聚甘露糖醛酸硫酸酯及寡糖在表达FGFR1c的BaF3细胞中可激活FGF1/19/21信号通路  

Polymannuronate sulfate and its oligosaccharides activates FGF1,FGF19,and FGF21 signaling in FGFR1c-expressing BaF3 cells

作　　者：兰莹[1] 郝翠[2] 张丽娟[1,2] 

机构地区：[1]中国海洋大学海洋药物教育部重点实验室,山东省糖科学与糖工程重点实验室,医药学院,山东青岛266003 [2]脑血管病研究所,青岛大学附属医院,山东青岛266003

出　　处：《中国海洋药物》2017年第1期1-6,共6页Chinese Journal of Marine Drugs

基　　金：国家自然科学基金项目(91129706);国家自然科学基金山东联合基金项目(U1406402);国家重点基础研究发展计划项目(2013BAB01B02);山东省重大科技项目(2015ZDJS04002);山东泰山学者专项基金(张丽娟)资助

摘　　要：目的近几年来发表的数据显示成纤维细胞生长因子(FGFs),包括FGF1,FGF19和FGF21,具有类似于胰岛素的代谢调节功能。例如,在饮食诱导的糖尿病小鼠中,FGF1的单次注射足以使血糖水平恢复到正常范围;同时FGF19或FGF21过表达可以校正糖耐量受损的小鼠。在细胞表面,FGFs通过FGF受体(FGFR)和糖胺聚糖进行信号传导。FGF1与属于糖胺聚糖的肝素具有高亲和力,而FGF19和FGF21与肝素无亲和力。糖胺聚糖结构多样,是信息含量最高的生物大分子。作者认为如果非肝素类多糖可以刺激FGF19/FGFR和FGF21/FGFR的信号传导,这类化合物有可能成为调节代谢疾病的新型药物。方法采用表达FGFR1c的BaF3细胞作为筛选具有活性多糖与寡糖的模型。结果发现聚甘露糖醛酸硫酸酯(PMS)及寡糖(PMS12及PMS25)可以增强FGF19和FGF21介导下的BaF3细胞中3 H-胸苷嘧啶标记的DNA合成,而聚甘露糖醛酸(PM)无此作用。此外,PMS,PMS寡糖包括其二糖与肝素类似具有增强FGF1/FGFR1c信号通路介导的BaF3的细胞增殖作用。结论由于PMS及其寡糖可通过口服途径被吸收,因此这些廉价的海藻酸衍生物有可能通过增强FGF1/FGFR1c,FGF19/FGFR1c和FGF21/FGFR1c的信号传导而被开发成为治疗2型糖尿病的新型口服药物。Objective Fibroblast growth factors （FGFs） including FGF1, FGF19, and FGF21 regulate metabolic functions in a way similar to that of insulin. For example, in mice with diet-induced diabetes, a single injection of FGF1 is enough to restore blood sugar level to a healthy range whereas over-ex- pressing FGF19 or FGF21 in mice also corrects impaired glucose tolerance. FGFs signal through FGF receptors （FGFRs） and glycosaminoglycans. Interestingly, FGF1 binds heparin with high affinity whereas FGF19 and FGF21 do not, indicating other polysaccharides other than heparin might enhance FGF19/FGFR and FGF21/FGFR signaling. Methods We used a FGF/FGFRlc signaling-dependent BaF3 cell proliferation assay to screen poly- and oligosaccharides that could activate FGF/FGFR signa- ling. Results We discovered that polymannuronate sulfate （PMS） and its oligosaccharides, PMS12 and PMS25, but not polymannuronate （PM）, a natural marine polysaceharide, enhanced FGF19/FGFRlc and FGF21/FGFRlc signaling better than that of heparin based on a H-thymidine incorporation in FG- FRlc-expressing BaF3 cells. In addition, PSM and PMS oligosaecharides including its sulfated disaccha- rides, but not PM, had FGF1/FGFRlc signal-stimulating activity similar to that of heparin. Conclusion Our results indicated that PMS and its oligosaccharides were excellent FGF1/FGFRlc, FGF19/FG- FRlc, and FGF21/FGFRlc signaling enhancers at cellular level. Since the inexpensive PMS and its oli- gosaccharides could be absorbed through oral route, these seaweed-derived compounds were interesting agents that might be useful for treating type 2 diabetes through enhancing FGF1/FGFRlc, FGF19/FG- FRlc, and FGF21/FGFRlc signaling in near future.

关 键 词：聚甘露糖醛酸硫酸酯 聚甘露糖醛酸硫酸酯寡糖 成纤维细胞生长因子(FGF) 成纤维细胞生长因子受体(FGFR) 糖尿病 

分 类 号：R965[医药卫生—药理学]