骨形态发生拮抗蛋白1参与调控脂毒性介导的胰岛β细胞功能障碍

Gremlin-1 protein is involved in the regulation of lipotoxicity-mediated islet β-cell dysfunction

目的探索骨形态发生拮抗蛋白1(Gremlin-1)在脂毒性介导的胰岛β细胞功能障碍中的作用和机制。方法利用棕榈酸(palmitic acid, PA)处理小鼠胰岛β细胞(MIN6)作为脂毒性介导胰岛β细胞功能障碍模型, 首先考察PA引起的脂质沉积及胰岛素分泌水平改变, 明确脂毒性对胰岛β细胞的影响, 进一步利用qPCR、Western blot等方法考察PA对Gremlin-1表达及其下游信号通路BMP4/Smads的影响。随后利用重组小鼠Gremlin-1和BMP信号通路抑制剂LDN193189干预细胞, 并与对照组进行比较。结果 PA刺激能够降低胰岛β细胞活力及胰岛素分泌能力(P<0.05)。同时, PA能够抑制细胞Gremlin-1的表达和分泌, 增加BMP-4及其下游Smad-1、Smad-5的表达(P<0.05)。利用重组小鼠Gremlin-1蛋白干预细胞可使细胞的胰岛素分泌显著升高, 同时BMP4/Smads信号通路中的关键分子表达降低(P<0.05)。而抑制BMP4/Smads信号通路可改善PA导致的胰岛β细胞功能障碍。结论 Gremlin-1参与调控脂毒性介导的胰岛β细胞功能障碍, 该作用可能与BMP4/Smads信号通路激活有关。

Objective Exploring the role and mechanism of gremlin-1 in lipotoxicity-mediated pancreaticβ-cell dysfunction.Methods The model of lipid toxicity-mediated pancreaticβ-cell dysfunction was constructed using palmitic acid(PA)to treat mouse pancreaticβ-cells(MIN6).Initially,to clarify the effects of lipotoxicity on isletβ-cells,the cellular lipid deposition and changes in the levels of insulin caused by PA were detected.The effects of PA on gremlin-1 expression and its downstream signaling pathway BMPs/Smads were further investigated using qPCR and Western Blot assay.Subsequently,recombinant mouse gremlin-1 protein and BMP signaling pathway inhibitor LDN193189 were used to intervene the cells to explore the effects of gremlin-1 and its downstream signaling pathway BMPs/Smads on pancreatic isletβ-cells.Results PA could reduce pancreaticβ-cell viability and insulin secretion capacity(P<0.05).Meanwhile,PA inhibited the expression and secretion of cell gremlin-1 and upregulated BMP-4 and its downstream Smad-1 and Smad-5(P<0.05).Intervention of cells with recombinant mouse gremlin-1 protein resulted in a significant elevation of insulin secretion and a concomitant decrease in the expression of key molecules in the BMP4/Smads signaling pathway(P<0.05).And inhibition of the BMP4/Smads signaling pathway ameliorated PA-induced pancreaticβ-cell dysfunction.Conclusion Gremlin-1 is involved in the regulation of lipotoxicity-mediated pancreatic isletβ-cell dysfunction,and this effect may be associated with activation of BMP4/Smads signaling pathway.