Department of Medicine, Yonsei University College of Medicine, Seoul 03722, Korea.
Department of Medical Science, BK21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Korea.
Int J Mol Sci. 2020 May 28;21(11):3824. doi: 10.3390/ijms21113824.
Glucagon-like peptide-1 (GLP-1) is a well-known incretin hormone secreted from enteroendocrinal L cells in response to nutrients, such as glucose and dietary fat, and controls glycemic homeostasis. However, the detailed intracellular mechanisms of how L cells control GLP-1 secretion in response to nutrients still remain unclear. Here, we report that bone morphogenetic protein (BMP) signaling pathway plays a pivotal role to control GLP-1 secretion in response to nutrient replenishment in well-established mouse enteroendocrinal L cells (GLUTag cells). Nutrient starvation dramatically reduced cellular respiration and GLP-1 secretion in GLUTag cells. Transcriptome analysis revealed that nutrient starvation remarkably reduced gene expressions involved in BMP signaling pathway, whereas nutrient replenishment rescued BMP signaling to potentiate GLP-1 secretion. Transient knockdown of inhibitor of DNA binding (ID)1, a well-known target gene of BMP signaling, remarkably reduced GLP-1 secretion. Consistently, LDN193189, an inhibitor of BMP signaling, markedly reduced GLP-1 secretion in L cells. In contrast, BMP4 treatment activated BMP signaling pathway and potentiated GLP-1 secretion in response to nutrient replenishment. Altogether, we demonstrated that BMP signaling pathway is a novel molecular mechanism to control GLP-1 secretion in response to cellular nutrient status. Selective activation of BMP signaling would be a potent therapeutic strategy to stimulate GLP-1 secretion in order to restore glycemic homeostasis.
胰高血糖素样肽 1（GLP-1）是一种众所周知的肠促胰岛素激素，它是响应葡萄糖和膳食脂肪等营养物质从肠内分泌 L 细胞分泌的，可控制血糖稳态。然而，L 细胞如何响应营养物质控制 GLP-1 分泌的详细细胞内机制仍不清楚。在这里，我们报告骨形态发生蛋白（BMP）信号通路在响应营养物质补充时控制 GLP-1 分泌中起关键作用，在成熟的小鼠肠内分泌 L 细胞（GLUTag 细胞）中也是如此。营养物质饥饿显著降低了 GLUTag 细胞中的细胞呼吸和 GLP-1 分泌。转录组分析显示，营养物质饥饿显著降低了 BMP 信号通路相关基因的表达，而营养物质补充则挽救了 BMP 信号，增强了 GLP-1 分泌。瞬时敲低 BMP 信号的靶基因 ID1（抑制剂 of DNA binding 1），显著降低了 GLP-1 的分泌。一致地，BMP 信号抑制剂 LDN193189 显著降低了 L 细胞中的 GLP-1 分泌。相比之下，BMP4 处理激活了 BMP 信号通路，并增强了响应营养物质补充时的 GLP-1 分泌。总之，我们证明了 BMP 信号通路是响应细胞营养状态控制 GLP-1 分泌的新分子机制。选择性激活 BMP 信号可能是刺激 GLP-1 分泌以恢复血糖稳态的有效治疗策略。
