SAD-A, a downstream mediator of GLP-1 signaling, promotes the phosphorylation of Bad S155 to regulate in vitro beta-cell functions
SAD-A, a downstream mediator of GLP-1 signaling, promotes the phosphorylation of Bad S155 to regulate in vitro beta-cell functions
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SAD-A 是 GLP-1 信号传导的下游介质，促进 Bad S155 的磷酸化以调节体外 β 细胞功能
DOI：
10.1016/j.bbrc.2018.12.063
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发表时间：
2019
影响因子：
3.1
通讯作者：
Han Xiao
中科院分区：
文献类型：
--
作者：
Wang Kai;Liu Dechen;Zhang Yaqin;Chang Xiaoai;Xu Rufeng;Pang Jing;Li Kai;Sun Peng;Zhu Yunxia;Han Xiao
肠促胰岛素激素 GLP-1 可减少 2 型糖尿病患者的 β 细胞衰竭。先前的研究表明，GLP-1 激活 AMPK 家族成员 SAD-A 来调节葡萄糖刺激分泌 (GSIS)，但 SAD-A 调节 β 细胞功能的潜在机制仍知之甚少。在此，我们提出 GLP-1 激活 SAD-A 会促进 Bad S155 的磷酸化，进而对 GSIS 和 β 细胞的存活产生积极影响。因此，Bad 似乎是 SAD-A 通路的下游分子，介导 GLP-1 触发的 β 细胞衰竭减少。内源性 SAD-A 表达的敲低会显着加剧脂毒性条件下的体外 β 细胞功能障碍，并促进脂毒性诱导的细胞凋亡，而 SAD-A 的过度表达会抑制 β 细胞凋亡。 SAD-A 沉默会增加 ER 应激并抑制自噬流，从而导致 β 细胞凋亡。因此，SAD-A 似乎充当 GLP-1 信号传导的下游分子，导致 Bad S155 磷酸化。因此，这种磷酸化可能参与 GLP-1 相关的针对 β 细胞功能障碍和细胞凋亡的保护。
The incretin hormone GLP-1 reduces β-cell failure in patients with type 2 diabetes. Previous studies demonstrated that GLP-1 activates SAD-A, a member of the AMPK family, to regulate glucose-stimulated secretion (GSIS), but the underlying mechanisms of SAD-A regulation of β-cell functions remain poorly understood. Here, we propose that activation of SAD-A by GLP-1 promotes the phosphorylation of Bad S155, which in turn positively affects GSIS and β-cell survival. Bad therefore appears to be a downstream molecule of a SAD-A pathway that mediates the GLP-1-triggered reduction in β-cell failure. Knockdown of endogenous SAD-A expression significantly exacerbated in vitro β-cell dysfunction under lipotoxic conditions and promoted lipotoxicity-induced apoptosis, whereas overexpression of SAD-A inhibited β-cell apoptosis. SAD-A silencing increased ER stress and inhibited the autophagic flux, which contributed to β-cell apoptosis. Thus, SAD-A appears to function as a downstream molecule of GLP-1 signaling that results in Bad S155 phosphorylation. This phosphorylation might therefore be involved in the GLP-1-linked protection against β-cell dysfunction and apoptosis.