Activation of Aldehyde Dehydrogenase 2 Ameliorates Glucolipotoxicity of Pancreatic Beta Cells.
Activation of Aldehyde Dehydrogenase 2 Ameliorates Glucolipotoxicity of Pancreatic Beta Cells.
复制标题
醛脱氢酶2的激活改善胰腺β细胞的糖脂毒性。
DOI：
10.3390/biom11101474
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发表时间：
2021-10-06
期刊：
影响因子：
5.5
通讯作者：
Chuang LM
中科院分区：
文献类型：
--
作者：
Chen SM;Hee SW;Chou SY;Liu MW;Chen CH;Mochly-Rosen D;Chang TJ;Chuang LM
慢性高血糖症和高脂血症阻碍β细胞功能，导致糖脂毒性。线粒体醛脱氢酶2（ALDH 2）使分别源自葡萄糖和脂质的反应性醛解毒，例如甲基乙二醛（MG）和4-羟基壬烯醛（4-HNE）。我们的目的是研究ALDH 2激活剂是否改善β细胞功能障碍和细胞凋亡诱导的糖脂毒性，及其潜在的作用机制。测定了MIN 6细胞中葡萄糖刺激的胰岛素分泌（GSIS）和灌流实验中分离的胰岛的胰岛素分泌。测定MIN 6细胞内ATP浓度和耗氧率。此外，细胞活力，凋亡，线粒体和细胞内活性氧（ROS）水平进行了测定。此外，还研究了促细胞凋亡、细胞凋亡和抗细胞凋亡信号通路。我们发现Alda-1通过改善胰腺β细胞的线粒体功能来增强GSIS。Alda-1从MG和4-HNE诱导的β细胞死亡、凋亡、线粒体功能障碍和ROS产生中拯救了MIN 6细胞。然而，在Aldh 2敲低的MIN 6细胞中，Alda-1的上述作用被消除。总之，我们报道了ALDH 2的激活剂不仅增强GSIS，而且通过降低线粒体和细胞内ROS水平来改善β细胞的糖脂毒性，从而改善线粒体功能，恢复β细胞功能，并保护β细胞免于凋亡和死亡。
Chronic hyperglycemia and hyperlipidemia hamper beta cell function, leading to glucolipotoxicity. Mitochondrial aldehyde dehydrogenase 2 (ALDH2) detoxifies reactive aldehydes, such as methylglyoxal (MG) and 4-hydroxynonenal (4-HNE), derived from glucose and lipids, respectively. We aimed to investigate whether ALDH2 activators ameliorated beta cell dysfunction and apoptosis induced by glucolipotoxicity, and its potential mechanisms of action. Glucose-stimulated insulin secretion (GSIS) in MIN6 cells and insulin secretion from isolated islets in perifusion experiments were measured. The intracellular ATP concentrations and oxygen consumption rates of MIN6 cells were assessed. Furthermore, the cell viability, apoptosis, and mitochondrial and intracellular reactive oxygen species (ROS) levels were determined. Additionally, the pro-apoptotic, apoptotic, and anti-apoptotic signaling pathways were investigated. We found that Alda-1 enhanced GSIS by improving the mitochondrial function of pancreatic beta cells. Alda-1 rescued MIN6 cells from MG- and 4-HNE-induced beta cell death, apoptosis, mitochondrial dysfunction, and ROS production. However, the above effects of Alda-1 were abolished in Aldh2 knockdown MIN6 cells. In conclusion, we reported that the activator of ALDH2 not only enhanced GSIS, but also ameliorated the glucolipotoxicity of beta cells by reducing both the mitochondrial and intracellular ROS levels, thereby improving mitochondrial function, restoring beta cell function, and protecting beta cells from apoptosis and death.
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