Abstract：
Impairment of the insulin signaling pathway is a key contributor to insulin resistance under arsenic exposure. Specifically, O-GlcNAcylation, an important post-translational modification, plays a crucial role in insulin resistance. Nevertheless, the concrete effect and mechanism of O-GlcNAcylation in arsenic-induced impairment of the insulin signaling pathway remain elusive. Herein, C57BL/6 mice were continuously fed arsenic-containing food, with a total arsenic concentration of 30 mg/kg. We observed that the IRS/Akt/GSK-3β insulin signaling pathway was impaired, and autophagy was activated in mouse livers and HepG2 cells exposed to arsenic. Additionally, O-GlcNAcylation expression in mouse livers and HepG2 cells was elevated, and the key O-GlcNAcylation homeostasis enzyme, O-GlcNAc transferase (OGT), was upregulated. In vitro, non-targeted metabolomic analysis showed that metabolic disorder was induced, and inhibition of O-GlcNAcylation restored the metabolic profile of HepG2 cells exposed to arsenic. In addition, we found that the compromised insulin signaling pathway was dependent on AMPK activation. Inhibition of AMPK mitigated autophagy activation and impairment of insulin signaling pathway under arsenic exposure. Furthermore, down-regulation of O-GlcNAcylation inhibited AMPK activation, thereby suppressing autophagy activation, and improving the impaired insulin signaling pathway. Collectively, our findings indicate that arsenic can impair the insulin signaling pathway by regulating O-GlcNAcylation homeostasis. Importantly, O-GlcNAcylation inhibition alleviated the impaired insulin signaling pathway by suppressing the AMPK/mTOR-autophagy pathway. This indicates that regulating O-GlcNAcylation may be a potential intervention for the impaired insulin signaling pathway induced by arsenic.
摘要：
胰岛素信号通路的受损是砷暴露下胰岛素抵抗的关键因素。具体来说,O-GlcNAcylation,一个重要的翻译后修饰，在胰岛素抵抗中起着至关重要的作用。然而，O-GlcNAcylation在砷诱导的胰岛素信号通路受损中的具体作用和机制尚不清楚。在这里，C57BL/6小鼠连续喂食含砷食物，总砷浓度为30mg/kg。我们观察到IRS/Akt/GSK-3β胰岛素信号通路受损,在暴露于砷的小鼠肝脏和HepG2细胞中，自噬被激活。此外,小鼠肝脏和HepG2细胞中的O-GlcNAcylation表达升高，和关键的O-GlcNAcylation稳态酶，O-GlcNAc转移酶（OGT），被上调了。体外，非靶向代谢组学分析表明,和O-GlcNAcylation的抑制恢复了暴露于砷的HepG2细胞的代谢谱。此外,我们发现受损的胰岛素信号通路依赖于AMPK的激活.抑制AMPK减轻砷暴露下自噬激活和胰岛素信号通路受损。此外，下调O-GlcNAcylation抑制AMPK激活，从而抑制自噬激活，改善受损的胰岛素信号通路。总的来说，我们的发现表明，砷可以通过调节O-GlcNAcylation稳态来损害胰岛素信号通路。重要的是,O-GlcNAcylation抑制通过抑制AMPK/mTOR-自噬途径减轻受损的胰岛素信号通路。这表明调节O-GlcNAcylation可能是砷诱导的胰岛素信号通路受损的潜在干预。
