Department of Endocrinology, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai 200137, China.
Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.
Oxid Med Cell Longev. 2022 Sep 6;2022:4674215. doi: 10.1155/2022/4674215. eCollection 2022.
Lipotoxicity can lead to beta-cell dysfunction and apoptosis because it induces oxidative stress. Recent studies have found that Irisin prevents pancreatic beta-cell dysfunction induced by palmitic acid (PA). However, an association between the protection against oxidative stress conferred by Irisin and beta-cell dysfunction has not been fully elucidated. In this study, we observed that Irisin treatment prevented INS-1 cell apoptosis induced by PA treatment and preserved the insulin-secreting function of INS-1 cells in vitro. These effects probably resulted from the Irisin-induced decrease in intracellular ROS levels triggered by PA treatment. In addition, PA treatment induced oxidative stress partially by inhibiting the activation of thioredoxin 2 (Trx2) through its increase of thioredoxin-interacting protein (Txnip) expression. However, Irisin administration blocked the increase in Txnip expression, which reversed the PA-induced inactivation of Trx2. Irisin also increased the nuclear translocation of Stat3, and the inhibition of Stat3 by siRNAs blocked Irisin-induced Trx2 expression, indicating that both Txnip and Stat3 are involved in Irisin-induced activation of Trx2. Furthermore, blockade of Stat3 by siRNAs led to the decreased gene expression of and and to cessation of glucose-induced insulin secretion that had been enhanced by Irisin. In vivo, HFD treatment led to reduced glucose tolerance and an increase in the level of the oxidative marker malondialdehyde (MDA) compared to that in the control group. However, these effects were ameliorated by Irisin injection due to the inhibition of beta-cell apoptosis and the activation of Trx2, probably through Txnip inhibition and Stat3 activation. In conclusion, our results reveal a possible mechanism for Irisin-induced beta-cell protection, which is mediated through Txnip inhibition and activation of the Stat3-Trx2 pathway.
脂毒性可导致β细胞功能障碍和细胞凋亡，因为它会诱导氧化应激。最近的研究发现，鸢尾素可防止棕榈酸（PA）诱导的胰岛β细胞功能障碍。然而，鸢尾素对氧化应激的保护作用与β细胞功能障碍之间的关系尚未完全阐明。在这项研究中，我们观察到鸢尾素处理可防止 PA 处理诱导的 INS-1 细胞凋亡，并在体外维持 INS-1 细胞的胰岛素分泌功能。这些作用可能是由于鸢尾素诱导的细胞内 ROS 水平降低所致，而这种降低是由 PA 处理触发的。此外，PA 处理通过增加硫氧还蛋白相互作用蛋白（Txnip）的表达来部分抑制硫氧还蛋白 2（Trx2）的激活，从而诱导氧化应激。然而，鸢尾素给药阻断了 Txnip 表达的增加，从而逆转了 PA 诱导的 Trx2 失活。鸢尾素还增加了 Stat3 的核转位，而 siRNAs 对 Stat3 的抑制阻断了鸢尾素诱导的 Trx2 表达，表明 Txnip 和 Stat3 均参与鸢尾素诱导的 Trx2 激活。此外，siRNAs 对 Stat3 的抑制导致葡萄糖诱导的胰岛素分泌增强的基因表达减少和 和 的基因表达减少，而这些作用被鸢尾素的抑制所减弱。在体内，与对照组相比，HFD 处理导致葡萄糖耐量降低和氧化标志物丙二醛（MDA）水平升高。然而，由于鸢尾素抑制β细胞凋亡和激活 Trx2，这些作用得到了改善，这可能是通过 Txnip 抑制和 Stat3 激活。总之，我们的结果揭示了鸢尾素诱导的β细胞保护的一种可能机制，该机制是通过 Txnip 抑制和 Stat3-Trx2 途径的激活介导的。
