肌肉因子Irisin经Stat3-Trx2通路改善胰岛β细胞氧化应激损伤的作用机制研究

Oxidative stress is one of the important causes of β cell dysfunction induced by glucolipotoxicity. Irisin, as a new myokine, was recently identified to exert protective roles on β cells. However, whether it can improve oxidative stress-induced injury of β cell upon glucolipotoxicity remains unclear. Our previous studies demonstrated that Irisin could ameliorate oxidative stress and mitochondrial dysfunction induced by high glucose and palmitate (HG/PA) treatment. This was triggered by the translocation of Signal transducer and activator of transcription 3 (STAT3) and up-regulated expression of mitochondrial antioxidant Thioredoxin 2 (Trx2). Thus, we hypothesize that the recovery of oxidative injury of β cells caused by Irisin may be resulted from the activation of STAT3-Trx2 pathway and the subsequent attenuation of mitochondrial dysfunction. We will investigate the molecular mechanisms of Trx2 expression modulated by Irisin-induced STAT3 activation and its roles in improving mitochondrial function and attenuating oxidative injury of β cells in vitro. Moreover, we will determine that STAT3-Trx2 activation induced by Irisin treatment protect islet β-cell of diabetic rats from mitochondrial damage and oxidative injury in vivo. The aim of this study is to provide direct evident on how Irisin exerts protection on the function of islet β cells. This will attempt to identify a new therapeutic target for improving the clinical treatment of diabetes.

氧化应激是糖脂毒性诱导胰岛β细胞功能减退的重要原因之一。Irisin是近来发现的一种新的肌肉因子，对胰岛β细胞具有保护作用，然而其是否可改善高糖高脂诱导的β细胞氧化应激损伤，目前尚无报道。我们前期研究发现Irisin可通过活化STAT3上调线粒体抗氧化酶Trx2表达；改善高糖高脂诱导β细胞氧化应激和线粒体损伤。据此提出“Irisin可通过Stat3-Trx2通路改善β细胞氧化应激损伤“。本研究拟通过体外实验明确Irisin激活STAT3调控Trx2表达的作用机制，阐明Stat3-Trx2通路调节线粒体功能改善β细胞氧化应激损伤的作用；并通过动物实验确定Irisin激活STAT3-Trx2通路在保护β细胞线粒体功能，进而改善糖尿病大鼠胰岛氧化应激损伤中的可行性。本研究旨在为Irisin抗氧化应激保护胰岛β细胞功能提供理论基础，为改善糖尿病患者胰岛β细胞功能提供新的研究方向和治疗靶点。

脂毒性通过氧化应激导致胰岛β细胞功能紊乱和细胞凋亡。研究发现肌肉因子Irisin对胰岛β细胞具有保护作用，但作用机制尚未完全阐明。本研究旨在探索Irisin对β细胞氧化应激损伤的保护作用及其机制。本研究拟通过体外实验明确Irisin激活STAT3调控Trx2表达的作用机制，阐明Irisin激活Stat3-Trx2通路改善β细胞氧化应激损伤的作用；并通过动物实验确定Irisin在改善高脂喂养小鼠的糖代谢紊乱，保护胰岛β细胞氧化应激损伤中的作用。研究发现：Irisin处理可抑制PA诱导的INS-1细胞凋亡，改善胰岛素分泌功能损伤，但Irisin中和抗体可部分逆转上述保护作用。Irisin和PA共处理可明显降低细胞内ROS水平，上调Trx2表达和活性。Irisin上调细胞内STAT3表达和核转位，抑制TXNIP表达，进一步上调细胞内Trx2表达和活性；抑制STAT3的表达和核内转位，阻断了Irisin诱导的Trx2表达和激活，降低了MafA和Ins的基因表达，并进一步抑制Irisin对胰岛素合成和分泌的调控。与对照组相比，高脂喂养导致小鼠空腹血糖升高和糖耐量受损，但给予Irisin腹腔注射后可明显降低小鼠空腹血糖水平，并改善糖耐量，减少胰岛β细胞的凋亡，改善胰岛素含量。同样，给予Irisin处理后可部分逆转高脂对Trx2的抑制作用，降低胰腺内氧化产物MDA水平。因此，本研究发现：Irisin可通过抑制TXNIP表达，同时促进STAT3活化和核转位，上调Trx2表达和活性，进而改善高脂诱导的β细胞氧化应激损伤。本研究为Irisin抗氧化应激保护胰岛β细胞功能提供理论基础，也为改善糖尿病患者胰岛β细胞功能提供新的研究方向和治疗靶点。