As a common chronic metabolic disease, the development of diabetes mellitus (DM) may also be accompanied by liver damage and inflammatory disorders. Sitagliptin is an inhibitor of dipeptidyl peptidase-4 (DPP4, also known as CD26), which is clinically used for DM treatment. However, the mechanism of sitagliptin’s efficiency in liver diseases is largely unknown. In this study, mice suffering from streptozotocin (STZ) exhibit elevated liver DPP4 expression and activity, as well as inflammatory and chronic liver injury phenotype, whereas specifically inhibiting the activity of DPP4 in mouse liver tissues and hepatocytes by sitagliptin contributes to decreased cytokines, oxidative stress, cell apoptosis, and inflammation in STZ-induced diabetic mice. Moreover, sitagliptin reduced TNFα or LPS-induced cellular reactive oxygen species (ROS) level, cell apoptosis, and protein expression in the NFκB signaling pathway in HepG2 cells or primary mouse hepatocytes. Altogether, our study confirms that sitagliptin may protect liver tissue by alleviating ROS production and NFκB signaling activation, providing a putative mechanism for preventing the development of diabetic liver disease.

作为一种常见的慢性代谢疾病，糖尿病（DM）的发展也可能伴有肝损伤和炎症性疾病。西格列汀是二肽基肽酶-4（DPP4，也称为CD26）的抑制剂，临床上用于DM治疗。然而，西格列汀在肝脏疾病中的作用机制在很大程度上是未知的。在这项研究中，患有链脲佐菌素 (STZ) 的小鼠表现出升高的肝脏 DPP4 表达和活性，以及​​炎症和慢性肝损伤表型，而西格列汀特异性抑制小鼠肝组织和肝细胞中 DPP4 的活性有助于减少细胞因子、氧化STZ 诱导的糖尿病小鼠的应激、细胞凋亡和炎症。此外，西格列汀降低了 TNFα 或 LPS 诱导的细胞活性氧 (ROS) 水平，细胞凋亡，以及 HepG2 细胞或原代小鼠肝细胞中 NFκB 信号通路中的蛋白质表达。总之，我们的研究证实，西格列汀可以通过减轻 ROS 产生和 NFκB 信号激活来保护肝组织，为预防糖尿病性肝病​​的发展提供了一种推定的机制。