Chen Lin, Zhang Xiujuan, Zhang Li, Zheng Dongmei
Department of Breast and Thyroid Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People's Republic of China.
Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong University, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, People's Republic of China.
Diabetes Metab Syndr Obes. 2020 Oct 6;13:3507-3518. doi: 10.2147/DMSO.S262284. eCollection 2020.
Non-alcoholic fatty liver disease (NAFLD) represents a broad spectrum of chronic liver disease characterized by aberrant accumulation of triglycerides (TG) in hepatocytes without excessive alcohol consumption. Hepatic lipotoxicity derived from overaccumulation of free fatty acids is considered as one of the typical hallmarks of NAFLD. Insulin resistance (IR) and chronic inflammation are widely recognized as the key etiological factors associated with NAFLD. Dipeptidyl peptidase 4 inhibitor (DPP4i) is a novel pharmacological agent extensively applied in the treatment of Type 2 Diabetes Mellitus (T2DM) for decades which also have a liver protective effect.
In order to invest the therapeutic efficiency and underlying mechanism of DPP4i saxagliptin, we used high-fat diet (HFD) and streptozotocin-induced NAFLD treated with saxagliptin. Biochemical, histomorphological, genetic and protein expression of related pathways were investigated.
Fasting blood glucose (FBG), TG, total cholesterol (TC), and low-density lipoprotein cholesterin significantly increased in NAFLD group, which also exhibited severe steatosis. Other remarkable findings were hyperinsulinemia, increased DPP4, and level and decreased GLP-1, , expression, concomitant with liver DPP4 expression enhancement and serum DPP4 elevation. These undesirable consequences were alleviated by saxagliptin to a certain degree.
DPP4i saxagliptin improves NAFLD by ameliorating IR, inflammation, downregulation of hepatic DPP4 and sDPP4, as well as subsequent steatosis. The elevation of hepatic DPP4 and sDPP4 and succedent post-treatment decrease suggested that DPP4 may involve in the development of NAFLD. The anti-lipotoxic effect of DPP4i may involve the activation of and related β-oxidation signaling pathway suppression of mediated inflammatory and . The results covered in this article showed that saxagliptin affects many aspects of the pathological characteristics of NAFLD, suggesting that DPP4i saxagliptin may offer a novel therapeutic option for NAFLD.
非酒精性脂肪性肝病（NAFLD）是一种广泛的慢性肝病，其特征是在无过量饮酒情况下肝细胞内甘油三酯（TG）异常蓄积。游离脂肪酸过度蓄积导致的肝脏脂毒性被认为是NAFLD的典型特征之一。胰岛素抵抗（IR）和慢性炎症被广泛认为是与NAFLD相关的关键病因。二肽基肽酶4抑制剂（DPP4i）是一种新型药物，数十年来广泛应用于2型糖尿病（T2DM）的治疗，且具有肝脏保护作用。
为了研究DPP4i沙格列汀的治疗效果及潜在机制，我们使用高脂饮食（HFD）和链脲佐菌素诱导的NAFLD模型并用沙格列汀进行治疗。对相关途径的生化、组织形态学、基因和蛋白表达进行了研究。
NAFLD组空腹血糖（FBG）、TG、总胆固醇（TC）和低密度脂蛋白胆固醇显著升高，且出现严重脂肪变性。其他显著发现包括高胰岛素血症、DPP4水平升高、GLP-1表达降低，同时肝脏DPP4表达增强和血清DPP4升高。这些不良后果在一定程度上被沙格列汀缓解。
DPP4i沙格列汀通过改善IR、炎症、下调肝脏DPP4和sDPP4以及随后的脂肪变性来改善NAFLD。肝脏DPP4和sDPP4的升高以及治疗后随后的降低表明DPP4可能参与NAFLD的发生发展。DPP4i的抗脂毒性作用可能涉及激活 以及 相关的β-氧化信号通路，抑制 介导的炎症和 。本文涵盖的结果表明沙格列汀影响NAFLD病理特征的多个方面，提示DPP4i沙格列汀可能为NAFLD提供一种新的治疗选择。
