GLP⁃1/GIP双受体激动剂替西帕肽改善db/db小鼠代谢相关脂 肪性肝病.

Objective: To compare the therapeutic of Tirzepatide and Liraglutide in improving metabolic associated fatty liver disease (MAFLD) in db/db mice. Methods: Db/db mice were used as the MAFLD model. Total 21 db/db mice were divided into the model group, Liraglutide group and Tirzepatide group, and 7 db/m mice were used as the control group. Mice in Liraglutide and Tirzepatide groups received intraperitoneal injections of 10 nmol/kg of Liraglutide and Tirzepatide daily for 10 consecutive weeks. The other two groups were intraperitoneally injected with the same volume of normal saline. After 10 weeks, the fasting blood glucose (FBG), glycated haemoglobin A1c (HbA1c) and body weight of mice in each group were compared. The levels of serum total cholesterol (TC), triglyceride (TG), low⁃density lipoprotein⁃cholesterol (LDL⁃C), high⁃density lipoprotein⁃cholesterol (HDL⁃C), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in each group were compared. HE staining and oil red O staining were used to compare the liver pathological changes and lipid deposition in each group. Western blot and RT ⁃PCR were used to detect the expressions of inflammatory factors and fibrosis mediators in the liver tissues of mice in each group. Western blot was used to detect the insulin signaling pathway and glucose metabolism related protein expression differences. Results: Compared with the model group, the levels of FBG, HbA1c, body weight, TC, TG, LDL⁃C, ALT and AST in the Liraglutide group decreased by 56%, 32%, 20%, 19%, 22%, 39%, 26% and 28%, respectively, while HDL⁃C increased by 25%. In Tirzepatide group, FBG, HbA1c, body weight, TC, TG, LDL⁃C, ALT, and AST decreased by 69%, 40%, 30%, 31%, 35%, 57%, 46% and 38%, respectively, while HDL⁃C increased by 61%. HE staining and oil red O staining showed that the liver of the model group showed obvious hepatocyte steatosis, balloon ⁃like degeneration and vacuolization, and a large number of lipid droplets were accumulated in hepatocytes. The hepatocyte steatosis and liver fat deposition of the two intervention groups were improved, and the effect of Tirzepatide was better than that of Liraglutide. Western blot and RT⁃PCR results showed that two drug intervention groups markedly reduced the expressions of inflammatory factors and fibrosis mediators, at the same time, the two drugs increased insulin metabolic pathways related protein expression and decreased the glucose metabolism related protein expression, and Tirzepatide was more effective than Liraglutide in improving the above indicators. Conclusion: Tirzepatide can improve glucose and lipid metabolism disorders, reduce body weight, improve liver injury, reduce liver fat deposition, and delay liver inflammation and fibrosis in MAFLD mice by activating insulin ⁃ related signaling pathway and reducing gluconogenemia, and its comprehensive efficacy is better than that of Liraglutide, which may provide a new treatment for MAFLD. [ABSTRACT FROM AUTHOR]