Available online:September 10, 2024, DOI:
Abstract:
Objective：To compare the therapeutic of the novel Glucagon-like peptide-1 (GLP-1)/Glucose-dependent insulinotropic polypeptide (GIP) dual receptor agonist tirzepatide and the GLP-1 receptor agonist liraglutide in improving metabolic associated fatty liver disease (MAFLD) in db/db mice. Methods：Db/db mice were used as the MAFLD Model and db/m mice as the Control group, which were divided into Control group, Model group, Liraglutide group and Tirzepatide group. Mice in Liraglutide and tirzepatide groups received intraperitoneal injections of 10 nmol/kg of Liraglutide and tirzepatide daily for 10 consecutive weeks. The mice in the Control group and the Model group were intraperitoneally injected with the same volume of saline at the same time. At the end of the experiment, the fasting blood glucose (FBG), glycated haemoglobin A1c (HbA1c) and body weight of mice in each group were compared. The levels of serum TC, TG, LDL-C, HDL-C, ALT and AST in each group were detected and compared by automatic biochemical analyzer. 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 protein and mRNA expressions of inflammatory factors and fibrosis mediators in the liver tissue of mice in each group. Results: Compared with the Control group, the FBG, HbA1c, body weight, TC, TG, LDL-C, ALT and AST in the Model group were significantly increased, while HDL-C was decreased. 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 60%, 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 compared with the Control group, 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. Compared with the Model group, 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 the protein expressions of IL-1β, IL-6, TNF-α, Fibronectin, Col-Ⅰ, and α-SMA in the Model group were significantly increased. The mRNA levels of IL-1β, IL-6, TNF-α, ASC, Caspase-1, Fibronectin, α-SMA, Col-Ⅰ, Col-IV, and TGF-β were significantly increased. After drug treatment, the expression levels of the above inflammatory factors and fibrosis mediators in the two groups were significantly decreased. Tirzepatide is more effective than liraglutide in improving the above indicators. Conclusions: The novel GLP-1/GIP dual receptor agonist 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, and its comprehensive efficacy is better than that of liraglutide, which may provide a new treatment for MAFLD.
