Tirzepatide but not Semaglutide Ameliorates Hepatic Steatosis and Inflammatory Infiltration in a Mouse Model of MASLD via Inhibition of the CCL2/CCR2-PI3K-Akt Pathway

Background/Objectives Metabolism-associated steatohepatitis (MASLD) is a common multisystem chronic progressive liver disease whose prevalence has been steadily increasing in recent years. Tirzepatide is a dual agonist of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors. Studies have shown that Tirzepatide can also reduce lipid accumulation and maintain hepatocyte function. The aim of this study was to compare the differences between GLP-1RA Semaglutide and Tirzepatide in improving the molecular mechanisms of MASLD mice. Methods We established a MASLD mouse model using a high-fat, high-fructose diet, then randomly divided 32 male C57BL/6J mice into four groups for intervention: CON group, HFHFr group, Sema group, and TZP group. The combination of RNA-seq and liquid chromatography-mass spectrometry (LC-MS) was used to study transcriptomics and proteomics, and the mRNA transcription level and protein expression level in liver tissue were detected by real-time fluorescence quantitative PCR and Westernblot. Results Both Semaglutide and Tirzepatide can effectively reduce the weight and liver damage of the HFHFr group mice, reduce liver lipid levels and reduce inflammatory infiltration. Compared with Semaglutide ,Tirzepatide showed more significant efficacy in reducing hepatic lipid degeneration and inflammation, and both transcriptomic and proteomic results show that this effect is related to the CCL2/CCR2-PI3K-Akt signaling pathway. In addition, the results of real-time fluorescence quantitative PCR and Westernblot showed that Tirzepatide inhibited the expression of genes and proteins of key molecules of this signaling pathway. Conclusion Tirzepatide but Semaglutide reduces hepatic lipid degeneration and inflammatory infiltration by downregulating the CCL2/CCR2-PI3K-Akt signaling pathway, thereby improving MASLD