Tirzepatide ameliorates MASLD in mice by downregulating CCL2/CCR2 and PI3K-AKT pathways

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent and progressive chronic liver condition, posing a significant global health burden. Despite its rising incidence, specific pharmacotherapies directly targeting MASLD remain limited, with current standards often falling short in halting disease progression. Dual agonists of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors, like tirzepatide, have demonstrated promising metabolic and hepatic benefits. However, the precise molecular mechanisms underlying tirzepatide's therapeutic effects in MASLD, particularly regarding inflammatory pathways, have been largely uncharacterized, representing a critical knowledge gap this study aimed to address.

Researchers established a MASLD mouse model by feeding male C57BL/8J mice a high-fat, high-fructose (HFHFr) diet. A total of n=32 mice were randomized into four groups: control (CON), HFHFr diet alone, HFHFr + semaglutide (Sema), and HFHFr + tirzepatide (TZP). Hepatic transcriptomic and proteomic profiles were generated using RNA sequencing and liquid chromatography-mass spectrometry (LC-MS). Key molecular targets identified were further validated through quantitative real-time PCR and immunoblotting of liver tissue, allowing for a comprehensive analysis of gene expression and protein abundance changes.

The HFHFr diet successfully induced MASLD, characterized by hyperglycemia, increased HOMA-IR, elevated ALT/AST levels, and pronounced hepatic steatosis and inflammatory injury. Both semaglutide and tirzepatide effectively ameliorated these metabolic and hepatic abnormalities. Tirzepatide treatment specifically led to a lower hepatosomatic index, improved fasting glucose levels, and reduced HOMA-IR. Furthermore, tirzepatide significantly decreased hepatic levels of inflammatory markers including MCP-1, IL-1β, TNF-α, and GSDMD, while partially restoring IL-10 levels. Integrated liver transcriptomic-proteomic profiling highlighted that tirzepatide was strongly associated with modulated chemokine signaling and the PI3K-AKT pathway signatures. > Further targeted validation confirmed that tirzepatide treatment was associated with reduced hepatic CCL2/CCR2 axis components, alongside decreased PI3K abundance and lower AKT phosphorylation, indicating a direct impact on key inflammatory and metabolic signaling cascades.