Dual GIP/GLP-1 receptor agonist tirzepatide ameliorates hepatic steatosis and inflammatory responses in a MASLD mouse model associated with the CCL2/CCR2 axis.
This mouse study investigated the molecular mechanisms by which tirzepatide (TZP), a dual GIP/GLP-1 receptor agonist, affects the liver in metabolic dysfunction-associated steatotic liver disease (MASLD). Male C57BL/6J mice (n=32) were fed a high-fat, high-fructose (HFHFr) diet to induce MASLD and then randomized to receive no treatment, semaglutide (Sema), or TZP. Researchers combined RNA sequencing and liquid chromatography-mass spectrometry (LC-MS) to generate hepatic transcriptomic and proteomic profiles, with key targets validated by PCR and immunoblotting. The study found that HFHFr feeding produced hyperglycemia, insulin resistance, elevated liver enzymes, and hepatic steatosis and inflammation. Both TZP and Sema were associated with improvements in these parameters; TZP was associated with reductions in pro-inflammatory markers (MCP-1, IL-1β, TNF-α, GSDMD) and partial restoration of IL-10. Integrated omics analysis implicated the CCL2/CCR2 chemokine axis and PI3K-AKT signaling pathway as key molecular signatures associated with TZP's hepatic effects. Key limitations include the exclusive use of an animal model, a small sample size, and the mechanistic (non-causal) nature of omics associations.
Why this grade: All experimental subjects were mice (n=32); no human participants were enrolled, so findings cannot be directly extrapolated to clinical outcomes in humans.
Background/objectives Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common multisystem chronic progressive liver disease with a rising burden. Tirzepatide (TZP), a dual agonist of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors, has shown beneficial hepatic effects, but the related molecular mechanisms remain unclear. The aim of this study was to investigate the hepatic molecular signatures associated with TZP in MASLD. Methods A MASLD mouse model was established using a high-fat, high-fructose (HFHFr) diet. Male C57BL/8J mice (n = 32) were randomized to four groups: control (CON), HFHFr, HFHFr + semaglutide (Sema), and HFHFr + TZP. Hepatic transcriptomic and proteomic profiles were generated by RNA sequencing and liquid chromatography-mass spectrometry (LC-MS), respectively. Key molecular targets were validated by quantitative real-time PCR and immunoblotting of liver tissue. Results HFHFr feeding induced hyperglycaemia, increased HOMA-IR, elevated ALT/AST, and marked hepatic steatosis and inflammatory injury. Both Sema and TZP ameliorated these abnormalities. TZP was associated with lower hepatosomatic index, improved fasting glucose and HOMA-IR, and reduced hepatic MCP-1, IL-1β, TNF-α and GSDMD, with partial restoration of IL-10. Integrated liver transcriptomic-proteomic profiling highlighted chemokine signaling and PI3K-AKT pathway signatures to be associated with TZP. Further targeted validation showed that TZP treatment was associated with reduced hepatic CCL2/CCR2 axis components, and decreased PI3K abundance and lower AKT phosphorylation. Conclusion TZP ameliorated hepatic steatosis and attenuated inflammatory responses in HFHFr-induced MASLD and was associated with downregulation of the CCL2/CCR2-linked chemokine signaling and PI3K-AKT-related inflammatory responses.
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