BMC gastroenterologyJun 5, 2026

Tirzepatide reduces liver fat and inflammation linked to the CCL2/CCR2 pathway in a mouse model of fatty liver disease

GLP-1 Therapies Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Jun 6, 2026

Abstract

Tirzepatide (TZP) treatment was associated with reduced hepatic inflammation and steatosis in a mouse model of metabolic dysfunction-associated steatotic liver disease (MASLD).

HFHFr feeding led to hyperglycemia, increased insulin resistance, and significant liver injury in the mouse model.
Both semaglutide and TZP improved metabolic abnormalities caused by the HFHFr diet.
TZP treatment resulted in lower liver weight relative to body weight, improved fasting glucose, and reduced insulin resistance.
A decrease in inflammatory markers such as MCP-1, IL-1β, TNF-α, and GSDMD was observed with TZP treatment, alongside a partial restoration of IL-10 levels.
Transcriptomic and proteomic analysis indicated that TZP may influence chemokine signaling and the PI3K-AKT signaling pathway.
Further validation revealed that TZP treatment was linked to decreased components of the CCL2/CCR2 signaling pathway and lower activation of the AKT protein.

Simplified

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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Funding

Competing interests

Declarations. Ethics approval and consent to participate: The animal study protocol was approved by the Ethics Committee of Hebei General Hospital (protocol code 2025DW002) on January 9, 2025. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.

PubMed

Tirzepatide reduces liver fat and inflammation linked to the CCL2/CCR2 pathway in a mouse model of fatty liver disease

Abstract

Full Text

Funding

Competing interests

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