Back to all available

Dual GIP and GLP-1 receptor agonist tirzepatide ameliorates hepatic steatosis and inflammatory infiltration in a mouse model of MASLD via inhibition of the CCL2/CCR2 signaling pathway

molecular-biology
diabetes-and-endocrinology
histology
metabolic-sciences

Abstract

Background/Objectives: Metabolically-dysfunction-associated steatotic liver disease (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 investigate the molecular mechanisms of tirzepatide on metabolic dysfunction-associated steatotic liver disease (MASLD)

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: control group, high-fat, high-fructose diet group, semaglutide group, and tirzepatide 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 Western blot.

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 inflammation, and both transcriptomic and proteomic results show that this effect is related to the CCL2/CCR2 signaling pathway. In addition, the results of real-time fluorescence quantitative PCR and western blot showed that tirzepatide inhibited the expression of genes and proteins of key molecules of this signaling pathway.

Conclusion: Tirzepatide reduces hepatic lipid degeneration and inflammatory infiltration by downregulating the CCL2/CCR2 signaling pathway, thereby improving MASLD.

Ask to review this manuscript

Notes for potential reviewers

  • Volunteering is not a guarantee that you will be asked to review. There are many reasons: reviewers must be qualified, there should be no conflicts of interest, a minimum of two reviewers have already accepted an invitation, etc.
  • This is NOT OPEN peer review. The review is single-blind, and all recommendations are sent privately to the Academic Editor handling the manuscript. All reviews are published and reviewers can choose to sign their reviews.
  • What happens after volunteering? It may be a few days before you receive an invitation to review with further instructions. You will need to accept the invitation to then become an official referee for the manuscript. If you do not receive an invitation it is for one of many possible reasons as noted above.
  • PeerJ does not judge submissions based on subjective measures such as novelty, impact or degree of advance. Effectively, reviewers are asked to comment on whether or not the submission is scientifically and technically sound and therefore deserves to join the scientific literature. Our Peer Review criteria can be found on the "Editorial Criteria" page - reviewers are specifically asked to comment on 3 broad areas: "Basic Reporting", "Experimental Design" and "Validity of the Findings".
  • Reviewers are expected to comment in a timely, professional, and constructive manner.
  • Until the article is published, reviewers must regard all information relating to the submission as strictly confidential.
  • When submitting a review, reviewers are given the option to "sign" their review (i.e. to associate their name with their comments). Otherwise, all review comments remain anonymous.
  • All reviews of published articles are published. This includes manuscript files, peer review comments, author rebuttals and revised materials.
  • Each time a decision is made by the Academic Editor, each reviewer will receive a copy of the Decision Letter (which will include the comments of all reviewers).

If you have any questions about submitting your review, please email us at [email protected].