Exploring the molecular mechanisms of tirzepatide in alleviating metabolic dysfunction-associated fatty liver in mice through integration of metabolomics, lipidomics, and proteomics
Abstract Clinical studies have suggested that tirzepatide may also possess hepatoprotective effects; however, the molecular mechanisms underlying this association remain unclear. In our study, we performed biochemical analyses of serum and histopathological examinations of liver tissue in mice. To p...
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BMC
2025-01-01
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| Series: | Lipids in Health and Disease |
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| Online Access: | https://doi.org/10.1186/s12944-024-02416-2 |
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| author | Jinliang Liang Huanyi Liu Guo Lv Xiaotong Chen Zhaoshou Yang Kunhua Hu Hongyan Sun |
| author_facet | Jinliang Liang Huanyi Liu Guo Lv Xiaotong Chen Zhaoshou Yang Kunhua Hu Hongyan Sun |
| author_sort | Jinliang Liang |
| collection | DOAJ |
| description | Abstract Clinical studies have suggested that tirzepatide may also possess hepatoprotective effects; however, the molecular mechanisms underlying this association remain unclear. In our study, we performed biochemical analyses of serum and histopathological examinations of liver tissue in mice. To preliminarily explore the molecular mechanisms of tirzepatide on metabolic dysfunction-associated fatty liver disease (MAFLD), liquid chromatography-mass spectrometry (LC-MS) was employed for comprehensive metabolomic, lipidomic, and proteomic analyses in MAFLD mice fed a high-fat diet (HFD). The results demonstrated that tirzepatide significantly reduced serum levels of alanine transaminase (ALT) and aspartate transaminase (AST), as well as hepatic triglycerides (TG) and total cholesterol (TC), indicating its efficacy in treating MAFLD. Further findings revealed that tirzepatide reduced fatty acid uptake by downregulating Cd36 and Fabp2/4, as well as enhance the mitochondrial-lysosomal function by upregulating Lamp1/2. In addition, tirzepatide promoted cholesterol efflux and reduced cholesterol reabsorption by upregulating the expression of Hnf4a, Abcg5, and Abcg8. These results suggest that tirzepatide exerts its therapeutic effects on MAFLD by reducing fatty acid uptake, promoting cholesterol excretion, and enhancing mitochondrial-lysosomal function, providing a theoretical basis for a comprehensive understanding of tirzepatide. |
| format | Article |
| id | doaj-art-dd9da6d494ff4c399a9c63df48ee5fb5 |
| institution | Kabale University |
| issn | 1476-511X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
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| series | Lipids in Health and Disease |
| spelling | doaj-art-dd9da6d494ff4c399a9c63df48ee5fb52025-01-12T12:37:57ZengBMCLipids in Health and Disease1476-511X2025-01-0124111710.1186/s12944-024-02416-2Exploring the molecular mechanisms of tirzepatide in alleviating metabolic dysfunction-associated fatty liver in mice through integration of metabolomics, lipidomics, and proteomicsJinliang Liang0Huanyi Liu1Guo Lv2Xiaotong Chen3Zhaoshou Yang4Kunhua Hu5Hongyan Sun6Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen UniversityGuangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen UniversityGuangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen UniversityGuangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen UniversityThe First Affiliated Hospital, The First School of Clinical Medicine of Guangdong Pharmaceutical University, Guangdong Pharmaceutical UniversityGuangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen UniversityThe State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer CenterAbstract Clinical studies have suggested that tirzepatide may also possess hepatoprotective effects; however, the molecular mechanisms underlying this association remain unclear. In our study, we performed biochemical analyses of serum and histopathological examinations of liver tissue in mice. To preliminarily explore the molecular mechanisms of tirzepatide on metabolic dysfunction-associated fatty liver disease (MAFLD), liquid chromatography-mass spectrometry (LC-MS) was employed for comprehensive metabolomic, lipidomic, and proteomic analyses in MAFLD mice fed a high-fat diet (HFD). The results demonstrated that tirzepatide significantly reduced serum levels of alanine transaminase (ALT) and aspartate transaminase (AST), as well as hepatic triglycerides (TG) and total cholesterol (TC), indicating its efficacy in treating MAFLD. Further findings revealed that tirzepatide reduced fatty acid uptake by downregulating Cd36 and Fabp2/4, as well as enhance the mitochondrial-lysosomal function by upregulating Lamp1/2. In addition, tirzepatide promoted cholesterol efflux and reduced cholesterol reabsorption by upregulating the expression of Hnf4a, Abcg5, and Abcg8. These results suggest that tirzepatide exerts its therapeutic effects on MAFLD by reducing fatty acid uptake, promoting cholesterol excretion, and enhancing mitochondrial-lysosomal function, providing a theoretical basis for a comprehensive understanding of tirzepatide.https://doi.org/10.1186/s12944-024-02416-2Metabolic dysfunction-associated fatty liver diseaseTirzepatideMetabolomicsLipidomicsProteomics |
| spellingShingle | Jinliang Liang Huanyi Liu Guo Lv Xiaotong Chen Zhaoshou Yang Kunhua Hu Hongyan Sun Exploring the molecular mechanisms of tirzepatide in alleviating metabolic dysfunction-associated fatty liver in mice through integration of metabolomics, lipidomics, and proteomics Lipids in Health and Disease Metabolic dysfunction-associated fatty liver disease Tirzepatide Metabolomics Lipidomics Proteomics |
| title | Exploring the molecular mechanisms of tirzepatide in alleviating metabolic dysfunction-associated fatty liver in mice through integration of metabolomics, lipidomics, and proteomics |
| title_full | Exploring the molecular mechanisms of tirzepatide in alleviating metabolic dysfunction-associated fatty liver in mice through integration of metabolomics, lipidomics, and proteomics |
| title_fullStr | Exploring the molecular mechanisms of tirzepatide in alleviating metabolic dysfunction-associated fatty liver in mice through integration of metabolomics, lipidomics, and proteomics |
| title_full_unstemmed | Exploring the molecular mechanisms of tirzepatide in alleviating metabolic dysfunction-associated fatty liver in mice through integration of metabolomics, lipidomics, and proteomics |
| title_short | Exploring the molecular mechanisms of tirzepatide in alleviating metabolic dysfunction-associated fatty liver in mice through integration of metabolomics, lipidomics, and proteomics |
| title_sort | exploring the molecular mechanisms of tirzepatide in alleviating metabolic dysfunction associated fatty liver in mice through integration of metabolomics lipidomics and proteomics |
| topic | Metabolic dysfunction-associated fatty liver disease Tirzepatide Metabolomics Lipidomics Proteomics |
| url | https://doi.org/10.1186/s12944-024-02416-2 |
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