Liang Jinliang, Liu Huanyi, Lv Guo, Chen Xiaotong, Yang Zhaoshou, Hu Kunhua, Sun Hongyan
Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China.
The First Affiliated Hospital, The First School of Clinical Medicine of Guangdong Pharmaceutical University, Guangdong Pharmaceutical University, Guangzhou, 510080, China.
Lipids Health Dis. 2025 Jan 10;24(1):8. doi: 10.1186/s12944-024-02416-2.
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.
临床研究表明，替尔泊肽可能还具有肝脏保护作用；然而，这种关联背后的分子机制仍不清楚。在我们的研究中，我们对小鼠的血清进行了生化分析，并对肝脏组织进行了组织病理学检查。为了初步探究替尔泊肽对代谢功能障碍相关脂肪性肝病（MAFLD）的分子机制，我们采用液相色谱 - 质谱联用（LC-MS）技术，对高脂饮食（HFD）喂养的MAFLD小鼠进行了全面的代谢组学、脂质组学和蛋白质组学分析。结果表明，替尔泊肽显著降低了血清谷丙转氨酶（ALT）和谷草转氨酶（AST）水平，以及肝脏甘油三酯（TG）和总胆固醇（TC）水平，表明其对MAFLD具有治疗效果。进一步的研究发现，替尔泊肽通过下调Cd36和Fabp2/4减少脂肪酸摄取，并通过上调Lamp1/2增强线粒体 - 溶酶体功能。此外，替尔泊肽通过上调Hnf4a、Abcg5和Abcg8的表达促进胆固醇流出并减少胆固醇重吸收。这些结果表明，替尔泊肽通过减少脂肪酸摄取、促进胆固醇排泄和增强线粒体 - 溶酶体功能对MAFLD发挥治疗作用，为全面了解替尔泊肽提供了理论依据。
