Yan Ran, Liu Lu, Tzoulaki Ioanna, Fan Jiangao, Targher Giovanni, Yuan Zhongshang, Zhao Jian
Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
Institute for Medical Dataology, Shandong University, Jinan, Shandong, China.
Liver Int. 2025 Apr;45(4):e16150. doi: 10.1111/liv.16150. Epub 2024 Nov 2.
Glucagon-like peptide-1 receptor (GLP1R) agonists and glucose-dependent insulinotropic polypeptide receptor (GIPR) agonists may help treat metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). However, their definitive effects are still unclear. Our study aims to clarify this uncertainty.
We utilised conventional Mendelian randomisation (MR) analysis to explore potential causal links between plasma GLP-1/GIP concentrations and MASLD and its related traits. Next, we conducted drug-target MR analysis using highly expressed tissue data to assess the effects of corresponding drug perturbation on these traits. Finally, mediation analysis was performed to ascertain whether the potential causal effect is direct or mediated by other MASLD-related traits.
Circulating 2-h GLP-1 and GIP concentrations measured during an oral glucose tolerance test showed hepatoprotective effects on MASLD risk (OR = 0.168 [95% CI 0.033-0.839], p = 0.030; OR = 0.331 [95% CI 0.222-0.494], p = 6.31 × 10). GLP1R expression in the blood had a minimal causal effect on MASLD risk, whereas GIPR expression significantly affected MASLD risk (OR = 0.671 [95% CI 0.531-0.849], p = 9.07 × 10). Expression levels of GLP1R or GIPR in the blood significantly influenced MASLD-related clinical traits. Mediation analysis revealed that GIPR expression protected against MASLD, even after adjusting for type 2 diabetes or body mass index.
GLP-1/GIP receptor agonists offer promise in lowering MASLD/MASH risk. GIP receptor agonists can exert direct and indirect effects on MASLD mediated by weight reduction or glycemic control improvement.
胰高血糖素样肽-1受体（GLP1R）激动剂和葡萄糖依赖性促胰岛素多肽受体（GIPR）激动剂可能有助于治疗代谢功能障碍相关脂肪性肝病（MASLD）和代谢功能障碍相关脂肪性肝炎（MASH）。然而，它们的确切效果仍不明确。我们的研究旨在阐明这种不确定性。
我们利用传统孟德尔随机化（MR）分析来探索血浆GLP-1/GIP浓度与MASLD及其相关特征之间的潜在因果联系。接下来，我们使用高表达组织数据进行药物靶点MR分析，以评估相应药物扰动对这些特征的影响。最后，进行中介分析以确定潜在的因果效应是直接的还是由其他MASLD相关特征介导的。
口服葡萄糖耐量试验期间测得的循环2小时GLP-1和GIP浓度对MASLD风险具有肝脏保护作用（OR = 0.168 [95% CI 0.033 - 0.839]，p = 0.030；OR = 0.331 [95% CI 0.222 - 0.494]，p = 6.31×10）。血液中GLP1R表达对MASLD风险的因果效应极小，而GIPR表达显著影响MASLD风险（OR = 0.671 [95% CI 0.531 - 0.849]，p = 9.07×10）。血液中GLP1R或GIPR的表达水平显著影响与MASLD相关的临床特征。中介分析显示，即使在调整2型糖尿病或体重指数后，GIPR表达仍能预防MASLD。
GLP-1/GIP受体激动剂在降低MASLD/MASH风险方面具有前景。GIP受体激动剂可通过减轻体重或改善血糖控制对MASLD产生直接和间接影响。
