胆酸对急性酒精肝损伤小鼠的保护作用及机制研究

Protective effect and mechanism of cholic acid on acute alcoholic liver injury in mice

目的 研究胆酸对急性酒精肝损伤的保护作用,并从代谢组学的角度探讨胆酸干预急性酒精肝损伤小鼠的潜在生物标志物和其保护机制。方法 采用56%酒精灌胃造急性酒精肝损伤小鼠模型,通过组织病理学染色和各项生化指标检测胆酸的保护作用。采用液相色谱-质谱联用技术(LC-MS)检测各组小鼠血清代谢物,使用SIMCA-P14.1、SPSS、Metabo Analyst等进行数据分析,研究各组间的差异代谢物和胆酸的作用机制。结果 胆酸组的谷丙转氨酶(ALT)、谷草转氨酶(AST)、丙二醛(MDA)、白介素-6(IL-6)、白介素-1β(IL-1β)、肿瘤坏死因子-α(TNF-α)指标低于模型组,差异有统计学意义(P<0.05),且胆酸组的谷胱甘肽(GSH)、超氧化物歧化酶(SOD)指标高于模型组,差异有统计学意义(P<0.05)。通过血清代谢组分析,在模型组与正常组中鉴定出31个差异代谢物,并发现其富集于苯丙氨酸代谢、嘌呤代谢、萜类骨架生物合成和不饱和脂肪酸生物合成途径。在胆酸组与模型组中鉴定出34个差异代谢物,并发现其富集于苯丙氨酸代谢和嘌呤代谢途径。结论 胆酸能够显著缓解小鼠因大量摄入酒精而导致的肝脏氧化应激和炎症反应,通过对比各组间的差异代谢物和差异代谢通路,发现胆酸能够调节嘌呤代谢和苯丙氨酸代谢异常,表明胆酸对急性酒精肝损伤有一定的保护作用,其机制可能与改善嘌呤代谢和苯丙氨酸代谢有关。

Objective To investigate the protective effect of cholic acid on acute alcoholic liver injury in mice,and to explore the potential biomarkers and protective mechanism of cholic acid in the intervention of acute alcoholic liver injury in mice from the perspective of metabolomics.Methods A mouse model of acute alcoholic liver injury was established by gavage of 56%alcohol,and the protective effect of cholic acid was detected by histopathological staining and various biochemical indicators.Liquid chromatography-mass spectrometry(LC-MS)was used to detect serum metabolites of mice in each group.SIMCA-P14.1,SPSS,MetaboAnalyst,etc.,were used for data analysis to study the differential metabolites among groups and the mechanism of bile acid.Results The levels of alanine aminotransferase(ALT),aspartate aminotransferase(AST),malondialdehyde(MDA),interleukin-6(IL-6),interleukin-1β(IL-1β)and tumor necrosis factor-α(TNF-α)in the cholic acid group were lower than those in the model group,and the differences were statistically significant(P<0.05).The glutathione(GSH)and superoxide dismutase(SOD)of the cholic acid group were higher than those of the model group,and the differences were statistically significant(P<0.05).Through serum metabolomics analysis,31 differential metabolites were identified between the model group and the normal group,and they were found to be enriched in phenylalanine metabolism,purine metabolism,terpenoid backbone biosynthesis and unsaturated fatty acid biosynthesis pathways.Thirty-four differential metabolites were identified between the cholic acid group and the model group, and they were found to be enriched in phenylalanine metabolism and purine metabolism pathways. Conclusion Cholic acid can significantly alleviate the oxidative stress and inflammatory response in the liver caused by large intake of alcohol in mice. By comparing the differential metabolites and metabolic pathways between groups, cholic acid can regulate the abnormalities of purine metabolism and phenylalanine metabolism, suggesting that cholic acid has a certain protective effect on acute alcoholic liver injury, and its mechanism may be related to the improvement of purine metabolism and phenylalanine metabolism.