Ursolic Acid Ameliorates Alcoholic Liver Injury through Attenuating Oxidative Stress-Mediated Ferroptosis and Modulating Gut Microbiota,Journal of Agricultural and Food Chemistry

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Ursolic Acid Ameliorates Alcoholic Liver Injury through Attenuating Oxidative Stress-Mediated Ferroptosis and Modulating Gut Microbiota
Journal of Agricultural and Food Chemistry ( IF 5.7 ) Pub Date : 2024-09-15 , DOI: 10.1021/acs.jafc.4c04762
Liangfu Zhou ₁ , Miao Xiao ₁ , Yuxin Li ₁ , Bimal Chitrakar ₁ , Qinghai Sheng ₁ , Wen Zhao ₁

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Ursolic acid (UA), a triterpenoid found in plants, has many health benefits for liver function. However, understanding how UA intervenes in alcohol-induced ferroptosis remains unclear because of the lack of research. This study explored the protective effects of UA on alcohol-induced liver injury and further elucidated its mechanism of action. Using a mouse model, acute liver injury was induced via high-dose alcohol gavage, and UA’s protective effects were assessed by analyzing serum and liver indicators. The results indicated that UA has a significant protective effect against alcohol-induced liver injury in mice. UA significantly decreased serum ALT, AST, TC, and TG levels. Histopathological examination revealed that UA significantly ameliorated liver damage. UA increased ADH, ALDH, and CYP2E1 enzyme expression levels and alleviated alcohol-induced oxidative damage by regulating alcohol metabolism. Moreover, UA increased SOD and GSH-Px levels and lowered the MDA levels in the liver. Furthermore, UA regulated ACC expression by activating the LKB1/AMPK pathway, thereby inhibiting lipid synthesis and peroxidation. UA also upregulated the expression of GPX4 and SLC7A11 in the liver and exerted hepatoprotective effects by inhibiting alcohol-induced ferroptosis. Additionally, 16S rRNA amplicon sequencing showed that excessive alcohol consumption significantly affected the composition of the mouse gut microbiota, with UA intervention proving to be beneficial for improving gut microbiota imbalance. We also validated the protective effects of UA on alcohol-treated HepG2 cells at the cellular level. In summary, these results revealed that UA can alleviate alcoholic liver injury by inhibiting oxidative stress-mediated ferroptosis and regulating gut microbiota. These findings suggest that UA may serve as a functional component in the prevention of alcoholic liver disease.

中文翻译：

熊果酸通过减轻氧化应激介导的铁死亡和调节肠道微生物群来改善酒精性肝损伤

熊果酸 (UA) 是植物中发现的一种三萜类化合物，对肝功能有许多健康益处。然而，由于缺乏研究，理解 UA 如何干预酒精诱导的铁死亡仍不清楚。本研究探讨UA对酒精性肝损伤的保护作用，并进一步阐明其作用机制。采用小鼠模型，通过高剂量酒精灌胃诱导急性肝损伤，并通过分析血清和肝脏指标评估UA的保护作用。结果表明，UA对小鼠酒精性肝损伤具有显着的保护作用。 UA显着降低血清ALT、AST、TC和TG水平。组织病理学检查显示UA显着改善肝损伤。 UA 增加 ADH、ALDH 和 CYP2E1 酶的表达水平，并通过调节酒精代谢减轻酒精引起的氧化损伤。此外，UA 增加了肝脏中 SOD 和 GSH-Px 的水平，并降低了 MDA 的水平。此外，UA通过激活LKB1/AMPK通路调节ACC表达，从而抑制脂质合成和过氧化。 UA还能上调肝脏中GPX4和SLC7A11的表达，通过抑制酒精引起的铁死亡发挥保肝作用。此外，16S rRNA扩增子测序显示，过量饮酒显着影响小鼠肠道菌群的组成，UA干预被证明有利于改善肠道菌群失衡。我们还在细胞水平上验证了 UA 对酒精处理的 HepG2 细胞的保护作用。总之，这些结果表明，UA可以通过抑制氧化应激介导的铁死亡和调节肠道微生物群来减轻酒精性肝损伤。这些发现表明，UA 可能作为预防酒精性肝病的功能成分。

更新日期：2024-09-15

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