School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China.
School of Chinese Pharmacy, Ningxia Medical University, Yinchuan, 750004, China.
Eur J Nutr. 2022 Feb;61(1):115-126. doi: 10.1007/s00394-021-02632-x. Epub 2021 Jul 2.
Alcoholic liver disease (ALD) is a major health issue globally. In addition to pharmacotherapy, dietary support is also regarded as reliable strategy for ALD management. As a widely distributed natural constituent within edible plants, the present study aims to investigate the hepatoprotective effects of ursolic acid (UA) against ALD and also to deepen insights into the underlying targets and mechanisms comprehensively.
The hepatoprotective activity of UA against chronic alcohol-induced liver injury was investigated on Lieber-DeCarli liquid diet-based mouse model. In-depth RNA-seq transcriptomics and TMT-based proteomics analyses were conducted in parallel. Data integration as well as bioinformatics analysis were also performed to unravel the targets and mechanisms associated with the hepatoprotective activity of UA intake against alcoholic liver injury comprehensively.
The serum biomarkers and pathological characteristics indicated the hepatoprotective effects of UA intake on alcoholic liver injury. 567 target genes and 377 target proteins related to the hepatoprotective activity of UA were identified in transcriptomics and proteomics analysis respectively, most of which were associated with function of cellular process, cell part and binding. After data integration, 56 co-regulated targets, including ADH4, CYP450 enzymes, NQO1, apolipoproteins, glutathione-S-transferase, etc. which were consistently modulated on both mRNA and protein levels were identified. These co-regulated targets were found to be correlated with 70 KEGG pathways led by carcinogenesis, retinol metabolism and CYP450 metabolism pathways.
UA intake ameliorated chronic alcohol-induced liver injury. Given the role of the co-regulated targets in ALD and the bioinformatics analysis results, CYP450-, glutathione and redox homeostasis-dependent antioxidation, promotion of lipid transport, and restoration of ethanol metabolic capacity are the potentially underlying mechanisms. This information will further deepen our insights into the hepatoprotective effects of UA-rich edible plants, and provide us valuable instruction for ALD management.
酒精性肝病（ALD）是全球的一个主要健康问题。除了药物治疗外，饮食支持也被认为是 ALD 管理的可靠策略。熊果酸（UA）作为一种广泛分布于食用植物中的天然成分，本研究旨在探讨其对 ALD 的保肝作用，并深入全面地研究其潜在靶点和机制。
在 Lieber-DeCarli 液体饮食小鼠模型上研究 UA 对慢性酒精性肝损伤的保护作用。同时进行深度 RNA-seq 转录组学和 TMT 基于蛋白质组学分析。还进行了数据整合和生物信息学分析，以全面揭示 UA 摄入对酒精性肝损伤的保护作用相关的靶点和机制。
血清生物标志物和病理特征表明 UA 摄入对酒精性肝损伤具有保护作用。在转录组学和蛋白质组学分析中分别鉴定出与 UA 保护活性相关的 567 个靶基因和 377 个靶蛋白，其中大多数与细胞过程、细胞成分和结合的功能有关。在数据整合后，鉴定出 56 个共同调节的靶点，包括 ADH4、CYP450 酶、NQO1、载脂蛋白、谷胱甘肽-S-转移酶等，这些靶点在 mRNA 和蛋白质水平上均被一致调节。这些共同调节的靶点与致癌作用、视黄醇代谢和 CYP450 代谢途径为主导的 70 个 KEGG 途径相关。
UA 摄入可改善慢性酒精性肝损伤。鉴于共同调节靶点在 ALD 中的作用以及生物信息学分析结果，CYP450-、谷胱甘肽和氧化还原稳态依赖的抗氧化作用、促进脂质转运以及恢复乙醇代谢能力是潜在的作用机制。这些信息将进一步加深我们对富含 UA 的食用植物的保肝作用的认识，并为 ALD 管理提供有价值的指导。
