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Multi-omics integration reveals the hepatoprotective mechanisms of ursolic acid intake against chronic alcohol consumption

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Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusion

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.

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Abbreviations

ALD:

Alcoholic liver disease

UA:

Ursolic acid

AST:

Aspartate aminotransferase

ALT:

Alanine aminotransferase

TG:

Triacylglycerol

TC:

Total cholesterol

TMT:

Transcriptomics and tandem mass tags

RSEM:

RNA-seq by expectation maximization

DEGs:

Differential expression genes

FPKM:

Fragments per kilobase of exon per million mapped reads

Edge R:

Empirical analysis of digital gene expression in R

UPLC:

Ultra performance liquid chromatographer

DEPs:

Differentially expressed proteins

GO:

Gene ontology

KEGG:

Kyoto encyclopedia of genes and genomes

PPI:

Protein–protein interaction

NQO1:

NAD(P)H dehydrogenase quinone 1

GSTA2:

Glutathione S-transferase alpha 2

BP:

Biological process

CC:

Cellular component

MF:

Molecular function

OS:

Organismal systems

CP:

Cellular processes

M:

Metabolism

HD:

Human diseases

EIP:

Environmental information processing

CYP450:

Cytochrome P450

GST:

Glutathione S-transferase

ROS:

Reactive oxygen species

ADH:

Alcohol dehydrogenase

RNS:

Reactive nitrogen species

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Acknowledgements

The authors gratefully acknowledge the financial support of National Natural Science Foundation of China (No. 81760769), the Ningxia Hui Autonomous Region key research and development program (2020BFG03007), and the Fundamental Research Funds for the Central Universities (2018-JYBZZ-JS017).

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Authors and Affiliations

  1. School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China

    Xin Yan, Xiaoyun Liu, Yu Wang, Xueyang Ren, Jiamu Ma, Ruolan Song, Xiuhuan Wang, Ying Dong, Qiqi Fan, Jing Wei, Axiang Yu & Gaimei She

  2. School of Chinese Pharmacy, Ningxia Medical University, Yinchuan, 750004, China

    Hong Sui

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  1. Xin Yan
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Yan, X., Liu, X., Wang, Y. et al. Multi-omics integration reveals the hepatoprotective mechanisms of ursolic acid intake against chronic alcohol consumption. Eur J Nutr 61, 115–126 (2022). https://doi.org/10.1007/s00394-021-02632-x

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  • DOI: https://doi.org/10.1007/s00394-021-02632-x

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