Transcriptomic Insight Based on Network Analysis Reveals the Effect of Ursolic Acid on Non-Alcoholic Steatohepatitis

Abstract

Abstract Background Non-alcoholic steatohepatitis (NASH) has attracted international attention. However, pharmaceutical treatments are not included in the current guidelines. Ursolic acid (UA) has the potential to treat metabolic disorders. Hence, this study aimed to investigate the impact of UA on NASH. Methods RNA sequencing from our own model mice was performed to detect differentially expressed genes (DEGs) in 12 mouse samples from 4 groups. DEGs were subjected to Gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Weighted gene co-expression network analysis (WGCNA) was applied to find modules associated with NASH's pathological characteristics and identified the hub genes in the relevant modules. Hub genes were further identified and the ceRNA network was constructed. In vitro and in vivo experiments were applied to identify the expected mRNAs. Results By comparing NASH mice to Wild type (WT) mice, we performed GO and KEGG enrichment analysis to identify pathways associated with NASH inflammatory metabolic disorders, and by doing the same for NASH mice treated with UA, we identified pathways via which UA may alter. Based on WGCNA, the modules associated with the pathological changes of NASH, as well as the hub genes in each module were identified. A ceRNA network was successfully constructed. RT-PCR results showed that Akr1a1 and Chchd2 were protective factors against NASH, and Ndufb9 was a risk factor. The level of ROS detected by flow cytometry indicated that UA could alleviate oxidative stress. Conclusion Akr1a1, Chchd2, and Ndufb9 were essential for the therapeutic effects of UA on NASH and the ceRNA network might act as prospective therapeutic and diagnostic biomarker targets.