Mechanisms of CCl4-induced liver fibrosis with combined transcriptomic and proteomic analysis

• Published in: Journal of toxicological sciences Vol. 41; no. 4; pp. 561 - 572
• Main Authors: Dong, Shu, Chen, Qi-Long, Song, Ya-Nan, Sun, Yang, Wei, Bin, Li, Xiao-Yan, Hu, Yi-Yang, Liu, Ping, Su, Shi-Bing
• Format: Journal Article
• Language: English
• Published: Japan The Japanese Society of Toxicology 2016; Japan Science and Technology Agency
• Subjects: Animals; Carbon Tetrachloride; CCl4; Chemical and Drug Induced Liver Injury - genetics; Chemical and Drug Induced Liver Injury - metabolism; Chemical and Drug Induced Liver Injury - pathology; Computational Biology; Gene Expression Profiling - methods; Gene Expression Regulation; Gene Regulatory Networks; Integrative analysis; Liver - metabolism; Liver - pathology; Liver Cirrhosis - chemically induced; Liver Cirrhosis - genetics; Liver Cirrhosis - metabolism; Liver Cirrhosis - pathology; Liver fibrosis; Oligonucleotide Array Sequence Analysis; Protein Interaction Maps; Proteomics; Proteomics - methods; Rats, Wistar; Reproducibility of Results; Toxicity; Transcriptomics
• ISSN: 0388-1350; 1880-3989
• DOI: 10.2131/jts.41.561

The classic toxicity of carbon tetrachloride (CCl4) is to induce liver lesion and liver fibrosis. Liver fibrosis is a consequence of chronic liver lesion, which can progress into liver cirrhosis even hepatocarcinoma. However, the toxicological mechanisms of CCl4-induced liver fibrosis remain not fully understood. We combined transcriptomic and proteomic analysis and biological network technology, predicted toxicological targets and regulatory networks of CCl4 in liver fibrosis. Wistar rats were treated with CCl4 for 9 weeks. Histopathological changes, hydroxyproline (Hyp) contents, serum ALT and AST in the CCl4-treated group were significantly higher than that of CCl4-untreated group. CCl4-treated and -untreated liver tissues were examined by microarray and iTRAQ. The results showed that 3535 genes (fold change ≥ 1.5, P < 0.05) and 1412 proteins (fold change ≥ 1.2, P < 0.05) were differentially expressed. Moreover, the integrative analysis of transcriptomics and proteomics data showed 523 overlapped proteins, enriched in 182 GO terms including oxidation reduction, response to oxidative stress, inflammatory response, extracellular matrix organization, etc. Furthermore, KEGG pathway analysis showed that 36 pathways including retinol metabolism, PPAR signaling pathway, glycolysis/gluconeogenesis, arachidonic acid metabolism, metabolism of xenobiotics by cytochrome P450 and drug metabolism. Network of protein-protein interaction (PPI) and key function with their related targets were performed and the degree of network was calculated with Cytoscape. The expression of key targets such as CYP4A3, ALDH2 and ALDH7A1 decreased after CCl4 treatment. Therefore, the toxicological mechanisms of CCl4-induced liver fibrosis may be related with multi biological process, pathway and targets which may provide potential protection reaction mechanism for CCl4 detoxication in the liver.