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

Abstract

-The classic toxicity of carbon tetrachloride (CCl 4 ) 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 CCl 4 -induced liver fibrosis remain not fully understood. We combined transcriptomic and proteomic analysis and biological network technology, predicted toxicological targets and regulatory networks of CCl 4 in liver fibrosis. Wistar rats were treated with CCl 4 for 9 weeks. Histopathological changes, hydroxyproline (Hyp) contents, serum ALT and AST in the CCl 4 -treated group were significantly higher than that of CCl 4 -untreated group. CCl 4 -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 CCl 4 treatment. Therefore, the toxicological mechanisms of CCl 4 -induced liver fibrosis may be related with multi biological process, pathway and targets which may provide potential protection reaction mechanism for CCl 4 detoxication in the liver.

Study of Protective Effects of Gold Nano Particles on the Liver Toxicity Induced by Carbon-Tetrachloride (CCl4) in Male Rats

“…Our results revealed that AST, ALT and ALP in group CCl 4 +AuNP did not show any significant differences with those of group CCL 4 and are then in in line with the findings by Clinton Rambanapasi, et al (2016) who reported that the indicators of liver damage, AST and ALT showed no significant differences between the control and experimental groups [18]. The results in the present study were promised by Shu Dong, et al (2016) who reported that toxicological mechanisms of CCl 4 -induced liver fibrosis may be related to multi biological manner mechanisms for CCl 4 detoxication in the liver [5]. Poli G, (2000) reported that fibrotic process in the liver, which is induced by chemical mediators, promotes expression and synthesis of inflammatory and pro-fibrogenic cytokine and lipid peroxidation products [21].…”

“…The classic toxicity of CCl 4 speeds up liver injury and liver fibrosis. Liver fibrosis is a result of chronic liver injury, which can progress into liver cirrhosis [5]. Since AuNps have hydrophilic and hydrophobic nature, they easily inter cells and alter the cell function but their effects depend commonly on the size of this nanoparticle [6,7].…”

Protective Effect of Diosgenin Against Carbon Tetrachloride and Cisplatin Induced Hepatotoxicity in Rats

“…The result of our study showed that activities of serum enzymes (ALT, AST, and ALP) in negative control group increased in comparison with the control group. ALT, AST, and ALP enzymes levels increase in serum confirmed hepatocytes cell membrane damage and enzymes leak from the hepatocytes [12]. Our result showed that cisplatin makes dosedependent changes in liver structure: some of these changes impair hepatocytes arrangement, liver lobulation, and necrosis.…”

Metabolomic mechanisms of gypenoside against liver fibrosis in rats: An integrative analysis of proteomics and metabolomics data

“…The fibrotic liver contains approximately 6 times ECM more than normal, which is a result of both increased synthesis and decreased degradation [17]. Our previous study explored the mechanisms of CCl 4 -induced liver fibrosis with combined transcriptomic and proteomic analysis [18]. On the other hand, when liver fibrosis occurs, a host of metabolic pathways will alter in hepatocytes, and related proteins and metabolites will be also involved hepatic disorder.…”