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Hepatitis C virus (HCV) is closely associated with insulin resistance (IS), acting primarily by interfering with insulin signaling pathways, increasing cytokine-mediated (tumor necrosis factor α, interleukin 6) inflammatory responses and enhancing oxidative stress. In the insulin signaling pathways, the insulin receptor substrate (IRS) is one of the key regulatory factors. The present study constructed gene regulatory sub-networks specific for IRS1 and IRS2 in Huh7 cells and HCV-infected Huh7 (HCV-Huh7) cells using linear programming and a decomposition algorithm, and investigated the possible mechanisms underlying the function of IRS1/2 in HCV-induced IS in Huh7 cells. All data were obtained from GSE20948 of the Gene Expression Omnibus database from the National Center for Biotechnology Information. Genes which were significantly differentially expressed between Huh7 and HCV-Huh7 cells were analyzed using the significance analysis of microarray algorithm. The top 50 genes, including IRS1/2, were used as target genes to determine the gene regulatory networks and next the sub-networks of IRS1 and IRS2 in HCV-Huh7 and Huh7 cells using Gene Regulatory Network Inference Tool, an algorithm based on linear programming and the decomposition process. The IRS1/2 sub-networks were divided into upstream/downstream groups and activation/suppression clusters, and were further analyzed using Molecule Annotation System 3.0 and Database for Annotation, Visualization, and Integrated Discovery software, two online platforms for enrichment and clustering analysis and visualization. The results indicated that in Huh7 cells, the downstream network of IRS2 is more complex than that of IRS1, indicating that the insulin metabolism in Huh7 cells may be primarily mediated by IRS2. In HCV-Huh7 cells, the downstream pathway of IRS2 is blocked, suggesting that this may be the underlying mechanism in HCV infection that leads to insulin resistance. The present findings add a further dimension to the understanding of the pathological mechanisms of HCV infection-associated insulin resistance, and provide novel concepts for insulin resistance and glucose metabolism research. [ABSTRACT FROM AUTHOR]

Activating transcription factor 3 (ATF3) is an adaptive-response gene of the ATF family. ATF3 activity may be induced in response to a number of different stress-associated signals and ATF3 is involved in a variety of cellular processes. However, the functions of ATF3 and its molecular networks in human hepatoma cells lines and hepatitis C virus-infected Huh7 (HCV-Huh7) cells are not well understood. In the present study, ATF3 regulatory networks in Huh7 and HCV-Huh7 cell lines were established using the linear programming-based GRNinfer software and molecule annotation system 3.0 software. The gene expression omnibus dataset, GSE20948, was analyzed. The resulting network consisted of clusters located upstream and downstream of ATF3 in Huh7 and HCV-Huh7 cell lines. Using the annotation, visualization and integrated discovery (DAVID) software, 10 activation and 2 inhibition enriched functional annotation clusters were identified downstream of ATF3 in HCV-Huh7 cells. However, there were no enriched functional annotation clusters identified upstream of ATF3 in HCV-Huh7 cells. Furthermore, no clusters were identified downstream nor upstream of ATF3 in Huh7 cells. Gene ontology term and Kyoto encyclopedia of genes and genomes pathway analyses demonstrated that ATF3 may be involved in a number of biological processes, in particular, in metabolism regulation in HCV-Huh7 cells. It is hypothesized that the ATF3 pathway may be activated in Huh7 cells following HCV infection and that it is a potential 'hub' in the network of HCV-Huh7 cells. [ABSTRACT FROM AUTHOR]