title: Application of network construction to estimate functional changes to insulin receptor substrates 1 and 2 in Huh7 cells following infection with the hepatitis C virus.
abstract: 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.
authors.affiliation: Department of Infectious Diseases, The Second Affiliated Hospital of Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China.
authors.forename: Jingkun
authors.initials: J
authors.lastname: Liu
authors.affiliation: The First Clinical Department, Chongqing Medical University, Chongqing 400016, P.R. China.
authors.forename: Linbang
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Infectious Diseases, The Second Affiliated Hospital of Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Infectious Diseases, The Second Affiliated Hospital of Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Infectious Diseases, The Second Affiliated Hospital of Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Jia
authors.affiliation: Department of Infectious Diseases, The Second Affiliated Hospital of Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China.
authors.forename: Song
authors.initials: S
authors.lastname: Zhai
authors.affiliation: Department of Infectious Diseases, The Second Affiliated Hospital of Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China.
authors.forename: Juan
authors.initials: J
authors.lastname: Shi
authors.affiliation: Department of Infectious Diseases, The Second Affiliated Hospital of Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China.
authors.forename: Shuangsuo
authors.initials: S
authors.lastname: Dang
mesh_terms: D045744:Cell Line, Tumor; D016000:Cluster Analysis; D019295:Computational Biology / Q000379:methods; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D016174:Hepacivirus; D006526:Hepatitis C / Q000235:genetics / Q000378:metabolism / Q000821:virology; D006801:Humans; D007328:Insulin / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics* / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics; D015398:Signal Transduction
chemical_list: D007328:Insulin; D055504:Insulin Receptor Substrate Proteins