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Proteome and computational analyses reveal new insights into the mechanisms of hepatitis C virus-mediated liver disease posttransplantation.

ABSTRACT: Liver transplant tissues offer the unique opportunity to model the longitudinal protein abundance changes occurring during hepatitis C virus (HCV)-associated liver disease progression in vivo. In this study, our goal was to identify molecular signatures, and potential key regulatory proteins, representative of the processes influencing early progression to fibrosis. We performed global protein profiling analyses on 24 liver biopsy specimens obtained from 15 HCV(+) liver transplant recipients at 6 and/or 12 months posttransplantation. Differentially regulated proteins associated with early progression to fibrosis were identified by analysis of the area under the receiver operating characteristic curve. Analysis of serum metabolites was performed on samples obtained from an independent cohort of 60 HCV(+) liver transplant patients. Computational modeling approaches were applied to identify potential key regulatory proteins of liver fibrogenesis. Among 4,324 proteins identified, 250 exhibited significant differential regulation in patients with rapidly progressive fibrosis. Patients with rapid fibrosis progression exhibited enrichment in differentially regulated proteins associated with various immune, hepatoprotective, and fibrogenic processes. The observed increase in proinflammatory activity and impairment in antioxidant defenses suggests that patients who develop significant liver injury experience elevated oxidative stresses. This was supported by an independent study demonstrating the altered abundance of oxidative stress-associated serum metabolites in patients who develop severe liver injury. Computational modeling approaches further highlight a potentially important link between HCV-associated oxidative stress and epigenetic regulatory mechanisms impacting on liver fibrogenesis.Our proteome and metabolome analyses provide new insights into the role for increased oxidative stress in the rapid fibrosis progression observed in HCV(+) liver transplant recipients. These findings may prove useful in prognostic applications for predicting early progression to fibrosis.

SUBMITTER: Diamond DL

PROVIDER: S-EPMC3387320 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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Proteome and computational analyses reveal new insights into the mechanisms of hepatitis C virus-mediated liver disease posttransplantation.

Diamond Deborah L DL Krasnoselsky Alexei L AL Burnum Kristin E KE Monroe Matthew E ME Webb-Robertson Bobbie-Jo BJ McDermott Jason E JE Yeh Matthew M MM Dzib Jose Felipe Golib JF Susnow Nathan N Strom Susan S Proll Sean C SC Belisle Sarah E SE Purdy David E DE Rasmussen Angela L AL Walters Kathie-Anne KA Jacobs Jon M JM Gritsenko Marina A MA Camp David G DG Bhattacharya Renuka R Perkins James D JD Carithers Robert L RL Liou Iris W IW Larson Anne M AM Benecke Arndt A Waters Katrina M KM Smith Richard D RD Katze Michael G MG

Hepatology (Baltimore, Md.) 20120424 1

<h4>Unlabelled</h4>Liver transplant tissues offer the unique opportunity to model the longitudinal protein abundance changes occurring during hepatitis C virus (HCV)-associated liver disease progression in vivo. In this study, our goal was to identify molecular signatures, and potential key regulatory proteins, representative of the processes influencing early progression to fibrosis. We performed global protein profiling analyses on 24 liver biopsy specimens obtained from 15 HCV(+) liver transp ...[more]

PMID: 22331615

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Project description:The Aryl hydrocarbon Receptor (AhR) is a transcription factor that mediates the biochemical response to xenobiotics and the toxic effects of a number of environmental contaminants, including dioxins. Recently, endogenous regulatory roles for the AhR in normal physiology and development have also been reported, thus extending the interest in understanding its molecular mechanisms of activation. Since dimerization with the AhR Nuclear Translocator (ARNT) protein, occurring through the Helix-Loop-Helix (HLH) and PER-ARNT-SIM (PAS) domains, is needed to convert the AhR into its transcriptionally active form, deciphering the AhR:ARNT dimerization mode would provide insights into the mechanisms of AhR transformation. Here we present homology models of the murine AhR:ARNT PAS domain dimer developed using recently available X-ray structures of other bHLH-PAS protein dimers. Due to the different reciprocal orientation and interaction surfaces in the different template dimers, two alternative models were developed for both the PAS-A and PAS-B dimers and they were characterized by combining a number of computational evaluations. Both well-established hot spot prediction methods and new approaches to analyze individual residue and residue-pairwise contributions to the MM-GBSA binding free energies were adopted to predict residues critical for dimer stabilization. On this basis, a mutagenesis strategy for both the murine AhR and ARNT proteins was designed and ligand-dependent DNA binding ability of the AhR:ARNT heterodimer mutants was evaluated. While functional analysis disfavored the HIF2?:ARNT heterodimer-based PAS-B model, most mutants derived from the CLOCK:BMAL1-based AhR:ARNT dimer models of both the PAS-A and the PAS-B dramatically decreased the levels of DNA binding, suggesting this latter model as the most suitable for describing AhR:ARNT dimerization. These novel results open new research directions focused at elucidating basic molecular mechanisms underlying the functional activity of the AhR.

Project description:BackgroundThe traditional Chinese medicine Huangqi decoction (HQD) consists of Radix Astragali and Radix Glycyrrhizae in a ratio of 6: 1, which has been used for the treatment of liver fibrosis. In this study, we tried to elucidate its action of mechanism (MoA) via a combination of metabolomics data, network pharmacology and molecular docking methods.MethodsFirstly, we collected prototype components and metabolic products after administration of HQD from a publication. With known and predicted targets, compound-target interactions were obtained. Then, the global compound-liver fibrosis target bipartite network and the HQD-liver fibrosis protein-protein interaction network were constructed, separately. KEGG pathway analysis was applied to further understand the mechanisms related to the target proteins of HQD. Additionally, molecular docking simulation was performed to determine the binding efficiency of compounds with targets. Finally, considering the concentrations of prototype compounds and metabolites of HQD, the critical compound-liver fibrosis target bipartite network was constructed.Results68 compounds including 17 prototype components and 51 metabolic products were collected. 540 compound-target interactions were obtained between the 68 compounds and 95 targets. Combining network analysis, molecular docking and concentration of compounds, our final results demonstrated that eight compounds (three prototype compounds and five metabolites) and eight targets (CDK1, MMP9, PPARD, PPARG, PTGS2, SERPINE1, TP53, and HIF1A) might contribute to the effects of HQD on liver fibrosis. These interactions would maintain the balance of ECM, reduce liver damage, inhibit hepatocyte apoptosis, and alleviate liver inflammation through five signaling pathways including p53, PPAR, HIF-1, IL-17, and TNF signaling pathway.ConclusionsThis study provides a new way to understand the MoA of HQD on liver fibrosis by considering the concentrations of components and metabolites, which might be a model for investigation of MoA of other Chinese herbs.

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Proteome and computational analyses reveal new insights into the mechanisms of hepatitis C virus-mediated liver disease posttransplantation.

Publications

Proteome and computational analyses reveal new insights into the mechanisms of hepatitis C virus-mediated liver disease posttransplantation.

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