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

Authors


  • Potential conflict of interest: Nothing to report.

  • Supported by National Institute on Drug Abuse grant 1P30DA01562501 (to M. G. K.). The proteomics measurements were performed in the Environmental Molecular Sciences Laboratory, a national scientific user facility sponsored by the Department of Energy (DOE) and located at Pacific Northwest National Laboratory, which is operated by Battelle Memorial Institute for the DOE under contract DE-AC05-76RL0 1830, and used capabilities developed under National Center for Research Resources grant RR018522 (to R. D. S.). J. F. G. D. is recipient of a CONACYT-Mexico Ph.D. Fellowship (no. 207676/302245).

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. Conclusion: 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. (HEPATOLOGY 2012;56:28–38)

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