title: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Microbiology, University of Washington School of Medicine, Seattle, WA 98195-8070, USA. ddiamond@u.washington.edu
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Diamond
authors.forename: Alexei L
authors.initials: AL
authors.lastname: Krasnoselsky
authors.forename: Kristin E
authors.initials: KE
authors.lastname: Burnum
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Monroe
authors.forename: Bobbie-Jo
authors.initials: BJ
authors.lastname: Webb-Robertson
authors.forename: Jason E
authors.initials: JE
authors.lastname: McDermott
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Yeh
authors.forename: Jose Felipe Golib
authors.initials: JF
authors.lastname: Dzib
authors.forename: Nathan
authors.initials: N
authors.lastname: Susnow
authors.forename: Susan
authors.initials: S
authors.lastname: Strom
authors.forename: Sean C
authors.initials: SC
authors.lastname: Proll
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Belisle
authors.forename: David E
authors.initials: DE
authors.lastname: Purdy
authors.forename: Angela L
authors.initials: AL
authors.lastname: Rasmussen
authors.forename: Kathie-Anne
authors.initials: KA
authors.lastname: Walters
authors.forename: Jon M
authors.initials: JM
authors.lastname: Jacobs
authors.forename: Marina A
authors.initials: MA
authors.lastname: Gritsenko
authors.forename: David G
authors.initials: DG
authors.lastname: Camp
authors.forename: Renuka
authors.initials: R
authors.lastname: Bhattacharya
authors.forename: James D
authors.initials: JD
authors.lastname: Perkins
authors.forename: Robert L
authors.initials: RL
authors.lastname: Carithers
authors.forename: Iris W
authors.initials: IW
authors.lastname: Liou
authors.forename: Anne M
authors.initials: AM
authors.lastname: Larson
authors.forename: Arndt
authors.initials: A
authors.lastname: Benecke
authors.forename: Katrina M
authors.initials: KM
authors.lastname: Waters
authors.forename: Richard D
authors.initials: RD
authors.lastname: Smith
authors.forename: Michael G
authors.initials: MG
authors.lastname: Katze
mesh_terms: D000328:Adult; D000368:Aged; D001707:Biopsy, Needle; D002853:Chromatography, Liquid / Q000379:methods; D015331:Cohort Studies; D003936:Diagnosis, Computer-Assisted / Q000379:methods; D018450:Disease Progression; D005260:Female; D006084:Graft Rejection; D006085:Graft Survival; D016174:Hepacivirus / Q000378:metabolism* / Q000472:pathogenicity; D006526:Hepatitis C / Q000150:complications* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008103:Liver Cirrhosis / Q000209:etiology / Q000473:pathology* / Q000601:surgery; D016031:Liver Transplantation / Q000009:adverse effects / Q000473:pathology*; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D008875:Middle Aged; D018384:Oxidative Stress / Q000502:physiology; D040081:Protein Array Analysis / Q000379:methods*; D020543:Proteome / Q000235:genetics / Q000378:metabolism*; D040901:Proteomics / Q000379:methods; D012008:Recurrence; D012016:Reference Values; D018570:Risk Assessment; D012494:Sampling Studies; D012680:Sensitivity and Specificity
chemical_list: D020543:Proteome