1887

Abstract

Persistent infection of hepatitis C virus (HCV) can lead to liver cirrhosis and hepatocellular carcinoma, which are currently diagnosed by invasive liver biopsy. Approximately 15–20 % of cases of chronic liver diseases in India are caused by HCV infection. In North India, genotype 3 is predominant, whereas genotype 1 is predominant in southern parts of India. The aim of this study was to identify differentially regulated serum proteins in HCV-infected Indian patients (genotypes 1 and 3) using a two-dimensional electrophoresis approach. We identified eight differentially expressed proteins by MS. Expression levels of one of the highly upregulated proteins, retinol-binding protein 4 (RBP4), was validated by ELISA and Western blotting in two independent cohorts. We also confirmed our observation in the JFH1 infectious cell culture system. Interestingly, the HCV core protein enhanced RBP4 levels and partial knockdown of RBP4 had a positive impact on HCV replication, suggesting a possible role for this cellular protein in regulating HCV infection. Analysis of RBP4-interacting partners using a bioinformatic approach revealed novel insights into the possible involvement of RBP4 in HCV-induced pathogenesis. Taken together, this study provided information on the proteome profile of the HCV-infected Indian population, and revealed a link between HCV infection, RBP4 and insulin resistance.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.062430-0
2014-08-01
2019-11-17
Loading full text...

Full text loading...

/deliver/fulltext/jgv/95/8/1654.html?itemId=/content/journal/jgv/10.1099/vir.0.062430-0&mimeType=html&fmt=ahah

References

  1. Albuquerque L. M., Trugilho M. R., Chapeaurouge A., Jurgilas P. B., Bozza P. T., Bozza F. A., Perales J., Neves-Ferreira A. G.. ( 2009; ). Two-dimensional difference gel electrophoresis (DiGE) analysis of plasmas from dengue fever patients. . J Proteome Res 8:, 5431–5441. [CrossRef] [PubMed]
    [Google Scholar]
  2. Alkhouri N., Lopez R., Berk M., Feldstein A. E.. ( 2009; ). Serum retinol-binding protein 4 levels in patients with nonalcoholic fatty liver disease. . J Clin Gastroenterol 43:, 985–989. [CrossRef] [PubMed]
    [Google Scholar]
  3. Amarapurkar D. N., Patel N. D.. ( 2008; ). Increased prevalence of type II diabetes mellitus in hepatitis C virus infection in western India. . Trop Gastroenterol 29:, 148–152.[PubMed]
    [Google Scholar]
  4. Benali-Furet N. L., Chami M., Houel L., De Giorgi F., Vernejoul F., Lagorce D., Buscail L., Bartenschlager R., Ichas F.. & other authors ( 2005; ). Hepatitis C virus core triggers apoptosis in liver cells by inducing ER stress and ER calcium depletion. . Oncogene 24:, 4921–4933. [CrossRef] [PubMed]
    [Google Scholar]
  5. Biddinger S. B., Kahn C. R.. ( 2006; ). From mice to men: insights into the insulin resistance syndromes. . Annu Rev Physiol 68:, 123–158. [CrossRef] [PubMed]
    [Google Scholar]
  6. Blum H., Beier H., Gross J. H.. ( 1987; ). Improved silver staining of plant proteins, RNA and DNA in polyacrylamide gels. . Electrophoresis 8:, 93–99. [CrossRef]
    [Google Scholar]
  7. Broch M., Vendrell J., Ricart W., Richart C., Fernández-Real J. M.. ( 2007; ). Circulating retinol-binding protein-4, insulin sensitivity, insulin secretion, and insulin disposition index in obese and nonobese subjects. . Diabetes Care 30:, 1802–1806. [CrossRef] [PubMed]
    [Google Scholar]
  8. Chen J. H., Chang Y. W., Yao C. W., Chiueh T. S., Huang S. C., Chien K. Y., Chen A., Chang F. Y., Wong C. H., Chen Y. J.. ( 2004; ). Plasma proteome of severe acute respiratory syndrome analyzed by two-dimensional gel electrophoresis and mass spectrometry. . Proc Natl Acad Sci U S A 101:, 17039–17044. [CrossRef] [PubMed]
    [Google Scholar]
  9. Chen Y. Y., Lin S. Y., Yeh Y. Y., Hsiao H. H., Wu C. Y., Chen S. T., Wang A. H.. ( 2005; ). A modified protein precipitation procedure for efficient removal of albumin from serum. . Electrophoresis 26:, 2117–2127. [CrossRef] [PubMed]
    [Google Scholar]
  10. Cheung K. J., Tilleman K., Deforce D., Colle I., Van Vlierberghe H.. ( 2009; ). The HCV serum proteome: a search for fibrosis protein markers. . J Viral Hepat 16:, 418–429. [CrossRef] [PubMed]
    [Google Scholar]
  11. Chowdhury A., Santra A., Chaudhuri S., Dhali G. K., Chaudhuri S., Maity S. G., Naik T. N., Bhattacharya S. K., Mazumder D. N.. ( 2003; ). Hepatitis C virus infection in the general population: a community-based study in West Bengal, India. . Hepatology 37:, 802–809. [CrossRef] [PubMed]
    [Google Scholar]
  12. El-Zayadi A., Anis M.. ( 2012; ). Hepatitis C virus induced insulin resistance impairs response to antiviral therapy. . World J Gastroenterol 183:, 212–224. [CrossRef]
    [Google Scholar]
  13. Frese M., Barth K., Kaul A., Lohmann V., Schwärzle V., Bartenschlager R.. ( 2003; ). Hepatitis C virus RNA replication is resistant to tumour necrosis factor-alpha. . J Gen Virol 84:, 1253–1259. [CrossRef] [PubMed]
    [Google Scholar]
  14. Gangadharan B., Antrobus R., Dwek R. A., Zitzmann N.. ( 2007; ). Novel serum biomarker candidates for liver fibrosis in hepatitis C patients. . Clin Chem 53:, 1792–1799. [CrossRef] [PubMed]
    [Google Scholar]
  15. Gangadharan B., Bapat M., Rossa J., Antrobus R., Chittenden D., Kampa B., Barnes E., Klenerman P., Dwek R. A., Zitzmann N.. ( 2012; ). Discovery of novel biomarker candidates for liver fibrosis in hepatitis C patients: a preliminary study. . PLoS ONE 7:, e39603. [CrossRef] [PubMed]
    [Google Scholar]
  16. Higgs M. R., Lerat H., Pawlotsky J. M.. ( 2012; ). Hepatitis C virus-induced activation of β-catenin promotes c-Myc expression and a cascade of pro-carcinogenetic events. . Oncogene 32:, 4683–4693. [CrossRef] [PubMed]
    [Google Scholar]
  17. Hissar S. S., Goyal A., Kumar M., Pandey C., Suneetha P. V., Sood A., Midha V., Sakhuja P., Malhotra V., Sarin S. K.. ( 2006; ). Hepatitis C virus genotype 3 predominates in North and Central India and is associated with significant histopathologic liver disease. . J Med Virol 78:, 452–458. [CrossRef] [PubMed]
    [Google Scholar]
  18. Huang J. F., Dai C. Y., Yu M. L., Shin S. J., Hsieh M. Y., Huang C. F., Lee L. P., Lin K. D., Lin Z. Y.. & other authors ( 2009; ). Serum retinol-binding protein 4 is inversely correlated with disease severity of chronic hepatitis C. . J Hepatol 50:, 471–478. [CrossRef] [PubMed]
    [Google Scholar]
  19. Janke J., Engeli S., Boschmann M., Adams F., Böhnke J., Luft F. C., Sharma A. M., Jordan J.. ( 2006; ). Retinol-binding protein 4 in human obesity. . Diabetes 55:, 2805–2810. [CrossRef] [PubMed]
    [Google Scholar]
  20. Kotnik P., Fischer-Posovszky P., Wabitsch M.. ( 2011; ). RBP4: a controversial adipokine. . Eur J Endocrinol 165:, 703–711. [CrossRef] [PubMed]
    [Google Scholar]
  21. Lavanchy D.. ( 2011; ). Evolving epidemiology of hepatitis C virus. . Clin Microbiol Infect 17:, 107–115. [CrossRef] [PubMed]
    [Google Scholar]
  22. Mangia A., Ripoli M.. ( 2013; ). Insulin resistance, steatosis and hepatitis C virus. . Hepatol Int 7: (Suppl 2), 782–789. [CrossRef] [PubMed]
    [Google Scholar]
  23. Okuda M., Li K., Beard M. R., Showalter L. A., Scholle F., Lemon S. M., Weinman S. A.. ( 2002; ). Mitochondrial injury, oxidative stress, and antioxidant gene expression are induced by hepatitis C virus core protein. . Gastroenterology 122:, 366–375. [CrossRef] [PubMed]
    [Google Scholar]
  24. Panigrahi A. K., Roca J., Acharya S. K., Jameel S., Panda S. K.. ( 1996; ). Genotype determination of hepatitis C virus from northern India: identification of a new subtype. . J Med Virol 48:, 191–198. [CrossRef] [PubMed]
    [Google Scholar]
  25. Petta S., Cammà C., Di Marco V., Alessi N., Barbaria F., Cabibi D., Caldarella R., Ciminnisi S., Licata A.. & other authors ( 2008; ). Retinol-binding protein 4: a new marker of virus-induced steatosis in patients infected with hepatitis c virus genotype 1. . Hepatology 48:, 28–37. [CrossRef] [PubMed]
    [Google Scholar]
  26. Qin S., Zhou Y., Lok A. S., Tsodikov A., Yan X., Gray L., Yuan M., Moritz R. L., Galas D.. & other authors ( 2012; ). SRM targeted proteomics in search for biomarkers of HCV-induced progression of fibrosis to cirrhosis in HALT-C patients. . Proteomics 12:, 1244–1252. [CrossRef] [PubMed]
    [Google Scholar]
  27. Raghuraman S., Shaji R. V., Sridharan G., Radhakrishnan S., Chandy G., Ramakrishna B. S., Abraham P.. ( 2003; ). Distribution of the different genotypes of HCV among patients attending a tertiary care hospital in south India. . J Clin Virol 26:, 61–69. [CrossRef] [PubMed]
    [Google Scholar]
  28. Ramia S., Eid-Fares J.. ( 2006; ). Distribution of hepatitis C virus genotypes in the Middle East. . Int J Infect Dis 10:, 272–277. [CrossRef] [PubMed]
    [Google Scholar]
  29. Rukmangadachar L. A., Kataria J., Hariprasad G., Samantaray J. C., Srinivasan A.. ( 2011; ). Two-dimensional difference gel electrophoresis (DIGE) analysis of sera from visceral leishmaniasis patients. . Clin Proteomics 8:, 4–8. [CrossRef] [PubMed]
    [Google Scholar]
  30. Shea J. L., Loredo-Osti J. C., Sun G.. ( 2010; ). Association of RBP4 gene variants and serum HDL cholesterol levels in the Newfoundland population. . Obesity (Silver Spring) 18:, 1393–1397. [CrossRef] [PubMed]
    [Google Scholar]
  31. Shi S. T., Polyak S. J., Tu H., Taylor D. R., Gretch D. R., Lai M. M. C.. ( 2002; ). Hepatitis C virus NS5A colocalizes with the core protein on lipid droplets and interacts with apolipoproteins. . Virology 292:, 198–210. [CrossRef] [PubMed]
    [Google Scholar]
  32. Simmonds P., Holmes E. C., Cha T. A., Chan S. W., McOmish F., Irvine B., Beall E., Yap P. L., Kolberg J., Urdea M. S.. ( 1993; ). Classification of hepatitis C virus into six major genotypes and a series of subtypes by phylogenetic analysis of the NS-5 region. . J Gen Virol 74:, 2391–2399. [CrossRef] [PubMed]
    [Google Scholar]
  33. Simmonds P., Bukh J., Combet C., Deléage G., Enomoto N., Feinstone S., Halfon P., Inchauspé G., Kuiken C.. & other authors ( 2005; ). Consensus proposals for a unified system of nomenclature of hepatitis C virus genotypes. . Hepatology 42:, 962–973. [CrossRef] [PubMed]
    [Google Scholar]
  34. Simula M. P., Notarpietro A., Toffoli G., De Re V.. ( 2012; ). 2-D gel electrophoresis: constructing 2D-gel proteome reference maps. . Methods Mol Biol 815:, 163–173. [CrossRef] [PubMed]
    [Google Scholar]
  35. Soriano V., Peters M. G., Zeuzem S.. ( 2009; ). New therapies for hepatitis C virus infection. . Clin Infect Dis 48:, 313–320. [CrossRef] [PubMed]
    [Google Scholar]
  36. Srivastava R., Ray S., Vaibhav V., Gollapalli K., Jhaveri T., Taur S., Dhali S., Gogtay N., Thatte U.. & other authors ( 2012; ). Serum profiling of leptospirosis patients to investigate proteomic alterations. . J Proteomics 76:, 56–68. [CrossRef] [PubMed]
    [Google Scholar]
  37. Valliammai T., Thyagarajan S. P., Zuckerman A. J., Harrison T. J.. ( 1995; ). Diversity of genotypes of hepatitis C virus in southern India. . J Gen Virol 76:, 711–716. [CrossRef] [PubMed]
    [Google Scholar]
  38. Wakita T., Pietschmann T., Kato T., Date T., Miyamoto M., Zhao Z., Murthy K., Habermann A., Kräusslich H. G.. & other authors ( 2005; ). Production of infectious hepatitis C virus in tissue culture from a cloned viral genome. . Nat Med 11:, 791–796. [CrossRef] [PubMed]
    [Google Scholar]
  39. White I. R., Patel K., Symonds W. T., Dev A., Griffin P., Tsokanas N., Skehel M., Liu C., Zekry A.. & other authors ( 2007; ). Serum proteomic analysis focused on fibrosis in patients with hepatitis C virus infection. . J Transl Med 5:, 33–36. [CrossRef] [PubMed]
    [Google Scholar]
  40. Xia M., Liu Y., Guo H., Wang D., Wang Y., Ling W.. ( 2013; ). Retinol binding protein 4 stimulates hepatic sterol regulatory element-binding protein 1 and increases lipogenesis through the peroxisome proliferator-activated receptor-γ coactivator 1β-dependent pathway. . Hepatology 58:, 564–575. [CrossRef] [PubMed]
    [Google Scholar]
  41. Yagmur E., Weiskirchen R., Gressner A. M., Trautwein C., Tacke F.. ( 2007; ). Insulin resistance in liver cirrhosis is not associated with circulating retinol-binding protein 4. . Diabetes Care 30:, 1168–1172. [CrossRef] [PubMed]
    [Google Scholar]
  42. Yang Q., Graham T. E., Mody N., Preitner F., Peroni O. D., Zabolotny J. M., Kotani K., Quadro L., Kahn B. B.. ( 2005; ). Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes. . Nature 436:, 356–362. [CrossRef] [PubMed]
    [Google Scholar]
  43. Yao-Borengasser A., Varma V., Bodles A. M., Rasouli N., Phanavanh B., Lee M. J., Starks T., Kern L. M., Spencer H. J. III. & other authors ( 2007; ). Retinol binding protein 4 expression in humans: relationship to insulin resistance, inflammation, and response to pioglitazone. . J Clin Endocrinol Metab 92:, 2590–2597. [CrossRef] [PubMed]
    [Google Scholar]
  44. Yoon S. Y., Kim J. M., Oh J. H., Jeon Y. J., Lee D. S., Kim J. H., Choi J. Y., Ahn B. M., Kim S.. & other authors ( 2006; ). Gene expression profiling of human HBV- and/or HCV-associated hepatocellular carcinoma cells using expressed sequence tags. . Int J Oncol 29:, 315–327.[PubMed]
    [Google Scholar]
  45. Zarkesh-Esfahani S. H., Kardi M. T., Edalati M.. ( 2010; ). Hepatitis C virus genotype frequency in Isfahan province of Iran: a descriptive cross-sectional study. . Virol J 7:, 69–75. [CrossRef] [PubMed]
    [Google Scholar]
  46. Zelcer N., Tontonoz P.. ( 2006; ). Liver X receptors as integrators of metabolic and inflammatory signaling. . J Clin Invest 116:, 607–614. [CrossRef] [PubMed]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.062430-0
Loading
/content/journal/jgv/10.1099/vir.0.062430-0
Loading

Data & Media loading...

Supplements

Supplementary Material 

PDF

Most Cited This Month

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error