title: Elevated hepatic lipid and interferon stimulated gene expression in HCV GT3 patients relative to non-alcoholic steatohepatitis.
abstract: OBJECTIVE
  HCV GT-3 has a more pronounced effect on hepatic steatosis and host lipids than other HCV genotypes and is proving less responsive to all oral interferon-free treatment with direct acting antiviral agents. As both HCV GT3 infection and NASH can result in steatosis and cirrhosis, we asked whether hepatic transcriptional profiles reflective of the host response to inflammation differed based on the etiology of injury.
  
  
  METHODS
  Hepatic gene expression was determined for 48 pre-selected genes known to be associated with hepatic interferon signaling and lipid metabolic pathways in treatment-naïve HCV GT-3 (n = 9) and NASH (n = 14) patients.
  
  
  RESULTS
  Genes with significantly higher expression in HCV included chemokines CXCL10, CXCL11 interferon IFNA2, interferon receptors IFNAR1, IL10RB negative regulators of interferon signaling SOCS3, USP18, JAK/STAT and IRF family members STAT1, STAT2, and IRF, and TGFB family members TGFB1, TGFBR1, and TGFBR2 and other ISGs like OAS2, IF127, IF144 and ISG15. HCV infection was also associated with higher expression of genes associated with lipid metabolism APOE, APOL3, SREBF1 and HMBS. Furthermore, our results suggest that, in HCV GT3-infected patients, IL28B (CC) genotype is associated with lower baseline ISG expression such as IRF9, ISG15, MX1, STAT1, CXCL10, CXCL11, and IFI27 compared to CT/TT genotype.
  
  
  CONCLUSIONS
  HCV GT-3 and NASH both induce hepatic steatosis and inflammation, while HCV GT-3 infection is uniquely associated with elevated transcription of hepatic ISGs and genes associated with lipid metabolism. These changes likely reflect the unique host response to HCV replication distinct from the inflammatory response induced by NASH.
authors.affiliation: Institute of Human Virology, University of Maryland, Baltimore, MD, USA.
authors.forename: Shikha
authors.initials: S
authors.lastname: Shrivastava
authors.affiliation: Division of Infectious Diseases, Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Eric G
authors.initials: EG
authors.lastname: Meissner
authors.affiliation: National Institute of Allergy and Infectious Diseases, NIH, Bethesda, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Funk
authors.affiliation: National Institute of Allergy and Infectious Diseases, NIH, Bethesda, USA.
authors.forename: Seerat
authors.initials: S
authors.lastname: Poonia
authors.affiliation: Institute of Liver and Biliary Sciences, New Delhi, India.
authors.forename: Virender
authors.initials: V
authors.lastname: Shokeen
authors.affiliation: Institute of Liver and Biliary Sciences, New Delhi, India.
authors.forename: Arun
authors.initials: A
authors.lastname: Thakur
authors.affiliation: Institute of Human Virology, University of Maryland, Baltimore, MD, USA.
authors.forename: Bhawna
authors.initials: B
authors.lastname: Poonia
authors.affiliation: Institute of Liver and Biliary Sciences, New Delhi, India.
authors.forename: Shiv Kumar
authors.initials: SK
authors.lastname: Sarin
authors.affiliation: Institute of Liver and Biliary Sciences, New Delhi, India. trehanpati@gmail.com.
authors.forename: Nirupma
authors.initials: N
authors.lastname: Trehanpati
authors.affiliation: Institute of Human Virology, University of Maryland, Baltimore, MD, USA. SKottilil@ihv.umaryland.edu.
authors.forename: Shyamasundaran
authors.initials: S
authors.lastname: Kottilil
mesh_terms: D000328:Adult; D016207:Cytokines / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics*; D006526:Hepatitis C / Q000235:genetics* / Q000276:immunology; D006801:Humans; D016898:Interferon-alpha / Q000235:genetics*; D050356:Lipid Metabolism; D008297:Male; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics* / Q000276:immunology; D015398:Signal Transduction
chemical_list: D016207:Cytokines; C554158:IFNA2 protein, human; D016898:Interferon-alpha
keywords: Hepatitis C virus genotype 3; ISG (interferon stimulated genes); NASH (non-alcoholic steatohepatitis)