title: Fatty Acids Induce a Pro-Inflammatory Gene Expression Profile in Huh-7 Cells That Attenuates the Anti-HCV Action of Interferon.
abstract: The pathogenesis of nonalcoholic steatohepatitis is primarily an immune-driven disease and a known factor associated with treatment failure of chronic hepatitis C with interferon (IFN) and ribavirin. We studied the hepatocyte response in a model of steatosis at the transcriptome level and the antiviral action of IFN against hepatitis C virus (HCV) in this setting. In this study, we have shown that lipid loading (oleic acid and palmitic acid, OA:PA) of Huh-7 cells leads to increased expression of classical interferon-stimulated genes (ISGs) and NF-κβ-dependent pro-inflammatory genes. A selective blocker of Toll-like receptor (TLR)2 signaling suppressed NF-κβ promoter activity by OA:PA, suggesting that free fatty acids (FFAs) act as a TLR2 pathogen-associated molecular pattern. Furthermore, in the presence of OA:PA, IFN stimulation and HCV infection (Jc1) increased ISG expression. Somewhat counterintuitive to the increase in ISGs, the anti-HCV activity of IFN was attenuated in the presence of OA:PA. Interestingly, the combination of OA:PA, HCV, and IFN-α stimulation resulted in a significant increase in CXCL8 protein production, a cytokine known to have anti-IFN modulating activity. Thus, in an in vitro model of steatosis, the FFAs OA and PA drive an NF-κβ-dependent inflammatory and ISG gene expression profile via TLR2 activation. Furthermore, FFA synergistically increases IFN-driven gene expression that may account for HCV treatment failure in vivo.
authors.affiliation: 1 School of Molecular and Biomedical Science, The University of Adelaide , Adelaide, South Australia, Australia .
authors.forename: Edmund
authors.initials: E
authors.lastname: Tse
authors.forename: Karla J
authors.initials: KJ
authors.lastname: Helbig
authors.forename: Kylie
authors.initials: K
authors.lastname: Van der Hoek
authors.forename: Erin M
authors.initials: EM
authors.lastname: McCartney
authors.forename: Mark
authors.initials: M
authors.lastname: Van der Hoek
authors.forename: Jacob
authors.initials: J
authors.lastname: George
authors.forename: Michael R
authors.initials: MR
authors.lastname: Beard
mesh_terms: D002460:Cell Line; D016000:Cluster Analysis; D004357:Drug Synergism; D005227:Fatty Acids / Q000378:metabolism* / Q000494:pharmacology; D005234:Fatty Liver / Q000209:etiology / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D016174:Hepacivirus / Q000187:drug effects / Q000502:physiology*; D019698:Hepatitis C, Chronic / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D007372:Interferons / Q000378:metabolism* / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism; D019301:Oleic Acid / Q000494:pharmacology; D019308:Palmitic Acid / Q000494:pharmacology; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D059467:Transcriptome; D014779:Virus Replication / Q000187:drug effects
chemical_list: D005227:Fatty Acids; D016328:NF-kappa B; D051195:Toll-Like Receptor 2; D019301:Oleic Acid; D019308:Palmitic Acid; D007372:Interferons