Fatty acids induce a pro-inflammatory gene expression profile in Huh-7 cells that attenuates the anti-HCV action of interferon

Online Ahead of Print: January 14, 2015The 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.Edmund Tse, Karla J. Helbig, Kylie Van der Hoek, Erin M. McCartney, Mark Van der Hoek, Jacob George, and Michael R. Bear