Up-regulation of fatty acid synthase promoter by hepatitis C virus core protein: genotype-3a core has a stronger effect than genotype-1b core.
BACKGROUND/AIMS: Hepatitis C virus genotype-3a (HCV-3a) is directly linked to steatosis development. We studied the effects of HCV-3a core protein on the promoter activity of fatty acid synthase (FAS), a major enzyme involved in de novo lipid synthesis. METHODS AND RESULTS: HCV-3a and -1b core genes were cloned and expressed. Using a FAS promoter-luciferase reporter, we demonstrated that both HCV-3a and -1b core proteins up-regulated the FAS promoter. However, HCV-3a core protein expression induced significantly higher FAS promoter activity than HCV-1b core. We further showed that FAS up-regulation by HCV core was dependent on transcription factor sterol response element binding protein-1. Mutational analysis showed that processing of HCV core protein of different genotypes was differentially involved in FAS promoter up-regulation. Although lipid droplet localization of HCV core protein was not important for FAS up-regulation, a specific amino acid residue (Phe(164)) within the FATG lipid droplet localization sequence of HCV-3a core protein played a major role in the stronger FAS activation by HCV-3a core. CONCLUSIONS: The stronger effect of HCV-3a core protein on FAS activation in comparison to HCV-1b core could contribute to the higher prevalence and severity of steatosis in HCV-3a infections.