003

UP-REGULATION OF FATTY ACID SYNTHASE PROMOTER BY HEPATITIS C VIRUS CORE PROTEIN: GENOTYPE 3A CORE HAS A STRONGER EFFECT THAN GENOTYPE 1B CORE

C Jackel-Cram, L Babiuk, Q Liu
Vaccine and Infectious Disease Organization, University of Saskatchewan, Saskatoon, Saskatchewan

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 core gene was cloned from HCV-3a infected sera. Expression, processing and subcellular localization of HCV-3a core protein was very similar to HCV-1b core. 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 fully processed HCV core protein failed to up-regulate FAS promoter. Although lipid droplet localization of HCV core protein was not important for FAS up-regulation, a specific amino acid residue (Phe¹⁶⁴) within the FATG lipid droplet localization sequence of HCV-3a core protein was critical for 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.

PREVIOUS NEXT