Up-regulation of fatty acid synthase promoter by hepatitis C virus core protein: genotype-3a core has a stronger effect than genotype-1b core.
OBJECTIVE
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.


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.
Jackel-Cram
Candice
C
Vaccine and Infectious Disease Organization, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
Babiuk
Lorne A
LA
Liu
Qiang
Q
D000595:Amino Acid Sequence; D002460:Cell Line; D003001:Cloning, Molecular; D004252:DNA Mutational Analysis; D064429:Fatty Acid Synthases / Q000235:genetics* / Q000378:metabolism; D005234:Fatty Liver; D015967:Gene Expression Regulation, Viral; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D017386:Sequence Homology, Amino Acid; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D015854:Up-Regulation; D014758:Viral Core Proteins / Q000235:genetics*
D051780:Sterol Regulatory Element Binding Protein 1; D014758:Viral Core Proteins; D064429:Fatty Acid Synthases