Fatty acid synthase is up-regulated during hepatitis C virus infection and regulates hepatitis C virus entry and production

Authors

  • Wei Yang,

    Corresponding author
    1. Department of Infectious Diseases and Microbiology, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA
    Current affiliation:
    1. Institute of Pathogen Biology, Chinese Academy of Medical Sciences, Peking Union Medical College, Tsinghua University, 5 Dong Dan San Tiao, Beijing 100005, China
    • Department of Infectious Diseases and Microbiology, Graduate School of Public Health, 130 DeSoto Street, Pittsburgh, PA 15261
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    • fax: 412-383-8926.

  • Brian L. Hood,

    1. Department of Cell Biology and Physiology, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA
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  • Sara L. Chadwick,

    1. Department of Infectious Diseases and Microbiology, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA
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  • Shufeng Liu,

    1. Department of Infectious Diseases and Microbiology, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA
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  • Simon C. Watkins,

    1. Department of Pharmacology and Chemical Biology, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA
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  • Guangxiang Luo,

    1. Clinical Proteomics Facility, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA
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  • Thomas P. Conrads,

    1. Department of Cell Biology and Physiology, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA
    2. Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky College of Medicine, Lexington, KY
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  • Tianyi Wang

    Corresponding author
    1. Department of Infectious Diseases and Microbiology, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA
    • Department of Infectious Diseases and Microbiology, Graduate School of Public Health, 130 DeSoto Street, Pittsburgh, PA 15261
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  • Potential conflict of interest: Nothing to report.

Abstract

Hepatitis C virus (HCV) is a major human pathogen that causes serious illness, including acute and chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Using a mass spectrometry–based proteomics approach, we have identified 175 proteins from a cell culture supernatant fraction containing the HCV genotype 2a (JFH1) virus, among which fatty acid synthase (FASN), the multifunctional enzyme catalyzing the de novo synthesis of fatty acids, was confirmed to be highly enriched. Subsequent studies showed that FASN expression increased in the human hepatoma cell line, Huh7, or its derivative, upon HCV infection. Blocking FASN activity by C75, a pharmacological FASN inhibitor, led to decreased HCV production. Reduction of FASN by RNA interference suppressed viral replication in both replicon and infection systems. Remarkably, FASN appeared to be selectively required for the expression of claudin-1, a tight junction protein that was recently identified as an entry coreceptor for HCV, but not for the expression of another HCV coreceptor, CD81. The decrease in Claudin-1 expression resulting from FASN inhibition was accompanied by a decrease in transepithelial electric resistance of Huh7 cells, implying a reduction in the relative tightness of the cell monolayer. Consequently, the entry of human immunodeficiency virus–HCV pseudotypes was significantly inhibited in C75-treated Huh7 cells. Conclusion: As far as we know, this is the first line of evidence that demonstrates that HCV infection directly induces FASN expression, and thus suggests a possible mechanism by which HCV infection alters the cellular lipid profile and causes diseases such as steatosis. (HEPATOLOGY 2008.)

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