Hepatitis C virus induced up-regulation of microRNA-27: A novel mechanism for hepatic steatosis

Authors

  • Ragunath Singaravelu,

    1. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada
    2. National Research Council of Canada, Ottawa, Ontario, Canada
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  • Ran Chen,

    1. Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada
    2. Li Ka Shing Institute of Virology, Katz Centre for Pharmacy and Health Research, Edmonton, Alberta, Canada
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  • Rodney K. Lyn,

    1. National Research Council of Canada, Ottawa, Ontario, Canada
    2. Department of Chemistry, University of Ottawa, Ottawa, Ontario, Canada
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  • Daniel M. Jones,

    1. Immunology and Infectious Diseases, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland, Canada
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  • Shifawn O'Hara,

    1. National Research Council of Canada, Ottawa, Ontario, Canada
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  • Yanouchka Rouleau,

    1. National Research Council of Canada, Ottawa, Ontario, Canada
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  • Jenny Cheng,

    1. National Research Council of Canada, Ottawa, Ontario, Canada
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  • Prashanth Srinivasan,

    1. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada
    2. National Research Council of Canada, Ottawa, Ontario, Canada
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  • Neda Nasheri,

    1. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada
    2. National Research Council of Canada, Ottawa, Ontario, Canada
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  • Rodney S. Russell,

    1. Immunology and Infectious Diseases, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland, Canada
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  • D. Lorne Tyrrell,

    1. Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada
    2. Li Ka Shing Institute of Virology, Katz Centre for Pharmacy and Health Research, Edmonton, Alberta, Canada
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  • John Paul Pezacki

    Corresponding author
    1. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada
    2. National Research Council of Canada, Ottawa, Ontario, Canada
    3. Department of Chemistry, University of Ottawa, Ottawa, Ontario, Canada
    • Address reprint requests to: John Pezacki, National Research Council of Canada, Ottawa, Canada, K1A 0R6. E-mail: John.Pezacki@nrc-cnrc.gc.ca; fax: 613-941-8447.

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  • Potential conflict of interest: D.L.T. owns stock in KMT Hepatech, Inc.

  • Supported by Canadian Institute for Health Research (CIHR) grants to J.P.P. and D.L.T.

Abstract

MicroRNAs (miRNAs) are small RNAs that posttranscriptionally regulate gene expression. Their aberrant expression is commonly linked with diseased states, including hepatitis C virus (HCV) infection. Herein, we demonstrate that HCV replication induces the expression of miR-27 in cell culture and in vivo HCV infectious models. Overexpression of the HCV proteins core and NS4B independently activates miR-27 expression. Furthermore, we establish that miR-27 overexpression in hepatocytes results in larger and more abundant lipid droplets, as observed by coherent anti-Stokes Raman scattering (CARS) microscopy. This hepatic lipid droplet accumulation coincides with miR-27b's repression of peroxisome proliferator-activated receptor (PPAR)-α and angiopoietin-like protein 3 (ANGPTL3), known regulators of triglyceride homeostasis. We further demonstrate that treatment with a PPAR-α agonist, bezafibrate, is able to reverse the miR-27b-induced lipid accumulation in Huh7 cells. This miR-27b-mediated repression of PPAR-α signaling represents a novel mechanism of HCV-induced hepatic steatosis. This link was further demonstrated in vivo through the correlation between miR-27b expression levels and hepatic lipid accumulation in HCV-infected SCID-beige/Alb-uPa mice. Conclusion: Collectively, our results highlight HCV's up-regulation of miR-27 expression as a novel mechanism contributing to the development of hepatic steatosis. (Hepatology 2014;58:98–108)

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