title: Hepatitis C virus induced up-regulation of microRNA-27: a novel mechanism for hepatic steatosis.
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.
  
  
  CONCLUSIONS
  Collectively, our results highlight HCV's up-regulation of miR-27 expression as a novel mechanism contributing to the development of hepatic steatosis.
authors.affiliation: Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada; National Research Council of Canada, Ottawa, Ontario, Canada.
authors.forename: Ragunath
authors.initials: R
authors.lastname: Singaravelu
authors.forename: Ran
authors.initials: R
authors.lastname: Chen
authors.forename: Rodney K
authors.initials: RK
authors.lastname: Lyn
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Jones
authors.forename: Shifawn
authors.initials: S
authors.lastname: O'Hara
authors.forename: Yanouchka
authors.initials: Y
authors.lastname: Rouleau
authors.forename: Jenny
authors.initials: J
authors.lastname: Cheng
authors.forename: Prashanth
authors.initials: P
authors.lastname: Srinivasan
authors.forename: Neda
authors.initials: N
authors.lastname: Nasheri
authors.forename: Rodney S
authors.initials: RS
authors.lastname: Russell
authors.forename: D Lorne
authors.initials: DL
authors.lastname: Tyrrell
authors.forename: John Paul
authors.initials: JP
authors.lastname: Pezacki
mesh_terms: D000818:Animals; D001629:Bezafibrate; D045744:Cell Line, Tumor; D005234:Fatty Liver / Q000209:etiology*; D016174:Hepacivirus / Q000502:physiology*; D006526:Hepatitis C / Q000150:complications* / Q000378:metabolism / Q000821:virology; D006706:Homeostasis; D006801:Humans; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D035683:MicroRNAs / Q000378:metabolism*; D047493:PPAR alpha / Q000819:agonists; D015854:Up-Regulation
chemical_list: C531388:MIRN27 microRNA, human; D035683:MicroRNAs; C540674:Mirn27 microRNA, mouse; D047493:PPAR alpha; D001629:Bezafibrate