Premium
Hepatitis C virus induced up‐regulation of microRNA‐27: A novel mechanism for hepatic steatosis
Author(s) -
Singaravelu Ragunath,
Chen Ran,
Lyn Rodney K.,
Jones Daniel M.,
O'Hara Shifawn,
Rouleau Yanouchka,
Cheng Jenny,
Srinivasan Prashanth,
Nasheri Neda,
Russell Rodney S.,
Tyrrell D. Lorne,
Pezacki John Paul
Publication year - 2014
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.26634
Subject(s) - steatosis , microrna , hepatology , hepatic stellate cell , psychological repression , fatty liver , hepatitis c virus , biology , peroxisome proliferator activated receptor , lipid droplet , microbiology and biotechnology , receptor , chemistry , medicine , endocrinology , gene expression , virus , virology , gene , biochemistry , disease
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. (H epatology 2014;58:98–108)