Potential conflict of interest: D.L.T. owns stock in KMT Hepatech, Inc.
Hepatitis C virus induced up-regulation of microRNA-27: A novel mechanism for hepatic steatosis
Article first published online: 19 NOV 2013
© 2013 by the American Association for the Study of Liver Diseases
Volume 59, Issue 1, pages 98–108, January 2014
How to Cite
Singaravelu, R., Chen, R., Lyn, R. K., Jones, D. M., O'Hara, S., Rouleau, Y., Cheng, J., Srinivasan, P., Nasheri, N., Russell, R. S., Tyrrell, D. L. and Pezacki, J. P. (2014), Hepatitis C virus induced up-regulation of microRNA-27: A novel mechanism for hepatic steatosis. Hepatology, 59: 98–108. doi: 10.1002/hep.26634
Supported by Canadian Institute for Health Research (CIHR) grants to J.P.P. and D.L.T.
- Issue published online: 20 DEC 2013
- Article first published online: 19 NOV 2013
- Accepted manuscript online: 29 JUL 2013 03:03PM EST
- Manuscript Accepted: 10 JUL 2013
- Manuscript Received: 9 JAN 2013
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)