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. 2014 Jan;59(1):98-108.
doi: 10.1002/hep.26634. Epub 2013 Nov 19.

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

Ragunath Singaravelu  1 , Ran Chen, Rodney K Lyn, Daniel M Jones, Shifawn O'Hara, Yanouchka Rouleau, Jenny Cheng, Prashanth Srinivasan, Neda Nasheri, Rodney S Russell, D Lorne Tyrrell, John Paul Pezacki
Affiliations

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

Ragunath Singaravelu et al. Hepatology. 2014 Jan.

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.

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