| Autor: |
Yanouchka Rouleau, Jenny Cheng, John Paul Pezacki, Ran Chen, Prashanth Srinivasan, Shifawn O'Hara, Rodney S. Russell, D. Lorne Tyrrell, Daniel M. Jones, Ragunath Singaravelu, Rodney K. Lyn, Neda Nasheri |
| Rok vydání: |
2013 |
| Předmět: |
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| Zdroj: |
Hepatology. 59:98-108 |
| ISSN: |
0270-9139 |
| Popis: |
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) |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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