Hepatitis C virus (HCV) infection is a leading cause of liver transplantation and hepatocellular carcinoma worldwide. HCV, like all obligate parasites, relies on host pathways to facilitate its pathogenesis. In particular, the virus possesses an intimate link with hepatic lipid metabolism, promoting a lipid-rich cellular environment conducive to HCV propagation. Clinically, these metabolic perturbations manifest as steatosis in over 50% of patients. The majority of research to-date examining how the virus co-opts hepatic lipid pathways has been focused on coding genes and their protein products.
MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression, which have been implicated in virtually every cellular process. Through interactions with partially complementary mRNAs, each individual miRNA has the capacity to repress the expression of hundreds of genes and induce significant regulatory effects. Herein, we demonstrate that hepatic miRNAs, including miR-7, miR-27a/b, miR-130b, and miR-185, act as crucial regulatory molecules to the maintenance of hepatic lipid homeostasis. These miRNAs cooperate to regulate fatty acid and cholesterol metabolism. HCV modulates the expression of a subset of these miRNAs (miR-27a/b, miR-130b, and miR-185) to promote hepatocellular lipid accumulation and the HCV life cycle. There appears to be a broad viral requirement for lipids, and the mammalian innate immune response strategically targets host metabolic pathways to restrict virus’ access to key lipid species. We demonstrate that 25-hydroxycholesterol, a broadly anti-viral oxysterol produced as part of the innate anti-viral response, activates miR-185 expression in the liver to deplete virus infected cells of lipids. HCV appears to actively counteract this anti-viral response by suppressing miR-185 expression. Collectively, our results highlight the role of microRNAs in hepatic lipid metabolism and the immunometabolic response to viral infection.
| Identifer | oai:union.ndltd.org:uottawa.ca/oai:ruor.uottawa.ca:10393/34456 |
| Date | January 2016 |
| Creators | Singaravelu, Ragunath |
| Contributors | Pezacki, John |
| Publisher | Université d'Ottawa / University of Ottawa |
| Source Sets | Université d’Ottawa |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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