Abstract
In this study, we investigated the role of microRNA-99a (miR-99a) in hepatitis C virus (HCV) replication and lipogenesis in hepatocytes. Cell-culture-derived HCV (HCVcc) infection caused down-regulation of miR-99a in Huh-7 cells, and the relative levels of miR-99a were significantly lower in the sera of the HCV-infected patients than in those of healthy controls. Transfection of miR-99a-5p mimics resulted in a decrease in the intracellular and secreted HCV RNA levels. It also caused a decreased mammalian target of rapamycin (mTOR) protein level and phosphorylation of its downstream targets in HCV-replicating cells. Sterol regulatory element binding protein (SREBP)-1c expression and intracellular lipid accumulation decreased when either miR-99a-5p mimics or si-mTOR was transfected in oleic acid-treated Huh-7 cells. Overexpression of mTOR rescued HCV RNA replication and lipid droplet accumulation in miR-99a-5p mimics-transfected HCV replicon cells. Our data demonstrated that miR-99a ameliorates intracellular lipid accumulation by regulating mTOR/SREBP-1c and causes inefficient replication and packaging of intracellular HCV.
Highlights
Worldwide, approximately 71 million people are infected with hepatitis C virus (HCV), and they have an increased risk of liver cirrhosis and hepatocellular carcinoma (HCC) [1,2,3]
Portsmann et al identified the role of mTORC1 in lipogenesis and found that rapamycin blocked the expression of genes involved in lipogenesis, impairing nuclear accumulation of the sterol regulatory element binding proteins (SREBPs) [8]
We confirmed that the expression levels of both mRNA and protein of SREBP-1c down-regulated in full-genomic replicon (FGR) cells that were transfected with miR-99a-5p mimics (Figure 3A)
Summary
Approximately 71 million people are infected with hepatitis C virus (HCV), and they have an increased risk of liver cirrhosis and hepatocellular carcinoma (HCC) [1,2,3]. The viral life cycle of HCV strongly depends on intracellular lipid droplets (LDs) [4]. Host lipid architectures and molecules involved in lipid metabolism are closely associated with the HCV life cycle [4,5]. The mammalian target of rapamycin (mTOR) signaling pathway is one of the major cellular pathways involved in the regulation of HCV infection [6]. MTOR directly phosphorylates the ribosomal protein S6 kinases (S6K1 and S6K2) and eukaryotic initiation factor 4E (eIF4E)-binding protein (4E-BP1 and 4E-BP2), which control specific steps in the initiation of cap-dependent translation [7]. Portsmann et al identified the role of mTORC1 in lipogenesis and found that rapamycin blocked the expression of genes involved in lipogenesis, impairing nuclear accumulation of the sterol regulatory element binding proteins (SREBPs) [8]. We studied the role of miRNA-99a (miR-99a) in HCV replication and lipogenesis via mTOR regulation in hepatocytes
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