MicroRNA-27a Regulates Lipid Metabolism and Inhibits Hepatitis C Virus Replication in Human Hepatoma Cells

Abstract

The replication and infectivity of the lipotropic hepatitis C virus (HCV) are regulated by cellular lipid status. Among differentially expressed microRNAs (miRNAs), we found that miR-27a was preferentially expressed in HCV-infected liver over hepatitis B virus (HBV)-infected liver. Gene expression profiling of Huh-7.5 cells showed that miR-27a regulates lipid metabolism by targeting the lipid synthetic transcription factor RXR␣ and the lipid transporter ATP-binding cassette subfamily A member 1. In addition, miR-27a repressed the expression of many lipid metabolism-related genes, including FASN, SREBP1, SREBP2, PPAR␣, and PPAR␥, as well as ApoA1, ApoB100, and ApoE3, which are essential for the production of infectious viral particles. miR-27a repression increased the cellular lipid content, decreased the buoyant density of HCV particles from 1.13 to 1.08 g/cm 3 , and increased viral replication and infectivity. miR-27a overexpression substantially decreased viral infectivity. Furthermore, miR-27a enhanced in vitro interferon (IFN) signaling, and patients who expressed high levels of miR-27a in the liver showed a more favorable response to pegylated IFN and ribavirin combination therapy. Interestingly, the expression of miR-27a was upregulated by HCV infection and lipid overload through the adipocyte differentiation transcription factor C/EBP␣. In turn, upregulated miR27a repressed HCV infection and lipid storage in cells. Thus, this negative feedback mechanism might contribute to the maintenance of a low viral load and would be beneficial to the virus by allowing it to escape host immune surveillance and establish a persistent chronic HCV infection. MicroRNA (miRNA) is a small, endogenous, single-stranded, noncoding RNA consisting of 20 to 25 bases that regulates gene expression. It plays an important role in various biological processes, including organ development, differentiation, and cellular death and proliferation, and is also involved in infection and diseases such as cancer (1).Previously, we examined miRNA expression in hepatocellular carcinoma (HCC) and noncancerous background liver tissue infected with hepatitis B virus (HBV) and HCV (2). We showed that some miRNAs were differentially expressed according to HBV or HCV infection but not according to the presence of HCC. These infection-specific miRNAs were believed to regulate HBV or HCV replication; however, their functional role has not been elucidated.HCV is described as a lipotropic virus because of its association with serum lipoprotein (3-5). It utilizes the low-density lipoprotein (LDL) receptor for cellular entry (6-8) and forms replication complexes on lipid rafts (9). The HCV core protein surrounds and binds lipid droplets (LDs) and nonstructural proteins on the endoplasmic reticulum (ER) membrane, which is essential for particle formation (10). Moreover, HCV cellular secretion is linked to very LDL (VLDL) secretion (11). In liver tissue histology, steatosis is often observed in chronic hepatitis C (CH-C) and is closely related to resistance ...

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