MicroRNA-27a regulates lipid metabolism and inhibits hepatitis C virus replication in human hepatoma cells

Takayoshi Shirasaki, Masao Honda, Tetsuro Shimakami, Rika Horii, Taro Yamashita, Yoshio Sakai, Akito Sakai, Hikari Okada, Risa Watanabe, Seishi Murakami, Min Kyung Yi, Stanley M. Lemon, Shuichi Kaneko

Research output: Contribution to journalArticle

112 Scopus citations

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 RXRα 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, PPARα, and PPARγ, 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/cm3, 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/EBPγ. In turn, upregulated miR-27a 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.

Original languageEnglish (US)
Pages (from-to)5270-5286
Number of pages17
JournalJournal of virology
Volume87
Issue number9
DOIs
StatePublished - May 2013

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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    Shirasaki, T., Honda, M., Shimakami, T., Horii, R., Yamashita, T., Sakai, Y., Sakai, A., Okada, H., Watanabe, R., Murakami, S., Yi, M. K., Lemon, S. M., & Kaneko, S. (2013). MicroRNA-27a regulates lipid metabolism and inhibits hepatitis C virus replication in human hepatoma cells. Journal of virology, 87(9), 5270-5286. https://doi.org/10.1128/JVI.03022-12