Metformin activates type I interferon signaling against HCV via activation of adenosine monophosphate-activated protein kinase

// Wei-Lun Tsai 1, 2 , Tsung-Hsien Chang 3, 4 , Wei-Chi Sun 1, 2 , Hoi-Hung Chan 1, 2 , Chun-Ching Wu 1 , Ping-I Hsu 1, 2 , Jin-Shiung Cheng 1, 2 and Ming-Lung Yu 5, 6, 7 1 Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan 2 School of Medicine, National Yang-Ming University, Taipei, Taiwan 3 Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan 4 Department of Medical Laboratory Science and Biotechnology, Chung Hwa University of Medical Technology, Tainan, Taiwan 5 Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan 6 Faculty of Internal Medicine, College of Medicine, and Graduate Institute of Clinical Medicine, and Lipid Science and Aging Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan 7 Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan Correspondence to: Ming-Lung Yu, email: fish6069@gmail.com Jin-Shiung Cheng, email: rcheng@ms2.hinet.net Tsung-Hsien Chang, email: changth@vghks.gov.tw Keywords: metformin, hepatits C virus, interferon, AMPK Received: January 23, 2017      Accepted: July 12, 2017      Published: August 14, 2017 ABSTRACT Activation of the type I interferon (IFN) signaling pathway is essential for the eradication of hepatitis C virus (HCV). Metformin can activate adenosine monophosphate-activated protein kinase (AMPK) to reduce insulin resistance. Cross talks between AMPK and IFN signaling remain unclear. To understand the influence of metformin on the type I IFN signaling pathway and HCV infection, the full-length HCV replicon OR6 cells and the infectious HCV clones JFH1 were used to assess the anti-HCV effect of the insulin sensitizers, metformin and pioglitazone. Immunofluorescence staining and the immunoblotting of HCV viral protein demonstrated that metformin, but not pioglitazone, inhibited HCV replication in OR-6 and JFH-1-infected Huh 7.5.1 cells. Immunoblotting data showed that metformin activated the phosphorylation of STAT-1 and STAT-2 in OR-6 and JFH-1 infected Huh 7.5.1 cells. Metformin enhanced the phosphorylation of AMPK, and the metformin-activated IFN signaling was down-regulated by AMPK inhibitor. After treatment of AMPK inhibitor, the level of HCV core protein decreased by metformin can be rescued. In conclusion, metformin activates type I interferon signaling and inhibits the replication of HCV via activation of AMPK.