Research Papers:

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

Wei-Lun Tsai, Tsung-Hsien Chang, Wei-Chi Sun, Hoi-Hung Chan, Chun-Ching Wu, Ping-I Hsu, Jin-Shiung Cheng and Ming-Lung Yu _

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Oncotarget. 2017; 8:91928-91937. https://doi.org/10.18632/oncotarget.20248

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Wei-Lun Tsai1,2, Tsung-Hsien Chang3,4, Wei-Chi Sun1,2, Hoi-Hung Chan1,2, Chun-Ching Wu1, Ping-I Hsu1,2, Jin-Shiung Cheng1,2 and Ming-Lung Yu5,6,7

1Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan

2School of Medicine, National Yang-Ming University, Taipei, Taiwan

3Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan

4Department of Medical Laboratory Science and Biotechnology, Chung Hwa University of Medical Technology, Tainan, Taiwan

5Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan

6Faculty of Internal Medicine, College of Medicine, and Graduate Institute of Clinical Medicine, and Lipid Science and Aging Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan

7Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan

Correspondence to:

Ming-Lung Yu, email: [email protected]

Jin-Shiung Cheng, email: [email protected]

Tsung-Hsien Chang, email: [email protected]

Keywords: metformin, hepatits C virus, interferon, AMPK

Received: January 23, 2017     Accepted: July 12, 2017     Published: August 14, 2017


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.

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