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; Ming-Lung Yu

doi:10.18632/oncotarget.20248

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

Oncotarget. 2017 Aug 14;8(54):91928-91937. doi: 10.18632/oncotarget.20248. eCollection 2017 Nov 3.

Authors

Wei-Lun Tsai^{1

2}, Tsung-Hsien Chang^{3

4}, Wei-Chi Sun^{1

2}, Hoi-Hung Chan^{1

2}, Chun-Ching Wu¹, Ping-I Hsu^{1

2}, Jin-Shiung Cheng^{1

2}, Ming-Lung Yu^{5

6

7}

Affiliations

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.

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.

Keywords: AMPK; hepatits C virus; interferon; metformin.