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.
Highlights
Hepatitis C virus (HCV) infection is a major cause of liver cirrhosis and hepatocellular carcinoma (HCC) in Taiwan [1]
We found metformin activated type I interferon signaling pathway and inhibited hepatitis C virus (HCV) replication via activation of AMPK
0.001 in metformin treated versus untreated control group. (C) The cell lysates from OR-6 cells treated with different doses of metformin for 48 h, were analyzed by immunoblotting with anti-HCV core protein antibody, and the β-actin was shown as the loading control
Summary
Hepatitis C virus (HCV) infection is a major cause of liver cirrhosis and hepatocellular carcinoma (HCC) in Taiwan [1]. In patients with acute HCV infection, 60-90% will develop a chronic infection and after 20-30 years of infection, 20-30% will develop cirrhosis of the liver or hepatocellular carcinoma [2, 3]. HCV causes many metabolic problems besides its damage of liver pathology. Insulin resistance (IR) is a very important one [4]. B (NF-κB), affect the expression of many cytokines such as TNF-alpha, -beta, interleukin 6 and 8, and inhibit insulin receptor substrate (IRS) as well as down-regulating adiponectin and causing IR [5, 6]. IR is associated with fatty liver and causes rapid progression of liver fibrosis [5,6,7,8] as well as being associated with poor response to interferon (IFN) and ribavirin combination therapy [9, 10]
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