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

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.

SUBMITTER: Tsai WL

PROVIDER: S-EPMC5696152 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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

Tsai Wei-Lun WL Chang Tsung-Hsien TH Sun Wei-Chi WC Chan Hoi-Hung HH Wu Chun-Ching CC Hsu Ping-I PI Cheng Jin-Shiung JS Yu Ming-Lung ML

Oncotarget 20170814 54

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 o ...[more]

PMID: 29190886

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Project description:AIMS:Oxidative stress plays a crucial role in the pathogenesis of diabetic nephropathy (DN). We evaluated whether extracellular superoxide dismutase (EC-SOD) has a renoprotective effect through activation of adenosine monophosphate-activated protein kinase (AMPK) in diabetic kidneys. RESULTS:Human recombinant EC-SOD (hEC-SOD) was administered to 8-week-old male C57BLKS/J db/db mice through intraperitoneal injection once a week for 8 weeks. Renal SOD3 expression was suppressed in db/db mice, which was significantly enhanced by hEC-SOD treatment. hEC-SOD improved albuminuria, mesangial expansion, and interstitial fibrosis in db/db mice. At the molecular level, hEC-SOD increased phosphorylation of AMPK, activation of peroxisome proliferative-activated receptor ? coactivator 1? (PGC-1?), and dephosphorylation of forkhead box O transcription factor (FoxO)1 and FoxO3a. The protective effects of hEC-SOD were attributed to enhanced nuclear translocation of nuclear factor E2-related factor 2 (Nrf2) and subsequently increased expression of NAD(P)H dehydrogenase 1 and heme oxygenase-1. Consequently, hEC-SOD recovered from systemic and renal inflammation and apoptosis, as reflected by the decreases of serum and renal monocyte chemoattractant protein-1 and tumor necrosis factor-? levels and increases of BCL-2/BAX ratio in diabetic kidney. hEC-SOD also improved oxidative stress and resulted in increased renal and urinary 8-hydroxy-2'-deoxyguanosine and 8-isoprostane levels in db/db mice. In cultured human glomerular endothelial cells, hEC-SOD ameliorated apoptosis and oxidative stress caused by high glucose exposure through activation of AMPK and PGC-1? and dephosphorylation of FoxOs. INNOVATION:These findings demonstrated for the first time that EC-SOD can potentially ameliorate hyperglycemia-induced oxidative stress, apoptosis, and inflammation through activation of AMPK and its downstream pathways in diabetic kidneys. CONCLUSIONS:EC-SOD is a potential therapeutic target for treatment of type 2 DN through intrarenal AMPK-PGC-1?-Nrf2 and AMPK-FoxOs signaling. Antioxid. Redox Signal. 28, 1543-1561.

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

Publications

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

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