Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 287, Issue 23, Pages 19564-19573Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M112.342709
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Funding
- Fundacion Mutua Madrilena
- Fondo de Investigacion Sanitaria, Spain [PI07/0052
- PI10/0312]
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Insulin resistance is a risk factor for non-response to interferon/ribavirin therapy in patients with chronic hepatitis C. The aim of this study was to determine the role played by protein-tyrosine phosphatases (PTPs) in the absence of interferon-alpha (IFN alpha) response associated with insulin resistance. We induced insulin resistance by silencing IRS-2 or by treating HepG2 cells with tumor necrosis factor-alpha (TNF alpha) and analyzed insulin response by evaluating Akt phosphorylation and IFN alpha response by measuring Stat-1 tyrosine phosphorylation and 2',5'-oligoadenylate synthase and myxovirus resistance gene expression. The response to IFN alpha was also measured in insulin-resistant obese mice (high fat diet and ob/ob mice) untreated and treated with metformin. Silencing IRS-2 mRNA induces insulin resistance and inhibits IFN alpha response. Likewise, TNF alpha suppresses insulin and IFN alpha response. Treatment of cells with pervanadate and knocking down PTP-1B restores insulin and IFN alpha response. Both silencing IRS-2 and TNF alpha treatment increase PTP and PTP-1B activity. Metformin inhibits PTP and improves IFN alpha response in insulin-resistant cells. Insulin-resistant ob/ob mice have increased PTP-1B gene expression and activity in the liver and do not respond to IFN alpha administration. Treatment with metformin improves this response. In HepG2 cells, insulin resistance provokes IFN alpha resistance, which is associated with an increased PTP-1B activity in the liver. Inhibition of PTP-1B activity with pervanadate and metformin or knocking down PTP-1B reestablishes IFN alpha response. Likewise, metformin decreases PTP-1B activity and improves response to IFN alpha in insulin-resistant obese mice. The use of PTP-1B inhibitors may improve the response to IFN alpha/ribavirin therapy.
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