Abstract
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-α (IFNα) response associated with insulin resistance. We induced insulin resistance by silencing IRS-2 or by treating HepG2 cells with tumor necrosis factor-α (TNFα) and analyzed insulin response by evaluating Akt phosphorylation and IFNα response by measuring Stat-1 tyrosine phosphorylation and 2',5'-oligoadenylate synthase and myxovirus resistance gene expression. The response to IFNα 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 IFNα response. Likewise, TNFα suppresses insulin and IFNα response. Treatment of cells with pervanadate and knocking down PTP-1B restores insulin and IFNα response. Both silencing IRS-2 and TNFα treatment increase PTP and PTP-1B activity. Metformin inhibits PTP and improves IFNα 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 IFNα administration. Treatment with metformin improves this response. In HepG2 cells, insulin resistance provokes IFNα 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 IFNα response. Likewise, metformin decreases PTP-1B activity and improves response to IFNα in insulin-resistant obese mice. The use of PTP-1B inhibitors may improve the response to IFNα/ribavirin therapy.
Highlights
Patients with insulin resistance respond poorly to interferon therapy
As protein-tyrosine phosphatase (PTP) reduce tyrosine phosphorylation of some proteins, we investigated the role played by these phosphatases in this IFN␣ resistance by pretreating cells with 0.1 mM pervanadate, an unspecific tyrosine phosphatase inhibitor
Silencing IRS-2 and Treatment of Cells with TNF␣ Increased PTP Activity—Because these results suggested that PTPs might be involved in the IFN␣ resistance associated with insulin resistance, we investigated the impact of silencing IRS-2 on the PTP activity
Summary
Patients with insulin resistance respond poorly to interferon therapy. Results: Induction of insulin resistance increased protein-tyrosine phosphatase (PTP) activity and provoked interferon resistance. The aim of this study was to determine the role played by proteintyrosine phosphatases (PTPs) in the absence of interferon-␣ (IFN␣) response associated with insulin resistance. Silencing IRS-2 mRNA induces insulin resistance and inhibits IFN␣ response. Treatment of cells with pervanadate and knocking down PTP-1B restores insulin and IFN␣ response. Both silencing IRS-2 and TNF␣ treatment increase PTP and PTP-1B activity. Metformin inhibits PTP and improves IFN␣ 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␣ administration. In HepG2 cells, insulin resistance provokes IFN␣ resistance, which is associated with an increased PTP-1B activity in the liver. Metformin decreases PTP-1B activity and improves response to IFN␣ in insulin-resistant obese mice. The use of PTP-1B inhibitors may improve the response to IFN␣/ribavirin therapy
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