title: Protein-tyrosine phosphatases are involved in interferon resistance associated with insulin resistance in HepG2 cells and obese mice.
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.
authors.affiliation: Research Institute, University Hospital 12 de Octubre, School of Medicine, Universidad Complutense, Madrid 28041, Spain.
authors.forename: Inmaculada
authors.initials: I
authors.lastname: García-Ruiz
authors.forename: Pablo
authors.initials: P
authors.lastname: Solís-Muñoz
authors.forename: Erica
authors.initials: E
authors.lastname: Gómez-Izquierdo
authors.forename: María Teresa
authors.initials: MT
authors.lastname: Muñoz-Yagüe
authors.forename: Angela M
authors.initials: AM
authors.lastname: Valverde
authors.forename: José A
authors.initials: JA
authors.lastname: Solís-Herruzo
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D056945:Hep G2 Cells; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism; D007333:Insulin Resistance; D016898:Interferon-alpha / Q000494:pharmacology*; D008297:Male; D008687:Metformin / Q000494:pharmacology; D051379:Mice; D008820:Mice, Obese; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D012254:Ribavirin / Q000494:pharmacology; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D014638:Vanadates / Q000494:pharmacology
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; C526297:IRS2 protein, human; D055504:Insulin Receptor Substrate Proteins; D016898:Interferon-alpha; C526298:Irs2 protein, mouse; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C494080:Stat1 protein, mouse; D014409:Tumor Necrosis Factor-alpha; C076715:pervanadate; D014638:Vanadates; D012254:Ribavirin; D008687:Metformin; D051057:Proto-Oncogene Proteins c-akt; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; C516609:Ptpn1 protein, mouse