Research Institute, University Hospital 12 de Octubre, School of Medicine, Universidad Complutense, Madrid 28041, Spain.
J Biol Chem. 2012 Jun 1;287(23):19564-73. doi: 10.1074/jbc.M112.342709. Epub 2012 Apr 9.
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.
胰岛素抵抗是慢性丙型肝炎患者对干扰素/利巴韦林治疗无反应的一个危险因素。本研究旨在确定蛋白酪氨酸磷酸酶（PTPs）在与胰岛素抵抗相关的缺乏干扰素-α（IFNα）反应中的作用。我们通过沉默 IRS-2 或用肿瘤坏死因子-α（TNFα）处理 HepG2 细胞来诱导胰岛素抵抗，并通过评估 Akt 磷酸化来分析胰岛素反应，通过测量 Stat-1 酪氨酸磷酸化和 2'，5'-寡聚腺苷酸合酶和流感病毒抗性基因表达来测量 IFNα 反应。还在未经和用二甲双胍治疗的胰岛素抵抗肥胖小鼠（高脂饮食和 ob/ob 小鼠）中测量 IFNα 的反应。沉默 IRS-2 mRNA 诱导胰岛素抵抗并抑制 IFNα 反应。同样，TNFα 抑制胰岛素和 IFNα 反应。用过钒酸钠处理细胞并敲低 PTP-1B 可恢复胰岛素和 IFNα 反应。沉默 IRS-2 和 TNFα 处理均增加 PTP 和 PTP-1B 活性。二甲双胍抑制 PTP 并改善胰岛素抵抗细胞中的 IFNα 反应。胰岛素抵抗的 ob/ob 小鼠肝脏中的 PTP-1B 基因表达和活性增加，并且对 IFNα 给药无反应。用二甲双胍治疗可改善这种反应。在 HepG2 细胞中，胰岛素抵抗引起 IFNα 抵抗，这与肝脏中 PTP-1B 活性增加有关。用过钒酸钠和二甲双胍抑制 PTP-1B 活性或敲低 PTP-1B 可恢复 IFNα 反应。同样，二甲双胍降低 PTP-1B 活性并改善胰岛素抵抗肥胖小鼠对 IFNα 的反应。使用 PTP-1B 抑制剂可能会改善对 IFNα/利巴韦林治疗的反应。
