Nelfinavir-induced insulin resistance is associated with impaired plasma membrane recruitment of the PI 3-kinase effectors Akt/PKB and PKC-ζ
Nelfinavir-induced insulin resistance is associated with impaired plasma membrane recruitment of the PI 3-kinase effectors Akt/PKB and PKC-ζ
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DOI：
10.1007/s00125-004-1408-5
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发表时间：
2004-06-01
期刊：
影响因子：
8.2
通讯作者：
Bashan, N
中科院分区：
文献类型：
--
作者：
Ben-Romano, R;Rudich, A;Bashan, N
目标/假设。3T3-L1脂肪细胞长期暴露于HIV蛋白水解酶抑制剂奈非那韦可诱导胰岛素抵抗，重述由这些药物诱导的脂肪营养不良综合征中脂肪组织的关键代谢变化。我们的目标是确定导致奈非那韦诱导的胰岛素抵抗的胰岛素信号转导级联中的缺陷。方法：研究方法。将完全分化的3T3-L1脂肪细胞暴露于30mumol/L的奈非那韦18h后，观察胰岛素信号转导通路中关键蛋白的数量、磷酸化和定位。结果。在Nelfinavir处理的细胞中，胰岛素诱导的磷脂酰肌醇3‘-激酶(PI-3-K)与IRS蛋白的相互作用是正常的，IRS-1相关的PI-3-K活性也是正常的。而胰岛素诱导的Akt/蛋白激酶B(PKB)、p70S6和细胞外信号调节激酶1/2的磷酸化明显受损。这不能归因于蛋白磷酸酶2A活性的增加或磷脂酰肌醇磷酸酶(SHIP2或PTEN)的表达增加。然而，胰岛素不能诱导PI 3-激酶效应分子Akt/PKB和蛋白激酶C-Zeta(PKC-Zeta)易位到奈非那韦处理的脂肪细胞的质膜部分。结论/解释。因此，我们得出结论，奈非那韦导致PI3-激酶激活下游的胰岛素信号级联出现缺陷。这一缺陷表现为胰岛素介导的Akt/PKB和PKC-Zeta向质膜的募集受损。
Aims/hypothesis. Chronic exposure of 3T3-L1 adipocytes to the HIV protease inhibitor nelfinavir induces insulin resistance, recapitulating key metabolic alterations of adipose tissue in the lipodystrophy syndrome induced by these agents. Our goal was to identify the defect in the insulin signal transduction cascade leading to nelfinavir-induced insulin resistance. Methods. Fully differentiated 3T3-L1 adipocytes were exposed to 30 mumol/l nelfinavir for 18 h, after which the amount, the phosphorylation and the localisation of key proteins in the insulin signalling cascade were evaluated. Results. Insulin-induced interaction of phosphatidylinositol 3'-kinase (PI 3-kinase) with IRS proteins was normal in cells treated with nelfinavir, as was IRS-1-associated PI 3-kinase activity. Yet insulin-induced phosphorylation of Akt/protein kinase B (PKB), p70S6 kinase and extracellular signal-regulated kinase 1/2 was significantly impaired. This could not be attributed to increased protein phosphatase 2A activity or to increased expression of phosphoinositide phosphatases (SHIP2 or PTEN). However, insulin failed to induce translocation of the PI 3-kinase effectors Akt/PKB and protein kinase C-zeta (PKC-zeta) to plasma membrane fractions of nelfinavir-treated adipocytes. Conclusions/interpretation. We therefore conclude that nelfinavir induces a defect in the insulin signalling cascade downstream of the activation of PI 3-kinase. This defect manifests itself by impaired insulin-mediated recruitment of Akt/PKB and PKC-zeta to the plasma membrane.