The bioactive lipid mediator sphingosine 1-phosphate (S1P) is considered to be involved in the development of insulin resistance (IR) via effects on oxidative stress; the mechanism however is not yet fully revealed. To this end, we investigated the role and mechanism of S1P on hepatic IR. We found that treatment of the normal human liver cell LO2 with 1000 nM insulin for 48 h reduced glucose uptake and increased serine phosphorylation of insulin receptor substrate-1, indicating a reduction in insulin receptor signaling. Moreover, the same concentration of insulin caused accumulation of reactive oxygen species (ROS) in the cytosol and mitochondria, and enhanced expression of the antioxidant transcription factor (Nrf2) and upregulated Nrf2 nuclear translocation. Using known inhibitors and donors of ROS (H2O2, ·O2-, ·OH), the results demonstrated the differential roles for the specific ROS in regulating IR in LO2 cells, with H2O2 having a more significant inhibitory role compared with ·O2- and ·OH. Cell treatment with S1P at 0.1-5.0 μM reversed the effects of high insulin concentrations on ROS generation, glucose uptake, and insulin signaling. H2O2 also reversed the beneficial effects of S1P in alleviating IR. These results show that H2O2 signaling plays a key determinant in hepatic IR induced by insulin. S1P can ameliorate hepatic IR by reducing mitochondrial ROS generation, and the possible anti-IR effect mechanism may be involved in H2O2 signaling.

中文翻译：

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线粒体氧化应激诱导的肝胰岛素抵抗可以通过1-磷酸鞘氨醇改善。

具有生物活性的脂质介导的1磷酸神经鞘氨醇（S1P）被认为通过对氧化应激的影响而参与了胰岛素抵抗（IR）的发展。但是该机制尚未完全揭示。为此，我们研究了S1P在肝IR中的作用和机制。我们发现用1000 nM胰岛素治疗正常人肝细胞LO2 48小时可减少葡萄糖摄取并增加胰岛素受体底物1的丝氨酸磷酸化，表明胰岛素受体信号转导减少。此外，相同浓度的胰岛素引起胞浆和线粒体中活性氧（ROS）的积累，并增强了抗氧化剂转录因子（Nrf2）的表达并上调了Nrf2核的转运。使用已知的ROS抑制剂和供体（H2O2，·O2-，·OH），结果表明，特定的ROS在调节LO2细胞的IR中具有不同的作用，与·O2-和·OH相比，H2O2具有更显着的抑制作用。用0.1-5.0μM的S1P进行细胞处理可逆转高胰岛素浓度对ROS生成，葡萄糖摄取和胰岛素信号传导的影响。H2O2还逆转了S1P减轻IR的有益作用。这些结果表明，H2O2信号在胰岛素诱导的肝IR中起着关键的决定性作用。S1P可以通过减少线粒体ROS的产生来改善肝脏IR，并且可能的抗IR作用机制可能与H2O2信号传导有关。0μM逆转了高胰岛素浓度对ROS生成，葡萄糖摄取和胰岛素信号传导的影响。H2O2还逆转了S1P减轻IR的有益作用。这些结果表明，H2O2信号在胰岛素诱导的肝IR中起着关键的决定性作用。S1P可以通过减少线粒体ROS的产生来改善肝脏IR，并且可能的抗IR作用机制可能与H2O2信号传导有关。0μM逆转了高胰岛素浓度对ROS生成，葡萄糖摄取和胰岛素信号传导的影响。H2O2还逆转了S1P减轻IR的有益作用。这些结果表明，H2O2信号在胰岛素诱导的肝IR中起着关键的决定性作用。S1P可以通过减少线粒体ROS的产生来改善肝脏IR，并且可能的抗IR作用机制可能与H2O2信号传导有关。