Bae Eun Ju, Yang Yoon Mee, Kim Sang Geon
College of Pharmacy, Seoul National University, Sillim-dong, Kwanak-gu, Seoul 151-742, Korea.
Mol Pharmacol. 2008 May;73(5):1502-12. doi: 10.1124/mol.107.044347. Epub 2008 Feb 5.
A previous study from this laboratory showed that oltipraz and synthetic dithiolethiones prevent tumor necrosis factor-alpha-induced hepatic insulin resistance via AMP-activated protein kinase-dependent p70S6 kinase (S6K) 1 inhibitory pathway. This study investigated whether oltipraz and a novel class of 1,2-dithiole-3-thiones were capable of preventing insulin resistance induced by hyperosmotic stress, thereby enhancing insulin-dependent signals, and, if so, whether the restoration of insulin signal was mediated with the inhibition of S6K1 activity stimulated by hyperosmotic stress. In HepG2 cells, oltipraz treatment inhibited insulin receptor substrate (IRS) 1 serine phosphorylation, a marker of insulin resistance, induced by sorbitol-, mannitol-, or sodium chloride-induced hyperosmotic stress. Consequently, this allowed cells to restore insulin signals, which was evidenced by decrease in the ratio of serine to tyrosine phosphorylations of IRS1 and increase in the phosphorylations of Akt and glycogen synthase kinase (GSK) 3beta. Hyperosmotic stress markedly activated S6K1; S6K1 activation was completely abolished by oltipraz pretreatment. An experiment using dominant-negative S6K1 supports the essential role of S6K1 in the hyperosmolarity-stimulated phosphorylation of IRS1. Transfection of constitutive active mutant S6K1 eliminated the protective effect of oltipraz on GSK3beta phosphorylation, indicating that oltipraz restores insulin signaling by inhibiting S6K1 activation. A variety of synthetic 1,2-dithiole-3-thione derivatives also inhibited S6K1 activity and insulin resistance induced by hyperosmotic stress in HepG2 cells. The results of this study demonstrate that a novel class of 1,2-dithiole-3-thiones improve insulin sensitivity under the condition of hyperosmotic stress, which results from the inhibition of S6K1 activation.
该实验室之前的一项研究表明，奥替普拉和合成二硫代硫酮可通过AMP激活的蛋白激酶依赖性p70S6激酶（S6K）1抑制途径预防肿瘤坏死因子-α诱导的肝胰岛素抵抗。本研究调查了奥替普拉和一类新型的1,2-二硫代-3-硫酮是否能够预防高渗应激诱导的胰岛素抵抗，从而增强胰岛素依赖性信号，如果是这样，胰岛素信号的恢复是否是通过抑制高渗应激刺激的S6K1活性介导的。在HepG2细胞中，奥替普拉处理可抑制由山梨醇、甘露醇或氯化钠诱导的高渗应激所导致的胰岛素抵抗标志物——胰岛素受体底物（IRS）1丝氨酸磷酸化。因此，这使得细胞能够恢复胰岛素信号，这可通过IRS1丝氨酸与酪氨酸磷酸化比值的降低以及Akt和糖原合酶激酶（GSK）3β磷酸化的增加来证明。高渗应激显著激活S6K1；奥替普拉预处理可完全消除S6K1的激活。使用显性负性S6K1的实验支持了S6K1在高渗刺激的IRS1磷酸化中的重要作用。组成型活性突变体S6K1的转染消除了奥替普拉对GSK3β磷酸化的保护作用，表明奥替普拉通过抑制S6K1激活来恢复胰岛素信号。多种合成的1,2-二硫代-3-硫酮衍生物也可抑制HepG2细胞中高渗应激诱导的S6K1活性和胰岛素抵抗。本研究结果表明，一类新型的1,2-二硫代-3-硫酮在高渗应激条件下可改善胰岛素敏感性，这是由于S6K1激活受到抑制所致。
