Phosphoinositide 3-kinase as a novel functional target for the regulation of the insulin signaling pathway by SIRT1
Phosphoinositide 3-kinase as a novel functional target for the regulation of the insulin signaling pathway by SIRT1
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DOI：
10.1016/j.mce.2011.01.008
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发表时间：
2011-03-30
影响因子：
4.1
通讯作者：
Pirola, Luciano
中科院分区：
文献类型：
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作者：
Froejdoe, Sara;Durand, Christine;Pirola, Luciano
蛋白质脱乙酰酶SIRT 1及其激活剂白藜芦醇对葡萄糖代谢产生有益作用。已经鉴定了不同的SIRT 1靶标，包括PTP 1B、AMPK、FOXO、PGC-1 alpha和IRS 2。后者可能强调了SIRT 1和胰岛素信号成分之间的紧密联系。然而，SIRT 1是否对胰岛素抵抗有直接影响，白藜芦醇是否直接或间接地在这种情况下起作用，仍然是一个有争议的问题，这个问题还没有在肌肉细胞中得到解决。这表明SIRT 1的减少在确定肌肉胰岛素抵抗中的作用。为了研究SIRT 1对胰岛素途径的功能影响，在通过RNAi使SIRT 1失活后评价胰岛素下游效应物PKB的活化。SIRT 1过度表达或白藜芦醇治疗。在肌肉细胞和HEK 293细胞中，SIRT 1下调减少，而过度表达增加，胰岛素诱导的PKB活化磷酸化。进一步的分子表征显示，SIRT 1以胰岛素非依赖性方式与PI 3 K衔接子亚基p85相互作用。然后，我们研究了白藜芦醇是否可以通过SIRT 1或替代靶点改善肌肉细胞中的胰岛素信号传导。用白藜芦醇孵育肌细胞可以逆转长期TNF α或胰岛素治疗诱导的胰岛素抵抗状态。白藜芦醇依赖性改善胰岛素抵抗发生通过抑制IRS 1/2的丝氨酸磷酸化，暗示白藜芦醇作为丝氨酸激酶抑制剂。最后，在C.我们的数据证实SIRT 1是通过PI 3 K介导的肌细胞胰岛素信号传导的正性调节剂，这种机制似乎与C. elegans通过humans人类. (C)2011爱思唯尔爱尔兰有限公司保留所有权利。
The protein deacetylase SIRT1, and its activator resveratrol, exert beneficial effects on glucose metabolism. Different SIRT1 targets have been identified, including PTP1B, AMPK, FOXO, PGC-1 alpha and IRS2. The latter may underscore a tight link between SIRT1 and insulin signaling components. However, whether SIRT1 has a direct effect on insulin resistance and whether resveratrol acts directly or indirectly in this context is still a matter of controversy and this question has not been addressed in muscle cells.Here, we show that SIRT1 protein expression is decreased in muscle biopsies and primary myotubes derived from type 2 diabetic patients, suggesting a contribution of diminished SIRT1 in the determination of muscle insulin resistance. To investigate the functional impact of SIRT1 on the insulin pathway, the activation of insulin downstream effector PKB was evaluated after SIRT1 inactivation by RNAi. SIRT1 overexpression, or resveratrol treatments. In muscle cells and HEK293 cells, downregulation of SIRT1 reduced, while overexpression increased, insulin-induced PKB activatory phosphorylation. Further molecular characterisation revealed that SIRT1 interacts in an insulin-independent manner with the PI3K adapter subunit p85. We then investigated whether resveratrol may improve insulin signaling in muscle cells via SIRT1, or alternative targets. Incubation of muscle cells with resveratrol reverted the insulin-resistant state induced by prolonged TNF alpha or insulin treatment. Resveratrol-dependent improvement of insulin-resistance occurred through inhibition of serine phosphorylation of IRS1/2, implicating resveratrol as a serine kinase inhibitor. Finally, a functional interaction between PI3K and SIRT1 was demonstrated in C. elegans, where constitutively active PI3K - mimicking increased IIS signaling - lead to shortened lifespan, while removal of sir-2.1 abolished PI3K-induced lifespan shortening.Our data identify SIRT1 as a positive modulator of insulin signaling in muscle cells through PI3K, and this mechanism appears to be conserved from C. elegans through humans. (C) 2011 Elsevier Ireland Ltd. All rights reserved.