Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
Cell Metab. 2009 Dec;10(6):516-23. doi: 10.1016/j.cmet.2009.09.012.
Receptor-interacting protein 140 (RIP140), a nuclear receptor corepressor, is important for lipid and glucose metabolism. In adipocytes, RIP140 can be phosphorylated by protein kinase C epsilon (PKCvarepsilon), followed by arginine methylation, and exported to the cytoplasm. This study demonstrates for the first time a cytoplasmic function for RIP140: to counteract insulin-stimulated glucose transporter 4 (GLUT4) membrane partitioning and glucose uptake in adipocytes. Cytoplasmic RIP140 interacts with the Akt substrate AS160, thereby impeding AS160 phosphorylation by Akt; this in turn reduces GLUT4 trafficking. This signal transduction pathway can be recapitulated in the epididymal adipocytes of diet-induced obese mice: nuclear PKCvarepsilon is activated, cytoplasmic RIP140 increases, and GLUT4 trafficking and glucose uptake are reduced. The data reveal a new, cytoplasmic function for RIP140 as a negative regulator of GLUT4 trafficking and glucose uptake, and shed insight into the regulation of basal and insulin-stimulated glucose disposal by a nuclear-initiated counteracting mechanism.
受体相互作用蛋白 140（RIP140）是核受体共抑制因子，对脂质和葡萄糖代谢很重要。在脂肪细胞中，蛋白激酶 C ɛ（PKCɛ）可使 RIP140 磷酸化，随后发生精氨酸甲基化，并被输出到细胞质。本研究首次证明了 RIP140 的细胞质功能：拮抗胰岛素刺激的葡萄糖转运蛋白 4（GLUT4）的膜分布和脂肪细胞中的葡萄糖摄取。细胞质 RIP140 与 Akt 底物 AS160 相互作用，从而阻碍 Akt 对 AS160 的磷酸化；这反过来又减少了 GLUT4 的运输。这条信号转导途径可以在饮食诱导肥胖小鼠的附睾脂肪细胞中重现：核 PKCɛ 被激活，细胞质 RIP140 增加，GLUT4 的运输和葡萄糖摄取减少。数据揭示了 RIP140 的新的细胞质功能，作为 GLUT4 运输和葡萄糖摄取的负调节剂，并深入了解了由核启动的拮抗机制对基础和胰岛素刺激的葡萄糖处置的调节。
