Motani Alykhan, Wang Zhulun, Conn Marion, Siegler Karen, Zhang Ying, Liu Qingxiang, Johnstone Sheree, Xu Haoda, Thibault Steve, Wang Yingcai, Fan Pingchen, Connors Richard, Le Hoa, Xu Guifen, Walker Nigel, Shan Bei, Coward Peter
Department of Metabolic Disorders, Amgen, Inc., South San Francisco, California 94080, USA.
J Biol Chem. 2009 Mar 20;284(12):7673-80. doi: 10.1074/jbc.M809654200. Epub 2009 Jan 15.
Retinol-binding protein 4 (RBP4) transports retinol from the liver to extrahepatic tissues, and RBP4 lowering is reported to improve insulin sensitivity in mice. We have identified A1120, a high affinity (K(i) = 8.3 nm) non-retinoid ligand for RBP4, which disrupts the interaction between RBP4 and its binding partner transthyretin. Analysis of the RBP4-A1120 co-crystal structure reveals that A1120 induces critical conformational changes at the RBP4-transthyretin interface. Administration of A1120 to mice lowers serum RBP4 and retinol levels but, unexpectedly, does not improve insulin sensitivity. In addition, we show that Rpb4(-/-) mice display normal insulin sensitivity and are not protected from high fat diet-induced insulin resistance. We conclude that lowering RBP4 levels does not improve insulin sensitivity in mice. Therefore, RBP4 lowering may not be an effective strategy for treating diabetes.
视黄醇结合蛋白4（RBP4）将视黄醇从肝脏转运至肝外组织，据报道降低RBP4可改善小鼠的胰岛素敏感性。我们已鉴定出A1120，一种对RBP4具有高亲和力（解离常数Ki = 8.3纳米）的非类视黄醇配体，它会破坏RBP4与其结合伴侣甲状腺素转运蛋白之间的相互作用。对RBP4 - A1120共晶体结构的分析表明，A1120在RBP4 - 甲状腺素转运蛋白界面诱导了关键的构象变化。给小鼠施用A1120可降低血清RBP4和视黄醇水平，但出乎意料的是，并未改善胰岛素敏感性。此外，我们发现Rpb4基因敲除小鼠表现出正常的胰岛素敏感性，并且对高脂饮食诱导的胰岛素抵抗没有抵抗力。我们得出结论，降低RBP4水平并不能改善小鼠的胰岛素敏感性。因此，降低RBP4水平可能不是治疗糖尿病的有效策略。
