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Identification and characterization of a non-retinoid ligand for retinol-binding protein 4 which lowers serum retinol-binding protein 4 levels in vivo. 2009
Alykhan Motani, and
Zhulun Wang, and
Marion Conn, and
Karen Siegler, and
Ying Zhang, and
Qingxiang Liu, and
Sheree Johnstone, and
Haoda Xu, and
Steve Thibault, and
Yingcai Wang, and
Pingchen Fan, and
Richard Connors, and
Hoa Le, and
Guifen Xu, and
Nigel Walker, and
Bei Shan, and
Peter Coward
Department of Metabolic Disorders, Amgen, Inc., South San Francisco, California 94080, USA.
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.
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