2. Academic Validation
  3. Identification and characterization of a non-retinoid ligand for retinol-binding protein 4 which lowers serum retinol-binding protein 4 levels in vivo

Identification and characterization of a non-retinoid ligand for retinol-binding protein 4 which lowers serum retinol-binding protein 4 levels in vivo

  • J Biol Chem. 2009 Mar 20;284(12):7673-80. doi: 10.1074/jbc.M809654200.
Alykhan Motani 1,  Zhulun Wang,  Marion Conn,  Karen Siegler,  Ying Zhang,  Qingxiang Liu,  Sheree Johnstone,  Haoda Xu,  Steve Thibault,  Yingcai Wang,  Pingchen Fan,  Richard Connors,  Hoa Le,  Guifen Xu,  Nigel Walker,  Bei Shan,  Peter Coward
Affiliations

Affiliation

  • 1 Department of Metabolic Disorders, Amgen, Inc., South San Francisco, California 94080, USA.
PMID: 19147488 DOI: 10.1074/jbc.M809654200
Abstract

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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