title: Identification and characterization of a non-retinoid ligand for retinol-binding protein 4 which lowers serum retinol-binding protein 4 levels in vivo.
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.
authors.affiliation: Department of Metabolic Disorders, Amgen, Inc., South San Francisco, California 94080, USA.
authors.forename: Alykhan
authors.initials: A
authors.lastname: Motani
authors.forename: Zhulun
authors.initials: Z
authors.lastname: Wang
authors.forename: Marion
authors.initials: M
authors.lastname: Conn
authors.forename: Karen
authors.initials: K
authors.lastname: Siegler
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Qingxiang
authors.initials: Q
authors.lastname: Liu
authors.forename: Sheree
authors.initials: S
authors.lastname: Johnstone
authors.forename: Haoda
authors.initials: H
authors.lastname: Xu
authors.forename: Steve
authors.initials: S
authors.lastname: Thibault
authors.forename: Yingcai
authors.initials: Y
authors.lastname: Wang
authors.forename: Pingchen
authors.initials: P
authors.lastname: Fan
authors.forename: Richard
authors.initials: R
authors.lastname: Connors
authors.forename: Hoa
authors.initials: H
authors.lastname: Le
authors.forename: Guifen
authors.initials: G
authors.lastname: Xu
authors.forename: Nigel
authors.initials: N
authors.lastname: Walker
authors.forename: Bei
authors.initials: B
authors.lastname: Shan
authors.forename: Peter
authors.initials: P
authors.lastname: Coward
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D003920:Diabetes Mellitus / Q000097:blood / Q000188:drug therapy; D004041:Dietary Fats / Q000009:adverse effects; D006575:Heterocyclic Compounds, 3-Ring / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D008024:Ligands; D051379:Mice; D018345:Mice, Knockout; D010880:Piperidines / Q000737:chemistry* / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D054839:Retinol-Binding Proteins, Plasma / Q000819:agonists / Q000737:chemistry / Q000378:metabolism; D014801:Vitamin A / Q000097:blood*
chemical_list: C540529:A1120 agent; D004041:Dietary Fats; D006575:Heterocyclic Compounds, 3-Ring; D007328:Insulin; D008024:Ligands; D010880:Piperidines; C101326:RBP4 protein, human; C502487:Rbp4 protein, mouse; D054839:Retinol-Binding Proteins, Plasma; D014801:Vitamin A