title: Oleanolic acid derivative NPLC441 potently stimulates glucose transport in 3T3-L1 adipocytes via a multi-target mechanism.
abstract: The natural product oleanolic acid (OA) has been discovered to exhibit varied pharmacological functions including anti-inflammation, anti-tumor and anti-diabetes, while appropriate synthetic oleanolic acid derivatives seem to possess more potent activities. Here we identified a new oleanolic acid derivative, 3-beta-(2-carboxybenzoyloxy)-oleanolic acid (NPLC441), which functioned as a competitive PTP1B inhibitor and enhanced insulin-stimulated phosphorylation of IR and AKT in HepG2 cells. As an RXRalpha antagonist, it could selectively activate LXRalpha:RXRalpha heterodimer and increase the promoter activities of ABCA1 and ABCG1 genes in transient transfection assays. Quantitative RT-PCR and Western blot analyses suggested that NPLC441 could up-regulate GLUT4 expression in 3T3-L1 adipocytes, and such effect was further proved to be dependent on LXRalpha:RXRalpha activation. Moreover, 2-deoxyglucose uptake technology-based characterization demonstrated that this compound could stimulate glucose uptake in 3T3-L1 adipocytes. Finally, NPLC441 was observed to be able to suppress 11beta-HSD(1) expression in HepG2 cells, following the discovery that activation of LXRalpha:RXRalpha could repress the expression of 11beta-HSD(1). Compared with NPLC441, OA showed no effects on the transactivation of either LXRalpha:RXRalpha heterodimer or RXRalpha-LBD. Our work is thus expected to provide a new insight into the anti-diabetic application for oleanolic acid derivatives via multi-target mechanism, and NPLC441 could be used as a potential lead compound for further research.
authors.affiliation: Drug Discovery and Design Centre, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Zhangjiang, Pu Dong, Shanghai 201203, China.
authors.forename: Zhonghui
authors.initials: Z
authors.lastname: Lin
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yinan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Hong
authors.initials: H
authors.lastname: Shen
authors.forename: Lihong
authors.initials: L
authors.lastname: Hu
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
authors.forename: Xu
authors.initials: X
authors.lastname: Shen
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D005947:Glucose / Q000819:agonists / Q000378:metabolism*; D051246:Glucose Transport Proteins, Facilitative / Q000819:agonists / Q000378:metabolism; D006801:Humans; D051379:Mice; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D051246:Glucose Transport Proteins, Facilitative; D009828:Oleanolic Acid; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; C516609:Ptpn1 protein, mouse; D005947:Glucose