Oleanolic acid derivative NPLC441 potently stimulates glucose transport in 3T3-L1 adipocytes via a multi-target mechanism.
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.
Lin
Zhonghui
Z
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.
Zhang
Yu
Y
Zhang
Yinan
Y
Shen
Hong
H
Hu
Lihong
L
Jiang
Hualiang
H
Shen
Xu
X
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
D051246:Glucose Transport Proteins, Facilitative; D009828:Oleanolic Acid; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; C516609:Ptpn1 protein, mouse; D005947:Glucose