Identification of liver X receptor and farnesoid X receptor dual agonists from Tithonia diversifolia

Tithonia diversifolia is a novel herbal medicine exerting antihyperglycemic and hepatoprotective effects, but the molecular mechanism underlying these therapeutic effects remains unclear. Liver X receptor (LXR) and farnesoid X receptor (FXR) are members of nuclear receptor superfamily. Their agonists were demonstrated to exhibit antihyperglycemic and hepatoprotective effects. In this study, sesquiterpene lactones, tirotundin and tagitinin A, were isolated from the crude oil of T. diversifolia and evaluated for their activity against LXR and FXR by the transient transfection reporter and mammalian one-hybrid assays. Tirotundin and tagitinin A stimulated LXR-dependent rat CYP7A1, SREBP-1c, and ABCA1 gene promoter transactivation by approximately two-fold of vehicle effect at 10 μM. They also transrepressed LXR-dependent PEPCK gene promoter activation by approximately 50 % of vehicle effect at 10 μM. Additionally, they enhanced the transactivation of FXR-dependent SHP gene promoter by more than two-fold of vehicle effect at 10 μM. These results strongly indicated that tirotundin and tagitinin A acted as dual LXR/FXR agonists so T. diversifolia might exert therapeutic effects through LXR and FXR pathways. © 2012 Springer Science+Business Media New York.