GSK3987

Tithonia diversifolia is a novel herbal medicine exerting antihyperglycemic and hepatoprotective effects, but the mol. 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 approx. two-fold of vehicle effect at 10 μM.They also transrepressed LXR-dependent PEPCK gene promoter activation by approx. 50 % of vehicle effect at 10 μM.Addnl., 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.

Paeoniflorin is one of the active ingredients of Paeonia lactiflora Pall., a novel traditional herbal medicine exerting pharmacological effects including antihyperlipidemic, neuroprotective, and anti-hepatofibrosis effects. Liver X receptor (LXR) acts as a ligand-activated transcription factor to exhibit antihyperlipidemic and neuroprotective effects. In this study, the activity of paeoniflorin against LXR was evaluated by the mammalian one-hybrid and transient transfection reporter assays. The results showed that paeoniflorin transactivated GAL4, rat cholesterol 7 α-hydroxylase, phospholipid transfer protein, and ATP-binding cassette A1 gene promoters in dose-dependent manner. Furthermore, the docking study demonstrated that paeoniflorin resided in the LXR ligand-binding pocket in the similar manner as GSK 3987, a novel LXR agonist. These results indicated that paeoniflorin might exert pharmacological effects through LXR pathway.