Discovery That Theonellasterol a Marine Sponge Sterol Is a Highly Selective FXR Antagonist That Protects against Liver Injury in Cholestasis
Figure 4
Theonellasterol is a selective FXR antagonist.
(A) (C) and (D) HepG2 cells were co-transfected with the Gal4 luciferase reporter and a series of chimeras in which the Gal4 DNA binding domain is fused to the LBD of the indicated nuclear receptors. Cells were treated with the appropriate agonists or specific agonists in combination with theonellasterol. (B) HepG2 cells were co-transfected with pSG5-PXR, pSG5-RXR and with the reporter pCYP3A4promoter-TKLuc and then stimulated with rifaximin, a PXR agonist, alone or in combination with theonellasterol. Data are the mean ± S.E. of three experiments. *P<0.05 versus not treated cells. (E) Microarray analysis showing the relative mRNA expression of various nuclear receptors and nuclear receptors co-activators following stimulation of HepG2 cells with CDCA, 10 µM, alone or in combination with theonellasterol, 50 µM. Data are the mean ± S.E. of three experiments.