Abstract
The nuclear receptors, steroid and xenobiotic receptor (SXR) and constitutive androstane receptor (CAR) play important functions in mediating lipid and drug metabolism in the liver. The present study demonstrates modulatory actions of estrogen in transactivations of SXR-mediated liver X receptor response element (LXRE) and CAR-mediated phenobarbital response element (PBRU). When human estrogen receptor (hERα) and SXR were exogenously expressed, treatment with either rifampicin or corticosterone promoted significantly the SXR-mediated transactivation of LXRE reporter gene in HepG2. However, combined treatment with estrogen plus either rifampicin or corticosterone resulted in less than 50% of the mean values of the transactivation by rifampicin or corticosterone alone. Thus, it is suggested that estrogen may repress the SXR-mediated transactivation of LXRE via functional cross-talk between ER and SXR. The CAR-mediated transactivation of PBRU was stimulated by hERa in the absence of estrogen. However, the potentiation by CAR agonist, TCPOBOP, was significantly repressed by moxestrol in the presence of ER. Thus, ER may play both stimulatory and inhibitory roles in modulating CAR-mediated transactivation of PBRU depending on the presence of their ligands. In summary, this study demonstrates that estrogen modulates transcriptional activity of SXR and CAR in mediating transactivation of LXRE and PBRU, respectively, of the nuclear receptor target genes through functional cross-talk between ER and the corresponding nuclear receptors.
Highlights
Estrogen plays important biological functions in the development of female reproduction and cellular proliferation and in lipid metabolism and biological homeostasis in different tissues of body (Archer et al, 1986; Croston et al, 1997; Blum and Cannon, 2001; Deroo and Korach, 2006; Glass, 2006)
Activation of steroid and xenobiotic receptor (SXR) by corticosterone did not affect the estrogen stimulated estrogen receptor (ER) transcriptional activity. These results indicate that estrogen induces ER-mediated transactivation of estrogen response element (ERE) in HepG2 cells and can be used as a functional control to examine the effects of ER on transcriptional modulations of the xenobiotic nuclear receptors, such as SXR and constitutive androstane receptor (CAR), in context to their target response elements in this assay system
This study demonstrates that ER may modulate transcriptional activity of xenobiotic nuclear receptors, SXR and CAR
Summary
Estrogen plays important biological functions in the development of female reproduction and cellular proliferation and in lipid metabolism and biological homeostasis in different tissues of body (Archer et al, 1986; Croston et al, 1997; Blum and Cannon, 2001; Deroo and Korach, 2006; Glass, 2006). Estrogen action is mediated by the nuclear estrogen receptor (ER), which is a ligand-dependent transcription factor and consists of different regulatory domains with distinct biological functions (Evans, 1988; Beato, 1989). Recent studies (Min et al, 2002b) demonstrated that the action of ER in transcriptional activity can be modulated by functional cross-talk between ER and other nuclear receptors. The xenobiotic nuclear receptors, constitutive androstane receptor (CAR) and steroid and xenobiotic receptor (SXR), inhibit ER-mediated transactivation. These xenobiotic receptors play important roles in modulating steroid hormone homeostasis and drug
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