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Estrogen modulates transactivations of SXR-mediated liver X receptor response element and CAR-mediated phenobarbital

Gyesik Min1

  • 1Department of Pharmaceutical Engineering, Jinju National University, Jinju 660-758, Korea. g-min@jinju.ac.kr

Experimental & Molecular Medicine
|September 28, 2010
PubMed

Insights

Estrogen modulates liver metabolism by interacting with steroid and xenobiotic receptor (SXR) and constitutive androstane receptor (CAR). This study reveals estrogen can repress SXR activity and either stimulate or inhibit CAR activity, depending on ligand presence.

Area of Science:

  • Hepatology and molecular endocrinology.
  • Nuclear receptor signaling pathways.

Background:

  • Steroid and xenobiotic receptor (SXR) and constitutive androstane receptor (CAR) are key regulators of hepatic lipid and drug metabolism.
  • Estrogen receptor (ER) signaling can influence metabolic processes, but its interaction with SXR and CAR is not fully understood.

Purpose of the Study:

  • To investigate the modulatory effects of estrogen on the transcriptional activity of SXR and CAR.
  • To elucidate the functional cross-talk between estrogen receptor (ER) and SXR/CAR in regulating target gene transactivation.

Main Methods:

  • Exogenous expression of human estrogen receptor alpha (hERα) and SXR in HepG2 cells.
  • Reporter gene assays measuring transactivation of liver X receptor response element (LXRE) for SXR and phenobarbital response element (PBRU) for CAR.
  • Treatment with nuclear receptor agonists and antagonists, including estrogen, rifampicin, corticosterone, TCPOBOP, and moxestrol.

Main Results:

  • Estrogen significantly repressed SXR-mediated LXRE transactivation when combined with SXR agonists (rifampicin or corticosterone).
  • hERα alone stimulated CAR-mediated PBRU transactivation, but estrogen (moxestrol) repressed TCPOBOP-potentiated CAR activity.
  • ER exhibits dual modulatory roles (stimulatory and inhibitory) on CAR activity, contingent on ligand availability.

Conclusions:

  • Estrogen modulates the transcriptional activity of SXR and CAR through functional cross-talk.
  • ER plays a complex role in regulating hepatic metabolic pathways controlled by SXR and CAR.
  • These findings highlight the intricate interplay between estrogen and key metabolic nuclear receptors.

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