Premium
Dual role of orphan nuclear receptor pregnane X receptor in bilirubin detoxification in mice
Author(s) -
Saini Simrat P. S.,
Mu Ying,
Gong Haibiao,
Toma David,
Uppal Hirdesh,
Ren Songrong,
Li Song,
Poloyac Samuel M.,
Xie Wen
Publication year - 2005
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.20570
Subject(s) - pregnane x receptor , constitutive androstane receptor , multidrug resistance associated protein 2 , nuclear receptor , detoxification (alternative medicine) , bilirubin , transporter , downregulation and upregulation , biology , pharmacology , receptor , chemistry , biochemistry , atp binding cassette transporter , endocrinology , transcription factor , gene , medicine , alternative medicine , pathology
The pregnane X receptor (PXR) and the constitutive androstane receptor (CAR) are implicated in xenobiotic and endobiotic detoxification, including the clearance of toxic bilirubin. Previous studies have suggested both overlapping and preferential regulation of target genes by these receptors, but the mechanism of cross‐talk remains elusive. Here we reveal a dual role of PXR in bilirubin detoxification in that both the loss and activation of PXR led to protection from hyperbilirubinemia induced by bilirubin infusion or hemolysis. The increased bilirubin clearance in PXR‐null mice was associated with selective upregulation of detoxifying enzymes and transporters, and the pattern of regulation is remarkably similar to that of transgenic mice expressing the activated CAR. Interestingly, the increased bilirubin clearance and associated gene regulation were absent in the CAR‐null or double‐knockout mice. In cell cultures, ligand‐free PXR specifically suppressed the ability of CAR to induce the multidrug resistance associated protein 2 (MRP2), a bilirubin‐detoxifying transporter. This suppression was, at least in part, the result of the disruption of ligand‐independent recruitment of coactivator by CAR. In conclusion , PXR plays both positive and negative roles in regulating bilirubin homeostasis, and this provides a novel mechanism that may govern receptor cross‐talk and the hierarchy of xenobiotic and endobiotic regulation. PXR is a potential therapeutic target for clinical treatment of jaundice. (H EPATOLOGY 2005;41:497–505.)