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Combined loss of orphan receptors PXR and CAR heightens sensitivity to toxic bile acids in mice
Author(s) -
Uppal Hirdesh,
Toma David,
Saini Simrat P.S.,
Ren Songrong,
Jones Thomas J.,
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.20512
Subject(s) - pregnane x receptor , bile acid , nuclear receptor , receptor , biology , detoxification (alternative medicine) , knockout mouse , gene knockout , transporter , downregulation and upregulation , lithocholic acid , endocrinology , toxicity , medicine , biochemistry , pharmacology , gene , transcription factor , pathology , alternative medicine
Efficient detoxification of bile acids is necessary to avoid pathological conditions such as cholestatic liver damage and colon cancer. The orphan nuclear receptors PXR and CAR have been proposed to play an important role in the detoxification of xeno‐ and endo‐biotics by regulating the expression of detoxifying enzymes and transporters. In this report, we showed that the combined loss of PXR and CAR resulted in a significantly heightened sensitivity to bile acid toxicity in a sex‐sensitive manner. A regimen of lithocholic acid treatment, which was tolerated by wild‐type and PXR null mice, caused a marked accumulation of serum bile acids and histological liver damage as well as an increased hepatic lipid deposition in double knockout males. The increased sensitivity in males was associated with genotype‐specific suppression of bile acid transporters and loss of bile acid–mediated downregulation of small heterodimer partner, whereas the transporter suppression was modest or absent in females. The double knockout mice also exhibited gene‐ and tissue‐specific dysregulation of PXR and CAR target genes in response to PXR and CAR agonists. In conclusion , although the cross‐regulation of target genes by PXR and CAR has been proposed, the current study represents in vivo evidence of the combined loss of both receptors causing a unique pattern of gene regulation that can be translated into physiological events such as sensitivity to toxic bile acids. (H EPATOLOGY 2005;41:168–176.)