Combined loss of orphan receptors PXR and CAR heightens sensitivity to toxic bile acids in mice

• Published in: Hepatology (Baltimore, Md.) Vol. 41; no. 1; pp. 168 - 176
• Main Authors: UPPAL, Hirdesh, TOMA, David, SAINI, Simrat P. S, SONGRONG REN, JONES, Thomas J, WEN XIE
• Format: Journal Article
• Language: English
• Published: Hoboken, NJ Wiley 2005
• Subjects: Animals; Biological and medical sciences; Carrier Proteins - antagonists & inhibitors; Coxsackie and Adenovirus Receptor-Like Membrane Protein; Drug Resistance; Female; Fundamental and applied biological sciences. Psychology; Gastroenterology. Liver. Pancreas. Abdomen; Lipid Metabolism; Lithocholic Acid - poisoning; Liver - drug effects; Liver - metabolism; Liver - pathology; Liver. Bile. Biliary tracts; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Male; Medical sciences; Membrane Glycoproteins - antagonists & inhibitors; Mice; Mice, Inbred Strains; Mice, Knockout; Other diseases. Semiology; Receptors, Cytoplasmic and Nuclear - deficiency; Receptors, Steroid - deficiency; Receptors, Virus - deficiency; Sex Characteristics; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Tumors; Vertebrates: digestive system; Agonist; Nuclear receptor; Toxicity; Sex; Hepatic disease; Lipids; Male; Biliary tract disease; Accumulation; Regulation(control); Microbiological investigation; Colon cancer; Bile acid; Gastroenterology; Intestinal disease; Female; Serum; Poison withdrawal; Typing; Rodentia; Detoxification; Genotype; Malignant tumor; Vertebrata; Sensitivity; Mammalia; Treatment; Mouse; Animal; Cholostasis; Digestive diseases
• ISSN: 0270-9139; 1527-3350
• DOI: 10.1002/hep.20512

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, althoughthe cross-regulation of target genes by PXR and CAR has b een 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.