Induction of bilirubin clearance by the constitutive androstane receptor (CAR).
Bilirubin clearance is one of the numerous important functions of the liver. Defects in this process result in jaundice, which is particularly common in neonates. Elevated bilirubin levels can be decreased by treatment with phenobarbital. Because the nuclear hormone receptor constitutive androstane receptor (CAR) mediates hepatic effects of this xenobiotic inducer, we hypothesized that CAR could be a regulator of bilirubin clearance. Activation of the nuclear hormone receptor CAR increases hepatic expression of each of five components of the bilirubin-clearance pathway. This induction is absent in homozygous CAR null mice but is observed in mice expressing human CAR instead of mouse CAR. Pretreatment with xenobiotic inducers markedly increases the rate of clearance of an exogenous bilirubin load in wild-type but not CAR knockout animals. Bilirubin itself can also activate CAR, and mice lacking CAR are defective in clearing chronically elevated bilirubin levels. Unexpectedly, CAR expression is very low in livers of neonatal mice and humans. We conclude that CAR directs a protective response to elevated bilirubin levels and suggest that a functional deficit of CAR activity may contribute to neonatal jaundice.
Huang
Wendong
W
Department of Molecular and Cellular Biology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
Zhang
Jun
J
Chua
Steven S
SS
Qatanani
Mohammed
M
Han
Yunqing
Y
Granata
Riccarda
R
Moore
David D
DD
D000199:Actins / Q000235:genetics; D000818:Animals; D001663:Bilirubin / Q000378:metabolism*; D000090702:Constitutive Androstane Receptor; D017931:DNA Primers; D005786:Gene Expression Regulation; D014453:Glucuronosyltransferase / Q000235:genetics; D022781:Hepatocytes / Q000502:physiology*; D006801:Humans; D008657:Metabolic Clearance Rate; D051379:Mice; D008822:Mice, Transgenic; D016133:Polymerase Chain Reaction; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D000099148:UGT1A1 Enzyme
D000199:Actins; D001663:Bilirubin; D000090702:Constitutive Androstane Receptor; D017931:DNA Primers; D014453:Glucuronosyltransferase; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D000099148:UGT1A1 Enzyme