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Hepatic PXR represses UGT1A1 gene expression during neonatal development
Author(s) -
Chen Shujuan,
Tukey Robert H.
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.1052.4
Subject(s) - pregnane x receptor , glucuronidation , gene expression , downregulation and upregulation , pregnane , bilirubin , regulation of gene expression , constitutive androstane receptor , endocrinology , biology , gene , medicine , nuclear receptor , transcription factor , biochemistry , enzyme , genetics , microsome
Bilirubin glucuronidation is catalyzed solely by UDP‐glucuronosyltransferase 1A1. The delayed development of UGT1A1 expression in neonates leads to hyperbilirubinemia. Under conditions of extreme hyperbilirubinemia, bilirubin induced neurological dysfunction (BIND) can result in irreversible brain damage. To understand those events that regulate UGT1A1 gene expression, our laboratory has reproduced neonatal hyperbilirubinemia in humanized UGT1 ( hUGT1 ) mice. The UGT1A1 gene is regulated by both the pregnane X receptor (PXR) and constitutive androstane receptor (CAR). In hUGT1/Car −/− mice, neonates become susceptible to the development of BIND, without alterations in hepatic UGT1A1 expression. Thus, CAR plays an important role in bilirubin access to the CNS. However, hUGT1/Pxr −/− mice are associated with a reduction in bilirubin and upregulation of hepatic UGT1A1 gene expression, suggesting that PXR represses UGT1A1 gene expression during neonatal development. This was confirmed by CHIP analysis, which demonstrated intense binding of PXR to the UGT1A1 gene. In primary hepatocytes isolated from neonatal hUGT1 mice transfected with PXR specific siRNA, de‐repression of UGT1A1 expression occurred following the arrest of PXR synthesis. Thus, PXR represses UGT1A1 gene expression in neonatal mice leading to the onset of hyperbilirubinemia. ( Supported by grant GM086713 )