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Regulation of Hepatic UGT1A4 by Liver X Receptor LXRα, and not LXRβ in hUGT1 Mice
Author(s) -
Rettenmeier Eva,
Yoda Emiko,
Schoor Lori,
Chen Shujuan,
Barbier Olivier,
Tukey Robert
Publication year - 2018
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.2018.32.1_supplement.826.7
Subject(s) - liver x receptor , nuclear receptor , biology , medicine , endocrinology , chemistry , transcription factor , gene , biochemistry
UDP‐glucuronosyltransferases (UGTs) are metabolic enzymes catalyzing the transformation of multiple xeno‐ and endobiotics into their more water‐soluble glucuronides. Among the UGT enzymes, UGT1A4 is known for the N‐glucuronidation of amine containing xenobiotics, including anticonvulsants, antidepressants and environmental mutagens. To examine the function of UGT1A4 and other genes associated with the human UGT1 locus, we have implemented humanized UGT1 mice ( hUGT1 ). In this study we identify UGT1A4 as a positively regulated target gene of the nuclear receptor liver X‐receptor (LXR). LXR is a member of the nuclear receptor superfamily. Two isoforms of LXR exist, LXRα and LXRβ. The treatment of neonatal hUGT1 mice with the conventional LXR agonist T0901317 led to transcriptional activation of downstream LXR target genes, including UGT1A1 , UGT1A4 , Scd1 and Scd2 . Since neonatal hUGT1 mice develop extreme hyperbilirubinemia, the induction of intestinal and liver UGT1A1 led to a dramatic reduction in total serum bilirubin. Repeating the induction patterns in hUGT1/Lxrα −/− and hUGT1/LXRβ −/− mice, expression of Scd1 and Scd2 displayed specificity for LXRα. There was significant induction of these genes in hUGT1/Lxrβ −/− mice with limited activation in hUGT1/Lxrα −/− mice. In contrast, the induction of UGT1A1 and the UGT1A1 gene by T0901317 is regulated by both activated LXRα and LXRβ. However, like Scd1 and Scd2 , induction of the UGT1A4 gene was selective towards LXRα, with greatly reduced expression in hUGT1/Lxrα −/− mice. Induction of the UGT1A4 gene was comparable in hUGT1/Lxrβ +/− and hUGT1/LXRβ −/− mice. Clearly, LXRα and LXRβ can display fine selectivity for downstream target gene activation, such as the UGT1A4 gene. Support or Funding Information USPHS grants GM086713 and ES010337, DFG (German Research Foundation) This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .