Format

Send to

Choose Destination
Drug Metab Dispos. 2020 Jan 24. pii: dmd.119.090068. doi: 10.1124/dmd.119.090068. [Epub ahead of print]

Differential role of LXRα and LXRβ in the regulation of UDP-glucuronosyltransferase 1A1 in humanized UGT1 mice.

Author information

1
UCSD.
2
Universite Laval, Quebec.
3
UCSD; rtukey@ucsd.edu.

Abstract

Liver X receptors (LXRs), LXRα and LXRβ, are nuclear receptors that regulate the metabolism of cholesterol and bile acids and are activated by oxysterols. Humanized UGT1 (hUGT1) mice express the 9-human UGT1A genes associated with the UGT1 locus in a Ugt1-null background. The expression of UGT1A1 is developmentally delayed in liver and intestines resulting in the accumulation of serum bilirubin during the neonatal period. Induction of UGT1A1 in newborn hUGT1 mice leads to rapid reduction in total serum bilirubin (TSB) levels, a phenotype measurement that allows for an accurate prediction on UGT1A1 expression. When neonatal hUGT1 mice were treated by oral gavage with the LXR agonist T0901317, TSB levels were dramatically reduced. To determine the LXR contribution to induction of UGT1A1 and the lowering of TSB levels, experiments were conducted in neonatal hUGT1/Lxrα-/-, hUGT1/Lxrβ-/- and hUGT1/Lxrαβ-/- mice treated with T0901317. Induction of liver UGT1A1 was highly dependent upon LXRα, with the induction pattern paralleling induction of LXRα specific Stearoyl-CoA desaturase 1 (SCD1). However, the actions of T0901317 were also shown to display a lack of specificity for LXR, with induction of liver UGT1A1 in hUGT1/Lxrαβ-/- mice, a result associated with activation of both PXR and CAR. An alternative LXR agonist, GW3965, was highly selective towards LXRα, showing no impact on lowering TSB values or inducing UGT1A1 in UGT1/Lxrα-/- mice. An LXR specific enhancer site on the UGT1A1 gene was identified, along with convincing evidence that LXRα is crucial in maintaining constitutive expression of UGT1A1 in adult hUGT1 mice SIGNIFICANCE STATEMENT: Implementing a reverse genetics approach, it has been established that activation of LXRα, and not LXRβ, is responsible for induction of liver UGT1A1 and metabolism of serum bilirubin in neonatal hUGT1 mice. While induction of the human UGT1A1 gene is initiated at a newly characterized LXR enhancer site, allelic deletion of the Lxrα gene drastically reduces constitutive expression of liver UGT1A1 in adult hUGT1 mice. Combined, these findings indicate that LXRα is critical for the developmental expression of UGT1A1.

KEYWORDS:

animal models; constitutive androstane receptor/CAR; glucuronidation/UDP-glucuronyltransferases/UGT; heme/heme metabolism; liver/hepatic; nuclear receptors; pregnane X receptor/PXR/SXR

PMID:
31980500
DOI:
10.1124/dmd.119.090068
Free full text

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center