Hepatic expression of thyroid hormone-responsive spot 14 protein is regulated by constitutive androstane receptor (NR1I3)

Abstract

The pregnane X receptors (PXRs) and the constitutive androstane receptor (CAR) were initially isolated as nuclearreceptorsregulatingxenobioticmetabolismandelimination, alleviatingchemicalinsults.However, recent works suggest that these xenoreceptors play an endobiotic role in modulating hepatic lipid metabolism. In this study, we show that CAR activators]phenobarbital and 6-(4-chlorophenyl) imidazo[2,1-b][1,3]thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime] induce the lipogenic gene thyroid hormoneresponsivespot14protein( THRSP)(orSpot14,S14) expression in human hepatocytes. In addition, wereport that treatment of wild-type mice with mCAR activators (phenobarbital and 1,4-Bis[2-(3,5- dichloropyridyloxy)] benzene) efficiently increases thrsp expression, in contrast to CAR null mice. We demonstrate that CAR directly transactivates THRSP promoter through the direct repeat with 4-bp spacer thyroid hormone and PXR response element. Deletion or point mutations within this PXR response element led to a drastic inhibition of CAR-mediated THRSP transactivation. Gel-shift analysis revealed that the CAR/retinoid X receptor complex binds to this element. In conclusion, our results indicate that THRSP gene is a CAR and PXR target gene. Because THRSP expression correlates with lipogenesis and insulin sensitivity, our data suggest that CAR and/or PXR activating drugs and xenobiotics may promote aberrant hepatic de novo lipogenesis leading potentially to fatty liver diseases and insulin resistance. Copyright © 2010 by The Endocrine Society.