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

Cyril Breuker, Amélie Moreau, Laila Lakhal, Viola Tamasi, Yannick Parmentier, Urs Meyer, Patrick Maurel, Serge Lumbroso, Marie José Vilarem, Jean Marc Pascussi

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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.

Original languageEnglish
Pages (from-to)1653-1661
Number of pages9
Issue number4
Publication statusPublished - Apr 1 2010


ASJC Scopus subject areas

  • Endocrinology

Cite this

Breuker, C., Moreau, A., Lakhal, L., Tamasi, V., Parmentier, Y., Meyer, U., Maurel, P., Lumbroso, S., Vilarem, M. J., & Pascussi, J. M. (2010). Hepatic expression of thyroid hormone-responsive spot 14 protein is regulated by constitutive androstane receptor (NR1I3). Endocrinology, 151(4), 1653-1661. https://doi.org/10.1210/en.2009-1435