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

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

Research output: Contribution to journalArticle

26 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1653-1661
Number of pages9
JournalEndocrinology
Volume151
Issue number4
DOIs
Publication statusPublished - Apr 2010

Fingerprint

Thyroid Hormones
Liver
Thyroid Gland
Proteins
Lipogenesis
Response Elements
Phenobarbital
Insulin Resistance
Genes
Retinoid X Receptors
Disease Resistance
constitutive androstane receptor
Sequence Deletion
Nucleic Acid Repetitive Sequences
Electrophoretic Mobility Shift Assay
Xenobiotics
Fatty Liver
Lipid Metabolism
Point Mutation
Transcriptional Activation

ASJC Scopus subject areas

  • Endocrinology

Cite this

Hepatic expression of thyroid hormone-responsive spot 14 protein is regulated by constitutive androstane receptor (NR1I3). / Breuker, Cyril; Moreau, Amélie; Lakhal, Laila; Tamási, V.; Parmentier, Yannick; Meyer, Urs; Maurel, Patrick; Lumbroso, Serge; Vilarem, Marie José; Pascussi, Jean Marc.

In: Endocrinology, Vol. 151, No. 4, 04.2010, p. 1653-1661.

Research output: Contribution to journalArticle

Breuker, C, Moreau, A, Lakhal, L, Tamási, V, Parmentier, Y, Meyer, U, Maurel, P, Lumbroso, S, Vilarem, MJ & Pascussi, JM 2010, 'Hepatic expression of thyroid hormone-responsive spot 14 protein is regulated by constitutive androstane receptor (NR1I3)', Endocrinology, vol. 151, no. 4, pp. 1653-1661. https://doi.org/10.1210/en.2009-1435
Breuker, Cyril ; Moreau, Amélie ; Lakhal, Laila ; Tamási, V. ; Parmentier, Yannick ; Meyer, Urs ; Maurel, Patrick ; Lumbroso, Serge ; Vilarem, Marie José ; Pascussi, Jean Marc. / Hepatic expression of thyroid hormone-responsive spot 14 protein is regulated by constitutive androstane receptor (NR1I3). In: Endocrinology. 2010 ; Vol. 151, No. 4. pp. 1653-1661.
@article{ab681b6f2edc40eb8eb73b894b8d6a37,
title = "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.",
author = "Cyril Breuker and Am{\'e}lie Moreau and Laila Lakhal and V. Tam{\'a}si and Yannick Parmentier and Urs Meyer and Patrick Maurel and Serge Lumbroso and Vilarem, {Marie Jos{\'e}} and Pascussi, {Jean Marc}",
year = "2010",
month = "4",
doi = "10.1210/en.2009-1435",
language = "English",
volume = "151",
pages = "1653--1661",
journal = "Endocrinology",
issn = "0013-7227",
publisher = "The Endocrine Society",
number = "4",

}

TY - JOUR

T1 - Hepatic expression of thyroid hormone-responsive spot 14 protein is regulated by constitutive androstane receptor (NR1I3)

AU - Breuker, Cyril

AU - Moreau, Amélie

AU - Lakhal, Laila

AU - Tamási, V.

AU - Parmentier, Yannick

AU - Meyer, Urs

AU - Maurel, Patrick

AU - Lumbroso, Serge

AU - Vilarem, Marie José

AU - Pascussi, Jean Marc

PY - 2010/4

Y1 - 2010/4

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=77950222547&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77950222547&partnerID=8YFLogxK

U2 - 10.1210/en.2009-1435

DO - 10.1210/en.2009-1435

M3 - Article

C2 - 20185760

AN - SCOPUS:77950222547

VL - 151

SP - 1653

EP - 1661

JO - Endocrinology

JF - Endocrinology

SN - 0013-7227

IS - 4

ER -