Hepatic expression of thyroid hormone-responsive spot 14 protein is regulated by constitutive androstane receptor (NR1I3).
The pregnane X receptors (PXRs) and the constitutive androstane receptor (CAR) were initially isolated as nuclear receptors regulating xenobiotic metabolism and elimination, alleviating chemical insults. 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 hormone-responsive spot 14 protein (THRSP) (or Spot14, S14) expression in human hepatocytes. In addition, we report 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.
Breuker
Cyril
C
Institut National de la Santé et de la Recherche Médicale, Unité 632, 1919 Route de Mende, F-34293 Montpellier, France.
Moreau
Amélie
A
Lakhal
Laila
L
Tamasi
Viola
V
Parmentier
Yannick
Y
Meyer
Urs
U
Maurel
Patrick
P
Lumbroso
Serge
S
Vilarem
Marie-José
MJ
Pascussi
Jean-Marc
JM
D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D000090702:Constitutive Androstane Receptor; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010091:Oximes / Q000494:pharmacology; D010634:Phenobarbital / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013844:Thiazoles / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection
D000090702:Constitutive Androstane Receptor; C000716327:NR1I3 protein, human; C000716328:Nr1i3 protein, mouse; D009687:Nuclear Proteins; D010091:Oximes; D011725:Pyridines; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; C501477:Thrsp protein, mouse; D014157:Transcription Factors; C028474:1,4-bis(2-(3,5-dichloropyridyloxy))benzene; C475093:6-(4-chlorophenyl)imidazo(2,1-b)(1,3)thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime; D010634:Phenobarbital