Transcriptional modulations by RXR agonists are only partially subordinated to PPARalpha signaling and attest additional, organ-specific, molecular cross-talks.
Nuclear hormone receptors (NR) are important transcriptional regulators of numerous genes involved in diverse pathophysiological and therapeutic functions. Following ligand activation, class II NR share the ability to heterodimerize with the retinoid X receptor (RXR). It is established that RXR activators, rexinoids, transactivate several peroxisome proliferator-activated receptor alpha (PPARalpha) target genes in a PPARalpha-dependent manner. We hypothesized that, once activated, RXR might signal through quiescent NR other than PPARalpha, in an organ-specific manner. To study this putative phenomenon in vivo, we developed an array of 120 genes relevant to the class II NR field. The genes were selected using both published data and high-density screenings performed on RXR or PPARalpha agonist-treated mice. Wild-type C57BL/6J and PPARalpha-deficient mice were treated with fenofibrate (PPARalpha activator) or LGD1069 (RXR activator). Using our customized array, we studied the hepatic, cardiac, and renal expression of this panel of 120 genes and compared them in both murine genotypes. The results obtained from this study confirmed the ability of an RXR agonist to modulate PPARalpha-restricted target genes in the liver and the kidney. Furthermore, we show that various organ-specific regulations occurring in both genotypes (PPARalpha +/+ or -/-) are highly indicative of the ability of RXR to recruit other class II NR pathways. Further development of this molecular tool may lead to a better understanding of the permissiveness of class II nuclear receptor dimers in vivo.
Martin
Pascal G P
PG
Laboratoire de Pharmacologie et Toxicologie, I.N.R.A., BP3, Toulouse, France.
Lasserre
Frédéric
F
Calleja
Cécile
C
Van Es
Armelle
A
Roulet
Alain
A
Concordet
Didier
D
Cantiello
Michela
M
Barnouin
Romain
R
Gauthier
Béatrice
B
Pineau
Thierry
T
D000818:Animals; D001053:Apolipoproteins / Q000378:metabolism; D000077610:Bexarotene; D015152:Blotting, Northern; D002467:Cell Nucleus / Q000378:metabolism; D016000:Cluster Analysis; D019281:Dimerization; D011345:Fenofibrate / Q000378:metabolism; D005786:Gene Expression Regulation; D005838:Genotype; D000960:Hypolipidemic Agents / Q000494:pharmacology; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D016410:Lymphoma, T-Cell, Cutaneous / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008957:Models, Genetic; D015233:Models, Statistical; D020411:Oligonucleotide Array Sequence Analysis; D047493:PPAR alpha / Q000378:metabolism*; D025341:Principal Component Analysis; D012313:RNA / Q000378:metabolism; D047490:Retinoid X Receptor alpha / Q000378:metabolism*; D012176:Retinoids / Q000378:metabolism; D015398:Signal Transduction; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D013997:Time Factors; D014018:Tissue Distribution; D014158:Transcription, Genetic; D014280:Triglycerides / Q000378:metabolism; D014807:Vitamin D / Q000378:metabolism
D001053:Apolipoproteins; D000960:Hypolipidemic Agents; D047493:PPAR alpha; D047490:Retinoid X Receptor alpha; D012176:Retinoids; D013764:Tetrahydronaphthalenes; D014280:Triglycerides; D014807:Vitamin D; D012313:RNA; D000077610:Bexarotene; D011345:Fenofibrate