Retinoid X receptor acts as a hormone receptor in vivo to induce a key metabolic enzyme for 1,25-dihydroxyvitamin D3.
We demonstrate here that RNA levels of 25-hydroxy-vitamin D3-24-hydroxylase (24-(OH)ase), a key catabolic enzyme for 1,25-dihydroxyvitamin D3, are increased by a highly selective retinoid X receptor (RXR) ligand, LG100268, in mice within hours. Correspondingly, upon LG100268 treatment, kidney 24-(OH)ase enzymatic activity increases 5-10-fold. The endogenous retinoid hormones, all-trans-retinoic acid and 9-cis-retinoic acid, and the synthetic retinoic acid receptor-selective compound, TTNPB, also stimulate 24-(OH)ase. Additionally, we show that LG100268 stimulates transcription of a luciferase reporter plasmid driven by 24-(OH)ase promoter sequences in the presence of RXR in CV-1 cell cotransactivation assays. This first demonstration of a gene that is regulated in the intact animal through an RXR-mediated pathway confirms earlier hypotheses that RXR is a bona fide hormone receptor. Regulation of a key gene in the vitamin D signaling pathway by a retinoid transducer may provide a molecular basis for some of the documented biological effects of vitamin A on bone and vitamin D metabolism.
Allegretto
E A
EA
Department of Biochemistry, Ligand Pharmaceuticals, San Diego, California 92121, USA.
Shevde
N
N
Zou
A
A
Howell
S R
SR
Boehm
M F
MF
Hollis
B W
BW
Pike
J W
JW
D000818:Animals; D002117:Calcitriol / Q000378:metabolism*; D002460:Cell Line; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004790:Enzyme Induction; D005260:Female; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000201:enzymology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009539:Nicotinic Acids / Q000097:blood / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000502:physiology*; D018168:Receptors, Retinoic Acid / Q000187:drug effects / Q000502:physiology*; D047488:Retinoid X Receptors; D012176:Retinoids / Q000494:pharmacology; D015398:Signal Transduction; D013250:Steroid Hydroxylases / Q000096:biosynthesis*; D013764:Tetrahydronaphthalenes / Q000097:blood / Q000494:pharmacology*; D014157:Transcription Factors / Q000187:drug effects / Q000502:physiology*; D015533:Transcriptional Activation; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology; D065668:Vitamin D3 24-Hydroxylase
D009539:Nicotinic Acids; D011956:Receptors, Cell Surface; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D012176:Retinoids; D013764:Tetrahydronaphthalenes; D014157:Transcription Factors; D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D065668:Vitamin D3 24-Hydroxylase; D002117:Calcitriol; C095104:LG 100268