Competition for RXR
RXR and its Brothers

Working hypothesis

The basic idea is that RXR heterodimerizes with nuclear receptors including CAR, FXR, LXR, PPAR, PXR, RAR, TR, and VDR to promote transcription of the downstream target gene into mRNA and eventually protein.

RXR amount is the limiting factor driving the total amount of proteins that a specific cell can synthesize.
The competition for RXR by liganded receptors will drive the choice of the proteins to be synthesized.

RXR scarcity can derive from:

1. absolute lack of RXR (diet poor in proteins??)
2. relative lack due to sequestration of RXR by an increased number of a specific liganded receptor (TR, VDR; RAR etc)
   • Crosstalk between the thyroid hormone and peroxisome proliferator-activated receptors in regulating peroxisome proliferator-responsive genes. 1996
     This inhibition was the result of competition between TR alpha and PPAR for limiting amounts of the heterodimerization partner RXR alpha and for binding to the PPRE.
   • Crosstalk between the peroxisome proliferator-activated receptor γ (PPARγ) and the vitamin D receptor (VDR) in human breast cancer cells: PPARγ binds to VDR and inhibits 1α,25-dihydroxyvitamin D3 mediated transactivation. 2012
     PPARγ was also found to compete with VDR for their binding partner retinoid X receptor alpha (RXRα).
   • Cross-talk between peroxisome proliferator-activated receptor (PPAR) alpha and liver X receptor (LXR) in nutritional regulation of fatty acid metabolism. II. LXRs suppress lipid degradation gene promoters through inhibition of PPAR signaling. 2003
     Addition of increasing amounts of RXRalpha restored these inhibitory effects in both luciferase and gel shift assays, suggesting the presence of RXRalpha competition.
   • Ligand-activated PPARbeta efficiently represses the induction of LXR-dependent promoter activity through competition with RXR. 2006
     Collectively, these results suggest that the binding of PPARβ-specific ligand enhances the affinity between RXRα and activated PPARβ and thus may regulate angptl3 gene expression through a DR4 element by competing with LXRα for RXRα.
   • Ligand-regulated heterodimerization of peroxisome proliferator-activated receptor α with liver X receptor α. 2015
     Complex interactions between the LXRα and PPARα pathways exist, including competition for the same heterodimeric partner, retinoid X receptor α (RXRα).
   • Peroxisome Proliferator Activated Receptor-α Association With Silent Information Regulator 1 Suppresses Cardiac Fatty Acid Metabolism in the Failing Heart. 2015
     Sirt1 competes with RXRα to dimerize with PPARα, thereby suppressing FA utilization in the failing heart.
   • Crosstalk between the thyroid hormone and peroxisome proliferator-activated receptors in regulating peroxisome proliferator-responsive genes. 1996
     This inhibition was the result of competition between TR alpha and PPAR for limiting amounts of the heterodimerization partner RXR alpha and for binding to the PPRE.
   • Peroxisome proliferator activated receptor-gamma (PPARgamma) represses thyroid hormone signaling in growth plate chondrocytes. 2005
     Overexpression of retinoid X receptor-alpha (RXRalpha) partially restored not only the inhibition of transcriptional activation by PPARgamma but also T3-induced hypertrophic differentiation.
   • Thyroid hormone receptor does not heterodimerize with the vitamin D receptor but represses vitamin D receptor-mediated transactivation. 1998
     No VDR-TR heterodimer binding on any of these VDREs was observed, although, as expected, there was binding by the VDR-RXR complex and strong TR-RXR binding to a consensus thyroid hormone response element.
   • Vitamin D interferes with transactivation of the growth hormone gene by thyroid hormone and retinoic acid. 1996
     Our data suggest the formation of TR-VDR and RAR-VDR heterodimers with RXR.
   • Chromosomal localization of the human retinoid X receptors. 1994
     The recently described retinoid X receptors (RXRs) respond to the novel retinoid 9-cis-retinoic acid and also serve as heterodimeric partners for the vitamin D, thyroid hormone, and retinoic acid receptors (VDR, TR, and RAR, respectively).
   • Clinical effect of competition
     • Bone mass in females with different thyroid disorders: influence of menopausal status. 1993
       Postmenopausal women subjected to excess thyroid hormone represent a population at greater risk for osteoporosis.
     • Metabolic and clinical consequences of hyperthyroidism on bone density. 2013
       Lastly, we report how different treatments for hyperthyroidism benefit thyroid hormone-induced osteoporosis.

Glucocorticoids

A case of late-onset congenital adrenal hyperplasia due to partial 3 beta-hydroxysteroid dehydrogenase deficiency. 1993

Hirsutism improved with the administration of dexamethasone (0.5 mg) every evening.