Retinoid X receptors: Common heterodimerization partners with distinct functions

Institut Pasteur de Lille, Lille, Nord-Pas-de-Calais, France
Trends in Endocrinology and Metabolism (Impact Factor: 9.39). 11/2010; 21(11):676-83. DOI: 10.1016/j.tem.2010.06.009
Source: PubMed


Retinoid X receptors (RXRs) have been implicated in a diversity of cellular processes ranging from cellular proliferation to lipid metabolism. These pleiotropic effects stem not only from the ability of RXRs to dimerize with diverse nuclear receptors, which exert transcriptional control on specific aspects of cell biology, but also because binding of RXR ligands to heterodimers can stimulate transcriptional activation by RXR partner receptors. This signaling network is rendered more complex by the existence of different RXR isotypes (RXRα, RXRβ, RXRγ) with distinct properties that thereby modulate the transcriptional activity of RXR-containing heterodimers. This review discusses the emerging roles of RXR isotypes in the RXR signaling network and possible implications for our understanding of nuclear receptor biology and pharmacology.

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Available from: Yacir Benomar
    • "A total of 10 candidate genes were selected. Peroxisome proliferator activated receptor γ (PPARG) and Retinoic X receptor γ (RXRG) are involved in gene expression regulation of adipogenesis and lipogenesis processes (Kersten, 2001; Lefebvre et al., 2010). Leptin (LEP ) is a hormone produced by adipose tissue, which controls energy balance and has also local effects inhibiting lipogenesis in adipose tissue and promoting FA catabolism (Wang et al., 1999). "
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    ABSTRACT: Diet influences animal body and tissue composition due to direct deposition and to the nutrients effects on metabolism. The influence of specific nutrients on the molecular regulation of lipogenesis is not well characterized and is known to be influenced by many factors including timing and physiological status. A trial was performed to study the effects of different dietary energy sources on lipogenic genes transcription in ham adipose tissue of Iberian pigs, at different growth periods and on feeding/fasting situations. A total of 27 Iberian male pigs of 28 kg BW were allocated to two separate groups and fed with different isocaloric feeding regimens: standard diet with carbohydrates as energy source (CH) or diet enriched with high oleic sunflower oil (HO). Ham subcutaneous adipose tissue was sampled by biopsy at growing (44 kg mean BW) and finishing (100 kg mean BW) periods. The first sampling was performed on fasted animals, while the last sampling was performed twice, with animals fasted overnight and 3 h after refeeding. Effects of diet, growth period and feeding/fasting status on gene expression were explored quantifying the expression of a panel of key genes implicated in lipogenesis and lipid metabolism processes. Quantitative PCR revealed several differentially expressed genes according to diet, with similar results at both timings: RXRG , LEP and FABP5 genes were upregulated in HO group while ME1 , FASN , ACACA and ELOVL6 were upregulated in CH. The diet effect on ME1 gene expression was conditional on feeding/fasting status, with the higher ME1 gene expression in CH than HO groups, observed only in fasting samples. Results are compatible with a higher de novo endogenous synthesis of fatty acids (FA) in the carbohydrate-supplemented group and a higher FA transport in the oleic acid-supplemented group. Growth period significantly affected the expression of most of the studied genes, with all but PPARG showing higher expression in finishing pigs according to a pattern dissimilar from the usual in cosmopolitan pig breeds. Feeding/fasting status only influenced PPARG gene transcription. The lack of effects of feeding/fasting status on lipogenic gene expression and the higher ME1 response to diet in fasting samples than in postprandial sampling, suggest the persistence of de novo lipogenesis during fasting. Overall results improve the understanding of the influence of different factors on lipid metabolism regulation in Iberian pigs.
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    • "RXR homodimer activated by RXR agonists is known to stimulate DR1 sequence transcription[10,11,33]. On the other hand, RXR agonists can stimulate DR5 sequence transcription via RXR-RAR heterodimer only in the presence of RAR agonists (non-permissive heterodimer)[10,11,34]. In the presence of RXRα, HX630 stimulated DR1 sequence transcription maximally at 1 μM (Fig 8A), while PA024 stimulated DR1 sequence transcription maximally at 10 μM (Fig 8B). "
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    ABSTRACT: Various retinoid X receptor (RXR) agonists have recently been developed, and some of them have shown anti-tumor effects both in vivo and in vitro. However, there has been no report showing the effects of RXR agonists on Cushing's disease, which is caused by excessive ACTH secretion in a corticotroph tumor of the pituitary gland. Therefore, we examined the effects of synthetic RXR pan-agonists HX630 and PA024 on the proliferation, apoptosis, ACTH secretion, and pro-opiomelanocortin (Pomc) gene expression of murine pituitary corticotroph tumor AtT20 cells. We demonstrated that both RXR agonists induced apoptosis dose-dependently in AtT20 cells, and inhibited their proliferation at their higher doses. Microarray analysis identified a significant gene network associated with caspase 3 induced by high dose HX630. On the other hand, HX630, but not PA024, inhibited Pomc transcription, Pomc mRNA expression, and ACTH secretion dose-dependently. Furthermore, we provide new evidence that HX630 negatively regulates the Pomc promoter activity at the transcriptional level due to the suppression of the transcription factor Nur77 and Nurr1 mRNA expression and the reduction of Nur77/Nurr1 heterodimer recruiting to the Pomc promoter region. We also demonstrated that the HX630-mediated suppression of the Pomc gene expression was exerted via RXRα. Furthermore, HX630 inhibited tumor growth and decreased Pomc mRNA expression in corticotroph tumor cells in female nude mice in vivo. Thus, these results indicate that RXR agonists, especially HX630, could be a new therapeutic candidate for Cushing's disease.
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    • "Finally, we assessed the effect of the treatments on the expression of RXR. RXR is a nuclear receptor that forms obligate heterodimers with PPARγ and LXR[41]. In contrast to PPARγ and LXR, RXR brain level was not altered by any feeding paradigm (Supplementary Fig. 3C). "

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