scholarly journals Retinoid X receptor activation is essential for docosahexaenoic acid protection of retina photoreceptors

2013 ◽  
Vol 54 (8) ◽  
pp. 2236-2246 ◽  
Author(s):  
Olga L. German ◽  
Sandra Monaco ◽  
Daniela L. Agnolazza ◽  
Nora P. Rotstein ◽  
Luis E. Politi
Keyword(s):  
Docosahexaenoic Acid ◽  
Receptor Activation ◽  
Retinoid X Receptor

scholarly journals Retinoid X receptor activation reverses age-related deficiencies in myelin debris phagocytosis and remyelination

Brain ◽  
2015 ◽  
Vol 138 (12) ◽  
pp. 3581-3597 ◽  
Author(s):  
Muktha S. Natrajan ◽  
Alerie G. de la Fuente ◽  
Abbe H. Crawford ◽  
Eimear Linehan ◽  
Vanessa Nuñez ◽  
...  
Keyword(s):  
Receptor Activation ◽  
Retinoid X Receptor ◽  
Age Related ◽  
Myelin Debris

scholarly journals Retinoid X Receptor (RXR) Agonist-Induced Activation of Dominant-Negative RXR-Retinoic Acid Receptor α403 Heterodimers Is Developmentally Regulated during Myeloid Differentiation

1999 ◽  
Vol 19 (5) ◽  
pp. 3372-3382 ◽  
Author(s):  
Barton S. Johnson ◽  
Roshantha A. S. Chandraratna ◽  
Richard A. Heyman ◽  
Elizabeth A. Allegretto ◽  
LeMoyne Mueller ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Trichostatin A ◽  
Receptor Activation ◽  
Nuclear Hormone Receptor ◽  
Retinoid X Receptor ◽  
Dominant Negative ◽  
Mouse Bone Marrow ◽  
Granulocytic Differentiation ◽  
Response Elements ◽  
Dominant Negative Activity

ABSTRACT The multiple biologic activities of retinoic acid (RA) are mediated through RAR and retinoid X receptor (RXR) nuclear receptors that interact with specific DNA target sequences as heterodimers (RXR-RAR) or homodimers (RXR-RXR). RA receptor activation appears critical to regulating important aspects of hematopoiesis, since transducing a COOH-terminally truncated RARα exhibiting dominant-negative activity (RARα403) into normal mouse bone marrow generates hematopoietic growth factor-dependent cell lines frozen at the multipotent progenitor (EML) or committed promyelocyte (MPRO) stages. Nevertheless, relatively high, pharmacological concentrations of RA (1 to 10 μM) overcome these differentiation blocks and induce terminal granulocytic differentiation of the MPRO promyelocytes while potentiating interleukin-3 (IL-3)-induced commitment of EML cells to the granulocyte/monocyte lineage. In the present study, we utilized RXR- and RAR-specific agonists and antagonists to determine how RA overcomes the dominant-negative activity of the truncated RARα in these different myeloid developmental stages. Unexpectedly, we observed that an RXR-specific, rather than an RAR-specific, agonist induces terminal granulocytic differentiation of MPRO promyelocytes, and this differentiation is associated with activation of DNA response elements corresponding to RAR-RXR heterodimers rather than RXR-RXR homodimers. This RXR agonist activity is blocked by RAR-specific antagonists, suggesting extensive cross-talk between the partners of the RXR-RARα403 heterodimer. In contrast, in the more immature, multipotent EML cells we observed that this RXR-specific agonist is inactive either in potentiating IL-3-mediated commitment of EML cells to the granulocyte lineage or in transactivating RAR-RXR response elements. RA-triggered GALdbd-RARα hybrid activity in these cells indicates that the multipotent EML cells harbor substantial nuclear hormone receptor coactivator activity. However, the histone deacetylase (HDAC) inhibitor trichostatin A readily activates an RXR-RAR reporter construct in the multipotent EML cells but not in the committed MPRO promyelocytes, indicating that differences in HDAC-containing repressor complexes in these two closely related but distinct hematopoietic lineages might account for the differential activation of the RXR-RARα403 heterodimers that we observed at these different stages of myeloid development.

Docosahexaenoic Acid, a Ligand for the Retinoid X Receptor in Mouse Brain

Science ◽  
2000 ◽  
Vol 290 (5499) ◽  
pp. 2140-2144 ◽  
Author(s):  
A. M. d. Urquiza ◽  
S. Liu ◽  
M. Sjoberg ◽  
R. H. Zetterstrom ◽  
W. Griffiths ◽  
...  
Keyword(s):  
Docosahexaenoic Acid ◽  
Mouse Brain ◽  
Retinoid X Receptor

scholarly journals D2-like receptor activation does not initiate a brain docosahexaenoic acid signal in unanesthetized rats

2014 ◽  
Vol 15 (1) ◽  
Author(s):  
Ameer Y Taha ◽  
Lisa Chang ◽  
Mei Chen ◽  
Stanley I Rapoport ◽  
Epolia Ramadan
Keyword(s):  
Docosahexaenoic Acid ◽  
Receptor Activation

scholarly journals Distinct retinoid X receptor activation function-2 residues mediate transactivation in homodimeric and vitamin D receptor heterodimeric contexts

2001 ◽  
Vol 27 (2) ◽  
pp. 211-227 ◽  
Author(s):  
PD Thompson ◽  
LS Remus ◽  
JC Hsieh ◽  
PW Jurutka ◽  
GK Whitfield ◽  
...  
Keyword(s):  
Gene Expression ◽  
Vitamin D ◽  
Vitamin D Receptor ◽  
Activation Function ◽  
Receptor Activation ◽  
Retinoid X Receptor ◽  
Dominant Negative ◽  
Dominant Negative Effect ◽  
C Terminus ◽  
Negative Effect

The vitamin D receptor (VDR) stimulates transcription as a 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3))-activated heterodimer with retinoid X receptor (RXR). RXR also forms homodimers to mediate 9-cis retinoic acid (9-cis RA)-induced gene expression. Both receptors possess a C-terminal hormone-dependent activation function-2 (AF-2), a highly conserved region that binds coactivators to transduce the transcriptional signal. By replacing single amino acids within the AF-2 of human RXR alpha (hRXR alpha) or mouse RXR beta (mRXR beta), the contribution of these residues to transactivation by the RXR-VDR heterodimer and the RXR-RXR homodimer was evaluated. In 9-cis RA-responsive homodimers, the second and fourth positions of the AF-2 (leucine and glutamate respectively) are essential. However, in the context of an RXR-VDR heterodimer activated by 1,25(OH)(2)D(3), alteration of these two RXR residues has little effect. Instead, AF-2 residues located towards the C-terminus, such as the penultimate position (L455 in hRXR alpha or L441 in mRXR beta), are crucial for RXR-VDR heterodimers. Indeed, L455A mutant RXR exerts a dominant negative effect on RXR-VDR transcriptional responsiveness to 1,25(OH)(2)D(3). Further experiments with a mutant hRXR alpha (F313A) which elicits 9-cis RA-independent transactivation as a homodimer demonstrate that, when heterodimerized with VDR, this RXR mutant is incapable of activating the RXR-VDR heterocomplex in the absence of the VDR ligand. Taken together, these results indicate that RXR is a subordinate, yet essential transcriptional partner in RXR-VDR-mediated activation of gene expression. Furthermore, a functional switch in RXR AF-2 signaling occurs between RXR residues in the homodimeric versus the heterodimeric states, likely reflecting different interactions between subregions of the AF-2 and coactivator(s).

scholarly journals Docosahexaenoic acid (DHA), a nutritional supplement, modulates steroid insensitivity in asthma

2020 ◽  
Author(s):  
Lipsa Panda ◽  
Atish P Gheware ◽  
Ashish Jaiswal ◽  
Dhurjhoti Saha ◽  
Bapu Koundinya Desiraju ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Docosahexaenoic Acid ◽  
Glucocorticoid Receptor ◽  
Airway Inflammation ◽  
Allergic Airway Inflammation ◽  
Nutritional Supplement ◽  
Retinoid X Receptor ◽  
Mice Model ◽  
Asthmatic Patients ◽  
Natural Ligand

AbstractAsthmatics with poor steroid responsiveness are now found to use health services at higher frequency and contribute to socio-economic burden disproportionately. We have previously shown that a ω-6 fatty acid metabolite leads to a severe and steroid insensitive asthma-like condition in mice. Here, we investigated the role of retinoid-x-receptor gamma (RXRγ) and Docosahexaenoic acid (DHA), a ω3 fatty acid rexinoid ligand of RXR, on the features of steroid insensitivity in asthmatic condition. RXRγ was found to be reduced in the lungs of human asthmatics and mice with steroid insensitive allergic airway inflammation. RXRγ knockdown in naïve mice led to spontaneous asthma like features whereas RXRγ knockdown in allergic mice led to steroid insensitive asthma features. We observed while RXRγ binds to the glucocorticoid receptor (GR) gene and regulates its transcription, DHA increases the GRα expression in human bronchial epithelial cells and reverses the steroid insensitive features in mice with allergic airway inflammation. Docosahexaenoic acid (DHA), a ligand of RXR, was reduced in the sera of steroid-insensitive asthmatics. We conclude that DHA may prove to be a promising steroid sensitizing agent for the treatment of steroid insensitive asthmatics.SummaryThe molecular regulation of glucocorticoid receptor by retinoid-x-receptor gamma (RXRgama) has an implication in steroid insensitive asthma as we found that Docosahexaenoic acid (DHA), a nutritional supplement and natural ligand of RXRgamma, improves steroid sensitivity in steroid insensitive mice model of asthma and DHA levels are found to be low in steroid insensitive asthmatic patients.

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