Increasing Human Th17 Differentiation through Activation of Orphan Nuclear Receptor Retinoid Acid-Related Orphan Receptor γ (RORγ) by a Class of Aryl Amide Compounds

2012 ◽  
Vol 82 (4) ◽  
pp. 583-590 ◽  
Author(s):  
Wei Zhang ◽  
Jing Zhang ◽  
Leiping Fang ◽  
Ling Zhou ◽  
Shuai Wang ◽  
...  
Keyword(s):  
Nuclear Receptor ◽  
Orphan Receptor ◽  
Orphan Nuclear Receptor ◽  
Th17 Differentiation ◽  
Retinoid Acid

scholarly journals The Orphan Nuclear Receptor 4A1: A Potential New Therapeutic Target for Metabolic Diseases

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Lei Zhang ◽  
Qun Wang ◽  
Wen Liu ◽  
Fangyan Liu ◽  
Ailing Ji ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Lipid Metabolism ◽  
Nuclear Receptor ◽  
Metabolic Diseases ◽  
Early Response ◽  
Orphan Receptor ◽  
Special Focus ◽  
Orphan Nuclear Receptor ◽  
Physiological Functions ◽  
The Impact

Orphan nuclear receptor 4A1 (NR4A1) is a transcriptional factor of the nuclear orphan receptor (NR4A) superfamily that has sparked interest across different research fields in recent years. Several studies have demonstrated that ligand-independent NR4A1 is an immediate-early response gene and the protein product is rapidly induced by a variety of stimuli. Hyperfunction or dysfunction of NR4A1 is implicated in various metabolic processes, including carbohydrate metabolism, lipid metabolism, and energy balance, in major metabolic tissues, such as liver, skeletal muscle, pancreatic tissues, and adipose tissues. No endogenous ligands for NR4A1 have been identified, but numerous compounds that bind and activate or inactivate nuclear NR4A1 or induce cytoplasmic localization of NR4A1 have been identified. This review summarizes recent advances in our understanding of the molecular biology and physiological functions of NR4A1. And we focus on the physiological functions of NR4A1 receptor to the development of the metabolic diseases, with a special focus on the impact on carbohydrate and lipid metabolism in skeletal muscle, liver, adipose tissue, and islet.

scholarly journals Thiazolidine Diones, Specific Ligands of the Nuclear Receptor Retinoid Z Receptor/Retinoid Acid Receptor-related Orphan Receptor α with Potent Antiarthritic Activity

1996 ◽  
Vol 271 (23) ◽  
pp. 13515-13522 ◽  
Author(s):  
Martin Missbach ◽  
Bruno Jagher ◽  
Ivo Sigg ◽  
Sepideh Nayeri ◽  
Carsten Carlberg ◽  
...  
Keyword(s):  
Nuclear Receptor ◽  
Orphan Receptor ◽  
Acid Receptor ◽  
Retinoid Acid

scholarly journals Spermatogenesis and Testis Development Are Normal in Mice Lacking Testicular Orphan Nuclear Receptor 2

2002 ◽  
Vol 22 (13) ◽  
pp. 4661-4666 ◽  
Author(s):  
Chih-Rong Shyr ◽  
Loretta L. Collins ◽  
Xiao-Min Mu ◽  
Kenneth A. Platt ◽  
Chawnshang Chang
Keyword(s):  
Protein Expression ◽  
Nuclear Receptor ◽  
Expression Patterns ◽  
Orphan Receptor ◽  
Orphan Nuclear Receptor ◽  
Male Mice ◽  
Orphan Nuclear Receptors ◽  
Nuclear Receptor Superfamily ◽  
Testis Development

ABSTRACT Early in vitro cell culture studies suggested that testicular orphan nuclear receptor 2 (TR2), a member of the nuclear receptor superfamily, may play important roles in the control of several pathways including retinoic acids, vitamin D, thyroid hormones, and ciliary neurotrophic factor. Here we report the surprising results showing that mice lacking TR2 are viable and have no serious developmental defects. Male mice lacking TR2 have functional testes, including normal sperm number and motility, and both male and female mice lacking TR2 are fertile. In heterozygous TR2+/− male mice we found that β-galactosidase, the indicator of TR2 protein expression, was first detected at the age of 3 weeks and its expression pattern was restricted mainly in the spermatocytes and round spermatids. These protein expression patterns were further confirmed with Northern blot analysis of TR2 mRNA expression. Together, results from TR2-knockout mice suggest that TR2 may not play essential roles in spermatogenesis and normal testis development, function, and maintenance. Alternatively, the roles of TR2 may be redundant and could be played by other close members of the nuclear receptor superfamily such as testicular orphan receptor 4 (TR4) or unidentified orphan receptors that share many similar functions with TR2. Further studies with double knockouts of both orphan nuclear receptors, TR2 and TR4, may reveal their real physiological roles.

scholarly journals Orphan Nuclear Receptor RORα Regulates Enzymatic Metabolism of Cerebral 24S-Hydroxycholesterol through CYP39A1 Intronic Response Element Activation

2020 ◽  
Vol 21 (9) ◽  
pp. 3309
Author(s):  
Hiroshi Matsuoka ◽  
Miyu Katayama ◽  
Ami Ohishi ◽  
Kaoruko Miya ◽  
Riki Tokunaga ◽  
...  
Keyword(s):  
Nuclear Receptor ◽  
Cholesterol Homeostasis ◽  
Orphan Receptor ◽  
Hek293 Cells ◽  
Luciferase Reporter ◽  
Metabolic Enzyme ◽  
Orphan Nuclear Receptor ◽  
Human Hepatoma Cells ◽  
Mobility Shift ◽  
The Brain

Oxysterols, important regulators of cholesterol homeostasis in the brain, are affected by neurodegenerative diseases. Early-onset Alzheimer’s disease is associated with higher levels of circulating brain-derived 24S-hydroxycholesterol (24S-OHC). Conversion of cholesterol to 24S-OHC is mediated by cholesterol 24S-hydroxylase in the brain, which is the major pathway for oxysterol elimination, followed by oxidation through hepatic first-pass metabolism by CYP39A1. Abnormal CYP39A1 expression results in accumulation of 24S-OHC, influencing neurodegenerative disease-related deterioration; thus, it is important to understand the normal elimination of 24S-OHC and the system regulating CYP39A1, a selective hepatic metabolic enzyme of 24S-OHC. We examined the role of transcriptional regulation by retinoic acid receptor-related orphan receptor α (RORα), a nuclear receptor that responds to oxysterol ligands. In humans, the promoter and first intronic regions of CYP39A1 contain two putative RORα response elements (ROREs). RORα binding and responses of these ROREs were assessed using electrophoretic mobility shift, chromatin immunoprecipitation, and luciferase reporter assays. CYP39A1 was upregulated by RORα overexpression in HEK293 cells, while RORα knockdown by siRNA significantly downregulated CYP39A1 expression in human hepatoma cells. Additionally, CYP39A1 was induced by RORα agonist treatment, suggesting that CYP39A1 expression is activated by RORα nuclear receptors. This may provide a way to increase CYP39A1 activity using RORα agonists, and help halt 24S-OHC accumulation in neurodegenerative illnesses.

scholarly journals Loss of Orphan Receptor Germ Cell Nuclear Factor Function Results in Ectopic Development of the Tail Bud and a Novel Posterior Truncation

2001 ◽  
Vol 21 (2) ◽  
pp. 663-677 ◽  
Author(s):  
Arthur C.-K. Chung ◽  
Deborah Katz ◽  
Fred A. Pereira ◽  
Kathy J. Jackson ◽  
Francesco J. DeMayo ◽  
...  
Keyword(s):  
Germ Cell ◽  
Nuclear Receptor ◽  
Germ Line ◽  
Physiological Role ◽  
Orphan Receptor ◽  
Marker Genes ◽  
Nuclear Factor ◽  
Orphan Nuclear Receptor ◽  
Embryonic Survival ◽  
Germ Cell Nuclear Factor

ABSTRACT The dynamic embryonic expression of germ cell nuclear factor (GCNF), an orphan nuclear receptor, suggests that it may play an important role during early development. To determine the physiological role of GCNF, we have generated a targeted mutation of theGCNF gene in mice. Germ line mutation of theGCNF gene proves that the orphan nuclear receptor is essential for embryonic survival and normal development. GCNF−/− embryos cannot survive beyond 10.5 days postcoitum (dpc), probably due to cardiovascular failure. Prior to death, GCNF−/− embryos suffer significant defects in posterior development. Unlike GCNF+/+ embryos, GCNF−/− embryos do not turn and remain in a lordotic position, the majority of the neural tube remains open, and the hindgut fails to close. GCNF−/− embryos also suffer serious defects in trunk development, specifically in somitogenesis, which terminates by 8.75 dpc. The maximum number of somites in GCNF−/− embryos is 13 instead of 25 as in the GCNF+/+ embryos. Interestingly, the tailbud of GCNF−/− embryos develops ectopically outside the yolk sac. Indeed, alterations in expression of multiple marker genes were identified in the posterior of GCNF−/− embryos, including the primitive streak, the node, and the presomitic mesoderm. These results suggest that GCNF is required for maintenance of somitogenesis and posterior development and is essential for embryonic survival. These results suggest that GCNF regulates a novel and critical developmental pathway involved in normal anteroposterior development.

scholarly journals Nuclear Receptor DAX-1 Recruits Nuclear Receptor Corepressor N-CoR to Steroidogenic Factor 1

1998 ◽  
Vol 18 (5) ◽  
pp. 2949-2956 ◽  
Author(s):  
Peter A. Crawford ◽  
Christoph Dorn ◽  
Yoel Sadovsky ◽  
Jeffrey Milbrandt
Keyword(s):  
Nuclear Receptor ◽  
Orphan Receptor ◽  
Orphan Nuclear Receptor ◽  
Loss Of Function ◽  
Steroidogenic Factor 1 ◽  
Naturally Occurring ◽  
Nuclear Receptor Corepressor ◽  
Human Disorder ◽  
Adrenal Hypoplasia ◽  
Adapter Molecule

ABSTRACT The orphan nuclear receptor steroidogenic factor 1 (SF-1) is a critical developmental regulator in the urogenital ridge, because mice targeted for disruption of the SF-1 gene lack adrenal glands and gonads. SF-1 was recently shown to interact with DAX-1, another orphan receptor whose tissue distribution overlaps that of SF-1. Naturally occurring loss-of-function mutations of the DAX-1 gene cause the human disorder X-linked adrenal hypoplasia congenita (AHC), which resembles the phenotype of SF-1-deficient mice. Paradoxically, however, DAX-1 represses the transcriptional activity of SF-1, and AHC mutants of DAX-1 lose repression function. To further investigate these findings, we characterized the interaction between SF-1 and DAX-1 and found that their interaction indeed occurs through a repressive domain within the carboxy terminus of SF-1. Furthermore, we demonstrate that DAX-1 recruits the nuclear receptor corepressor N-CoR to SF-1, whereas naturally occurring AHC mutations of DAX-1 permit the SF-1–DAX-1 interaction, but markedly diminish corepressor recruitment. Finally, the interaction between DAX-1 and N-CoR shares similarities with that of the nuclear receptor RevErb and N-CoR, because the related corepressor SMRT was not efficiently recruited by DAX-1. Therefore, DAX-1 can serve as an adapter molecule that recruits nuclear receptor corepressors to DNA-bound nuclear receptors like SF-1, thereby extending the range of corepressor action.

scholarly journals The nuclear receptor PPARγ selectively inhibits Th17 differentiation in a T cell–intrinsic fashion and suppresses CNS autoimmunity

2009 ◽  
Vol 206 (10) ◽  
pp. 2079-2089 ◽  
Author(s):  
Luisa Klotz ◽  
Sven Burgdorf ◽  
Indra Dani ◽  
Kaoru Saijo ◽  
Juliane Flossdorf ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Autoimmune Diseases ◽  
Nuclear Receptor ◽  
Cd4 T Cells ◽  
Transforming Growth Factor ◽  
Physiological Role ◽  
Negative Regulator ◽  
Orphan Receptor ◽  
Th17 Differentiation

T helper cells secreting interleukin (IL)-17 (Th17 cells) play a crucial role in autoimmune diseases like multiple sclerosis (MS). Th17 differentiation, which is induced by a combination of transforming growth factor (TGF)-β/IL-6 or IL-21, requires expression of the transcription factor retinoic acid receptor–related orphan receptor γt (RORγt). We identify the nuclear receptor peroxisome proliferator–activated receptor γ (PPARγ) as a key negative regulator of human and mouse Th17 differentiation. PPARγ activation in CD4+ T cells selectively suppressed Th17 differentiation, but not differentiation into Th1, Th2, or regulatory T cells. Control of Th17 differentiation by PPARγ involved inhibition of TGF-β/IL-6–induced expression of RORγt in T cells. Pharmacologic activation of PPARγ prevented removal of the silencing mediator for retinoid and thyroid hormone receptors corepressor from the RORγt promoter in T cells, thus interfering with RORγt transcription. Both T cell–specific PPARγ knockout and endogenous ligand activation revealed the physiological role of PPARγ for continuous T cell–intrinsic control of Th17 differentiation and development of autoimmunity. Importantly, human CD4+ T cells from healthy controls and MS patients were strongly susceptible to PPARγ-mediated suppression of Th17 differentiation. In summary, we report a PPARγ-mediated T cell–intrinsic molecular mechanism that selectively controls Th17 differentiation in mice and in humans and that is amenable to pharmacologic modulation. We therefore propose that PPARγ represents a promising molecular target for specific immunointervention in Th17-mediated autoimmune diseases such as MS.

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