scholarly journals A Retrospective on Nuclear Receptor Regulation of Inflammation: Lessons from GR and PPARs

PPAR Research ◽  
2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
Author(s):  
Min-Dian Li ◽  
Xiaoyong Yang
Keyword(s):  
Glucocorticoid Receptor ◽  
Signaling Pathways ◽  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Receptor Regulation ◽  
Peroxisome Proliferator ◽  
Novel Therapies ◽  
Nuclear Receptor Superfamily ◽  
Founding Member ◽  
Peroxisome Proliferator Activated Receptors

Members of the nuclear receptor superfamily have vital roles in regulating immunity and inflammation. The founding member, glucocorticoid receptor (GR), is the prototype to demonstrate immunomodulation via transrepression of the AP-1 and NF-κB signaling pathways. Peroxisome proliferator-activated receptors (PPARs) have emerged as key regulators of inflammation. This review examines the history and current advances in nuclear receptor regulation of inflammation by the crosstalk with AP-1 and NF-κB signaling, focusing on the roles of GR and PPARs. A better understanding of the molecular mechanism by which nuclear receptors inhibit proinflammatory signaling pathways will enable novel therapies to treat chronic inflammation.

scholarly journals The Nuclear Receptor-Coactivator Interaction Surface as a Target for Peptide Antagonists of the Peroxisome Proliferator-Activated Receptors

2007 ◽  
Vol 21 (10) ◽  
pp. 2361-2377 ◽  
Author(s):  
Niharika B. Mettu ◽  
Thomas B. Stanley ◽  
Mary A. Dwyer ◽  
Michelle S. Jansen ◽  
John E. Allen ◽  
...  
Keyword(s):  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Target Genes ◽  
Binding Motif ◽  
Peroxisome Proliferator ◽  
Constitutive Activity ◽  
Phage Display Technology ◽  
Nuclear Receptor Coactivator ◽  
Peroxisome Proliferator Activated Receptors ◽  
Interaction Surface

Abstract The peroxisome proliferator-activated receptors (PPARα, PPARδ, and PPARγ) constitute a family of nuclear receptors that regulates metabolic processes involved in lipid and glucose homeostasis. Although generally considered to function as ligand-regulated receptors, all three PPARs exhibit a high level of constitutive activity that may result from their stimulation by intracellularly produced endogenous ligands. Consequently, complete inhibition of PPAR signaling requires the development of inverse agonists. However, the currently available small molecule antagonists for the PPARs function only as partial agonists, or their efficacy is not sufficient to inhibit the constitutive activity of these receptors. Due to the lack of efficacious antagonists that interact with the ligand-binding domain of the PPARs, we decided to target an interaction that is central to nuclear receptor-mediated gene transcription: the nuclear receptor-coactivator interaction. We utilized phage display technology to identify short LXXLL-containing peptides that bind to the PPARs. Analysis of these peptides revealed a consensus binding motif consisting of HPLLXXLL. Cross-screening of these peptides for binding to other nuclear receptors enabled the identification of a high-affinity PPAR-selective peptide that has the ability to repress PPARγ1-dependent transcription of transfected reporter genes. Most importantly, when introduced into HepG2 cells, the peptide inhibited the expression of endogenous PPARγ1 target genes, adipose differentiation-related protein and mitochondrial 3-hydroxy-3-methylglutaryl coenzyme A synthase 2. This work lends support for the rational development of peptidomimetics that block receptor-mediated transcription by targeting the nuclear receptor-coactivator interaction surface.

scholarly journals PPAR-δin Vascular Pathophysiology

PPAR Research ◽  
2008 ◽  
Vol 2008 ◽  
pp. 1-10 ◽  
Author(s):  
Nanping Wang
Keyword(s):  
Transcription Factors ◽  
Cell Growth ◽  
Glucose Metabolism ◽  
Nuclear Receptor ◽  
Therapeutic Intervention ◽  
Peroxisome Proliferator ◽  
Cardiovascular Disorders ◽  
Direct Effects ◽  
Cell Growth And Differentiation ◽  
Peroxisome Proliferator Activated Receptors

Peroxisome proliferator-activated receptors belong to the superfamily of ligand-dependent nuclear receptor transcription factors, which include three subtypes: PPAR-α,β/δ, andγ. PPAR-δ, play important roles in the regulation of cell growth and differentiation as well as tissue wound and repair. Emerging evidence has also demonstrated that PPAR-δis implicated in lipids and glucose metabolism. Most recently, the direct effects of PPAR-δon cardiovascular processes such as endothelial function and angiogenesis have also been investigated. Therefore, it is suggested that PPAR-δmay have critical roles in cardiovascular pathophysiology and is a potential target for therapeutic intervention of cardiovascular disorders such as atherosclerosis.

scholarly journals Cannabinoids: A New Group of Agonists of PPARs

PPAR Research ◽  
2007 ◽  
Vol 2007 ◽  
pp. 1-7 ◽  
Author(s):  
Yan Sun ◽  
Andy Bennett
Keyword(s):  
Cannabinoid Receptor ◽  
Peroxisome Proliferator ◽  
Cannabinoid Receptor 1 ◽  
Nuclear Receptor Superfamily ◽  
Psychotropic Effects ◽  
Inflammatory Drugs ◽  
Peroxisome Proliferator Activated Receptors ◽  
New Compounds ◽  
G Protein Coupled ◽  
Recreational Use

Cannabinoids have been used medicinally and recreationally for thousands of years and their effects were proposed to occur mainly via activation of the G-protein-coupled receptorCB1/CB2(cannabinoid receptor 1/2). Discovery of potent synthetic analogs of the natural cannabinoids as clinically useful drugs is the sustained aim of cannabinoid research. This demands that these new compounds be free of the psychotropic effects that connected with the recreational use of cannabinoids. In preclinical studies cannabinoids displayed many of the characteristics of nonsteroidal anti-inflammatory drugs (NSAIDs) and it seems to be free of unwanted side effects. An increasing number of therapeutic actions of cannabinoid are being reported that do not appear to be mediated by eitherCB1orCB2, and recently nuclear receptor superfamily PPARs (peroxisome-proliferator-activated receptors) have been suggested as the target of certain cannabinoids. This review summarizes the evidence for cannabinoid activation on PPARs and possible associated remedial potentials.

scholarly journals PPARs in Calorie Restricted and Genetically Long-Lived Mice

PPAR Research ◽  
2007 ◽  
Vol 2007 ◽  
pp. 1-7 ◽  
Author(s):  
Michal M. Masternak ◽  
Andrzej Bartke
Keyword(s):  
Transcription Factors ◽  
Energy Metabolism ◽  
Nuclear Receptors ◽  
Calorie Restriction ◽  
Insulin Action ◽  
Peroxisome Proliferator ◽  
Physiological Functions ◽  
Multiple Organs ◽  
Longevity Genes ◽  
Peroxisome Proliferator Activated Receptors

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptors superfamily. The three subtypes, PPARα, PPARγ, and PPARβ/δ, are expressed in multiple organs. These transcription factors regulate different physiological functions such as energy metabolism (including lipid and carbohydrate metabolism), insulin action, and immunity and inflammation, and apparently also act as important mediators of longevity and aging. Calorie restriction (CR) is the most effective intervention known to delay aging and increase lifespan. Calorie restriction affects the same physiological functions as PPARs. This review summarizes recent findings on the effects of CR and aging on the expression of PPARγ,α, andβ/δin mice and discusses possible involvement of PPARs in mediating the effects of murine longevity genes. The levels of PPARs change with age and CR appears to prevent these alterations which make “PPARs-CR-AGING” dependence of considerable interest.

scholarly journals Hormone receptor 4 is required in muscles and distinct ovarian cell types to regulate specific steps of Drosophila oogenesis

Development ◽  
2021 ◽  
pp. dev.198663
Author(s):  
Lesley N. Weaver ◽  
Daniela Drummond-Barbosa
Keyword(s):  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Hormone Receptor ◽  
Cell Types ◽  
Germline Stem Cell ◽  
Follicle Growth ◽  
Peripheral Tissues ◽  
Ovarian Cell ◽  
Nuclear Receptor Superfamily ◽  
Germline Cyst

The conserved nuclear receptor superfamily has critical roles in many processes, including reproduction. Nuclear receptors with known roles in oogenesis have been studied mostly in the context of their ovary-intrinsic requirement. Recent studies in Drosophila, however, have begun to reveal new roles of nuclear receptor signaling in peripheral tissues in controlling reproduction. Here, we identified Hormone receptor 4 (Hr4) as an oogenesis regulator required in the ovary and muscles. Global Hr4 knockdown leads to increased germline stem cell (GSC) loss, reduced GSC proliferation, early germline cyst death, slowed follicle growth, and vitellogenic follicle degeneration. Tissue-specific knockdown experiments uncovered ovary-intrinsic and peripheral tissue requirements for Hr4. In the ovary, Hr4 is required in the niche for GSC proliferation and in the germline for GSC maintenance. Hr4 functions in muscles to promote GSC maintenance and follicle growth. The specific tissues that require Hr4 for survival of early germline cysts and vitellogenic follicles remain unidentified. These results add to the few examples of muscles controlling gametogenesis and expand our understanding of the complexity of nuclear receptor regulation of various aspects of oogenesis.

scholarly journals Nuclear Receptors as Autophagy-Based Antimicrobial Therapeutics

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 1979
Author(s):  
Prashanta Silwal ◽  
Seungwha Paik ◽  
Sang Min Jeon ◽  
Eun-Kyeong Jo
Keyword(s):  
Retinoic Acid ◽  
Nuclear Receptors ◽  
Hormone Receptors ◽  
Emerging Infectious Diseases ◽  
Peroxisome Proliferator ◽  
Vitamin D Receptors ◽  
Gene Sets ◽  
Intracellular Process ◽  
Peroxisome Proliferator Activated Receptors ◽  
X Receptors

Autophagy is an intracellular process that targets intracellular pathogens for lysosomal degradation. Autophagy is tightly controlled at transcriptional and post-translational levels. Nuclear receptors (NRs) are a family of transcriptional factors that regulate the expression of gene sets involved in, for example, metabolic and immune homeostasis. Several NRs show promise as host-directed anti-infectives through the modulation of autophagy activities by their natural ligands or small molecules (agonists/antagonists). Here, we review the roles and mechanisms of NRs (vitamin D receptors, estrogen receptors, estrogen-related receptors, and peroxisome proliferator-activated receptors) in linking immunity and autophagy during infection. We also discuss the potential of emerging NRs (REV-ERBs, retinoic acid receptors, retinoic acid-related orphan receptors, liver X receptors, farnesoid X receptors, and thyroid hormone receptors) as candidate antimicrobials. The identification of novel roles and mechanisms for NRs will enable the development of autophagy-adjunctive therapeutics for emerging and re-emerging infectious diseases.

scholarly journals Alteration of a Single Amino Acid in Peroxisome Proliferator-Activated Receptor-α (PPARα) Generates a PPARδ Phenotype

2000 ◽  
Vol 14 (5) ◽  
pp. 733-740 ◽  
Author(s):  
Ichiro Takada ◽  
Ruth T. Yu ◽  
H. Eric Xu ◽  
Millard H. Lambert ◽  
Valerie G. Montana ◽  
...  
Keyword(s):  
Amino Acid ◽  
Nuclear Receptors ◽  
Site Directed Mutagenesis ◽  
Single Amino Acid ◽  
Peroxisome Proliferator ◽  
Transcriptional Responses ◽  
Peroxisome Proliferator Activated Receptor ◽  
Single Amino Acid Change ◽  
Close Relationship ◽  
Peroxisome Proliferator Activated Receptors

Abstract Three pharmacologically important nuclear receptors, the peroxisome proliferator-activated receptors (PPARs α,γ , and δ), mediate key transcriptional responses involved in lipid homeostasis. The PPARα and γ subtypes are well conserved from Xenopus to man, but the β/δ subtypes display substantial species variations in both structure and ligand activation profiles. Characterization of the avian cognates revealed a close relationship between chick (c) α and γ subtypes to their mammalian counterparts, whereas the third chicken subtype was intermediate to Xenopus (x) β and mammalian δ, establishing that β and δ are orthologs. Like xPPARβ, cPPARβ responded efficiently to hypolipidemic compounds that fail to activate the human counterpart. This provided the opportunity to address the pharmacological problem as to how drug selectivity is achieved and the more global evolutionary question as to the minimal changes needed to generate a new class of receptor. X-ray crystallography and chimeric analyses combined with site-directed mutagenesis of avian and mammalian cognates revealed that a Met to Val change at residue 417 was sufficient to switch the human and chick phenotype. These results establish that the genetic drive to evolve a novel and functionally selectable receptor can be modulated by a single amino acid change and suggest how nuclear receptors can accommodate natural variation in species physiology.

scholarly journals Coregulator Function: A Key to Understanding Tissue Specificity of Selective Receptor Modulators

2004 ◽  
Vol 25 (1) ◽  
pp. 45-71 ◽  
Author(s):  
Carolyn L. Smith ◽  
Bert W. O’Malley
Keyword(s):  
Estrogen Receptor ◽  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Critical Role ◽  
Dependent Manner ◽  
Nuclear Receptor Superfamily ◽  
Binding Domains ◽  
Receptor Modulator ◽  
Cellular Environment ◽  
Receptor Modulators

Ligands for the nuclear receptor superfamily control many aspects of biology, including development, reproduction, and homeostasis, through regulation of the transcriptional activity of their cognate receptors. Selective receptor modulators (SRMs) are receptor ligands that exhibit agonistic or antagonistic biocharacter in a cell- and tissue context-dependent manner. The prototypical SRM is tamoxifen, which as a selective estrogen receptor modulator, can activate or inhibit estrogen receptor action. SRM-induced alterations in the conformation of the ligand-binding domains of nuclear receptors influence their abilities to interact with other proteins, such as coactivators and corepressors. It has been postulated, therefore, that the relative balance of coactivator and corepressor expression within a given target cell determines the relative agonist vs. antagonist activity of SRMs. However, recent evidence reveals that the cellular environment also plays a critical role in determining SRM biocharacter. Cellular signaling influences the activity and subcellular localization of coactivators and corepressors as well as nuclear receptors, and this contributes to gene-, cell-, and tissue-specific responses to SRM ligands. Increased understanding of the effect of cellular environment on nuclear receptors and their coregulators has the potential to open the field of SRM discovery and research to many members of the nuclear receptor superfamily.

scholarly journals Mitochondria, PPARs, and Cancer: Is Receptor-Independent Action of PPAR Agonists a Key?

PPAR Research ◽  
2008 ◽  
Vol 2008 ◽  
pp. 1-10 ◽  
Author(s):  
Roberto Scatena ◽  
Patrizia Bottoni ◽  
Bruno Giardina
Keyword(s):  
Cell Differentiation ◽  
Side Effects ◽  
Nuclear Receptors ◽  
Cancer Biology ◽  
Experimental Models ◽  
Peroxisome Proliferator ◽  
Ppar Agonists ◽  
Peroxisome Proliferator Activated Receptors ◽  
Reciprocal Influences ◽  
Ppar Ligands

Before the discovery of peroxisome proliferator activated receptors (PPARs), it was well known that certain drugs considered as classical PPAR-alpha agonists induced hepatocarcinoma or peroxisome proliferation in rodents. These drugs were derivatives of fibric acid, and they included clofibrate, bezafibrate, and fenofibrate. However, such toxicity has never been observed in human patients treated with these hypolipidemic drugs. Thiazolidinediones are a new class of PPAR activators showing greater specificity for the isoform of PPARs. These drugs are used as insulin sensitizers in the treatment of type II diabetes. In addition, they have been shown to induce cell differentiation or apoptosis in various experimental models of cancer. PPAR- ligands have also been shown to induce cancer cell differentiation and, paradoxically, PPAR- drug activators have been reported to act as carcinogens. The confusing picture that emerges from these data is further complicated by the series of intriguing side effects observed following administration of pharmacological PPAR ligands (rhabdomyolysis, liver and heart toxicity, anemia, leucopenia). These side effects cannot be easily explained by simple interactions between the drug and nuclear receptors. Rather, these side effects seem to indicate that the ligands have biological activity independent of the nuclear receptors. Considering the emerging role of mitochondria in cancer and the potential metabolic connections between this organelle and PPAR physiology, characterization of the reciprocal influences is fundamental not only for a better understanding of cancer biology, but also for more defined pharmacotoxicological profiles of drugs that modulate PPARs.

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