scholarly journals Nuclear Hormone Receptor NHR-49 controls a HIF-1-independent hypoxia adaptation pathway inCaenorhabditis elegans

2021 ◽  
Author(s):  
Kelsie R. S. Doering ◽  
Xuanjin Cheng ◽  
Luke Milburn ◽  
Ramesh Ratnappan ◽  
Arjumand Ghazi ◽  
...  
Keyword(s):  
Hormone Receptor ◽  
Hypoxia Inducible Factor ◽  
Nuclear Hormone Receptor ◽  
Negative Regulator ◽  
Peroxisome Proliferator ◽  
Rna Seq ◽  
Peroxisome Proliferator Activated Receptor ◽  
Interacting Protein ◽  
Hypoxia Response ◽  
Synthetic Lethal

AbstractThe response to insufficient oxygen (hypoxia) is orchestrated by the conserved Hypoxia-Inducible Factor (HIF). However, HIF-independent hypoxia response pathways exist that act in parallel to HIF to mediate the physiological hypoxia response. Here, we describe a HIF-independent hypoxia response pathway controlled byCaenorhabditis elegansNuclear Hormone Receptor NHR-49, an orthologue of mammalian Peroxisome Proliferator-Activated Receptor alpha (PPARα). We show thatnhr-49is required for worm survival in hypoxia and is synthetic lethal withhif-1in this context, demonstrating that these factors act independently. RNA-seq analysis shows that in hypoxianhr-49regulates a set of genes that arehif-1-independent, including autophagy genes that promote hypoxia survival. We further show that Nuclear Hormone Receptornhr-67is a negative regulator and Homeodomain-interacting Protein Kinasehpk-1is a positive regulator of the NHR-49 pathway. Together, our experiments define a new, essential hypoxia response pathway that acts in parallel to the well-known HIF-mediated hypoxia response.

scholarly journals Temporal Recruitment of Transcription Factors and SWI/SNF Chromatin-Remodeling Enzymes during Adipogenic Induction of the Peroxisome Proliferator-Activated Receptor γ Nuclear Hormone Receptor

2004 ◽  
Vol 24 (11) ◽  
pp. 4651-4663 ◽  
Author(s):  
Nunciada Salma ◽  
Hengyi Xiao ◽  
Elisabetta Mueller ◽  
Anthony N. Imbalzano
Keyword(s):  
Transcription Factors ◽  
Chromatin Remodeling ◽  
Hormone Receptor ◽  
Complex Function ◽  
Nuclear Hormone Receptor ◽  
Dominant Negative ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Pol Ii ◽  
Histone Hyperacetylation

ABSTRACT The peroxisome proliferator-activated receptor gamma (PPARγ) regulates adipogenesis, lipid metabolism, and glucose homeostasis, and roles have emerged for this receptor in the pathogenesis and treatment of diabetes, atherosclerosis, and cancer. We report here that induction of the PPARγ activator and adipogenesis forced by overexpression of adipogenic regulatory proteins is blocked upon expression of dominant-negative BRG1 or hBRM, the ATPase subunits of distinct SWI/SNF chromatin-remodeling enzymes. We demonstrate that histone hyperacetylation and the binding of C/EBP activators, polymerase II (Pol II), and general transcription factors (GTFs) initially occurred at the inducible PPARγ2 promoter in the absence of SWI/SNF function. However, the polymerase and GTFs were subsequently lost from the promoter in cells expressing dominant-negative SWI/SNF, explaining the inhibition of PPARγ2 expression. To corroborate these data, we analyzed interactions at the PPARγ2 promoter in differentiating preadipocytes. Changes in promoter structure, histone hyperacetylation, and binding of C/EBP activators, Pol II, and most GTFs preceded the interaction of SWI/SNF enzymes with the PPARγ2 promoter. However, transcription of the PPARγ2 gene occurred only upon subsequent association of SWI/SNF and TFIIH with the promoter. Thus, induction of the PPARγ nuclear hormone receptor during adipogenesis requires SWI/SNF enzymes to facilitate preinitiation complex function.

scholarly journals The Nuclear Hormone Receptor Peroxisome Proliferator-Activated Receptor β/δ Potentiates Cell Chemotactism, Polarization, and Migration

2007 ◽  
Vol 27 (20) ◽  
pp. 7161-7175 ◽  
Author(s):  
Nguan Soon Tan ◽  
Guillaume Icre ◽  
Alexandra Montagner ◽  
Béatrice Bordier-ten Heggeler ◽  
Walter Wahli ◽  
...  
Keyword(s):  
Cell Migration ◽  
Hormone Receptor ◽  
Hormone Receptors ◽  
Rho Gtpase ◽  
Three Dimensional ◽  
Nuclear Hormone Receptor ◽  
Peroxisome Proliferator ◽  
Strong Impact ◽  
Peroxisome Proliferator Activated Receptor

ABSTRACT After an injury, keratinocytes acquire the plasticity necessary for the reepithelialization of the wound. Here, we identify a novel pathway by which a nuclear hormone receptor, until now better known for its metabolic functions, potentiates cell migration. We show that peroxisome proliferator-activated receptor β/δ (PPARβ/δ) enhances two phosphatidylinositol 3-kinase-dependent pathways, namely, the Akt and the Rho-GTPase pathways. This PPARβ/δ activity amplifies the response of keratinocytes to a chemotactic signal, promotes integrin recycling and remodeling of the actin cytoskeleton, and thereby favors cell migration. Using three-dimensional wound reconstructions, we demonstrate that these defects have a strong impact on in vivo skin healing, since PPARβ/δ−/− mice show an unexpected and rare epithelialization phenotype. Our findings demonstrate that nuclear hormone receptors not only regulate intercellular communication at the organism level but also participate in cell responses to a chemotactic signal. The implications of our findings may be far-reaching, considering that the mechanisms described here are important in many physiological and pathological situations.

scholarly journals The Nuclear Hormone Receptor PPARγas a Therapeutic Target in Major Diseases

2010 ◽  
Vol 10 ◽  
pp. 2181-2197 ◽  
Author(s):  
Martina Victoria Schmidt ◽  
Bernhard Brüne ◽  
Andreas von Knethen
Keyword(s):  
Therapeutic Target ◽  
Hormone Receptor ◽  
Target Genes ◽  
Inflammatory Responses ◽  
Nuclear Hormone Receptor ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Insulin Sensitizers

The peroxisome proliferator-activated receptor γ (PPARγ) belongs to the nuclear hormone receptor superfamily and regulates gene expression upon heterodimerization with the retinoid X receptor by ligating to peroxisome proliferator response elements (PPREs) in the promoter region of target genes. Originally, PPARγwas identified as being essential for glucose metabolism. Thus, synthetic PPARγagonists, the thiazolidinediones (TZDs), are used in type 2 diabetes therapy as insulin sensitizers. More recent evidence implied an important role for the nuclear hormone receptor PPARγin controlling various diseases based on its anti-inflammatory, cell cycle arresting, and proapoptotic properties. In this regard, expression of PPARγis not restricted to adipocytes, but is also found in immune cells, such as B and T lymphocytes, monocytes, macrophages, dendritic cells, and granulocytes. The expression of PPARγin lymphoid organs and its modulation of macrophage inflammatory responses, lymphocyte proliferation, cytokine production, and apoptosis underscore its immune regulating functions. Moreover, PPARγexpression is found in tumor cells, where its activation facilitates antitumorigenic actions. This review provides an overview about the role of PPARγas a possible therapeutic target approaching major, severe diseases, such as sepsis, cancer, and atherosclerosis.

scholarly journals CITED2 Restrains Proinflammatory Macrophage Activation and Response

2017 ◽  
Vol 38 (5) ◽  
Author(s):  
Gun-Dong Kim ◽  
Riku Das ◽  
Xiaoquan Rao ◽  
Jixin Zhong ◽  
Jeffrey A. Deiuliis ◽  
...  
Keyword(s):  
Gene Expression ◽  
Target Gene ◽  
Hypoxia Inducible Factor ◽  
Myeloid Cell ◽  
Negative Regulator ◽  
Peroxisome Proliferator ◽  
Gene Promoters ◽  
Loss Of Function ◽  
Peroxisome Proliferator Activated Receptor ◽  
Anti Inflammatory

ABSTRACT Macrophages are strategically distributed in mammalian tissues and play an essential role in priming the immune response. However, macrophages need to constantly strike a balance between activation and inhibition states to avoid a futile inflammatory reaction. Here, we identify the CBP/p300-interacting transactivator with glutamic acid/aspartic acid-rich carboxyl-terminal domain 2 (CITED2) as a potent repressor of macrophage proinflammatory activation. Gain- and loss-of-function studies revealed that CITED2 is required for optimal peroxisome proliferator-activated receptor gamma (PPARγ) activation and attendant select anti-inflammatory gene expression in macrophages. More importantly, deficiency of CITED2 resulted in significant attenuation of rosiglitazone-induced PPARγ activity, PPARγ recruitment to target gene promoters, and anti-inflammatory target gene expression in macrophages. Interestingly, deficiency of Cited2 strikingly heightened proinflammatory gene expression through stabilization of hypoxia-inducible factor 1 alpha (HIF1α) protein in macrophages. Further, overexpression of Egln3 or inhibition of HIF1α in Cited2 -deficient macrophages completely reversed elevated proinflammatory cytokine/chemokine gene expression. Importantly, mice bearing a myeloid cell-specific deletion of Cited2 were highly susceptible to endotoxin-induced sepsis symptomatology and mortality. Collectively, our observations identify CITED2 as a novel negative regulator of macrophage proinflammatory activation that protects the host from inflammatory insults.

scholarly journals Research Resource: Nuclear Hormone Receptor Expression in the Endocrine Pancreas

2008 ◽  
Vol 22 (10) ◽  
pp. 2353-2363 ◽  
Author(s):  
Jen-Chieh Chuang ◽  
Ji-Young Cha ◽  
James C. Garmey ◽  
Raghavendra G. Mirmira ◽  
Joyce J. Joyce J.
Keyword(s):  
Cell Lines ◽  
Hormone Receptor ◽  
Endocrine Pancreas ◽  
Nuclear Hormone Receptor ◽  
Receptor Expression ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Β Cells ◽  
Β Cell ◽  
Peroxisome Proliferator Activated Receptor

Abstract The endocrine pancreas comprises the islets of Langerhans, tiny clusters of cells that contribute only about 2% to the total pancreas mass. However, this little endocrine organ plays a critical role in maintaining glucose homeostasis by the regulated secretion of insulin (by β-cells) and glucagon (by α-cells). The rapid increase in the incidence of diabetes worldwide has spurred renewed interest in islet cell biology. Some of the most widely prescribed oral drugs for treating type 2 diabetes include agents that bind and activate the nuclear hormone receptor, peroxisome proliferator-activated receptor-γ. As a first step in addressing potential roles of peroxisome proliferator-activated receptor-γ and other nuclear hormone receptors (NHRs) in the biology of the endocrine pancreas, we have used quantitative real-time PCR to profile the expression of all 49 members of the mouse NHR superfamily in primary islets, and cell lines that represent α-cells (αTC1) and β-cells (βTC6 and MIN6). In summary, 19 NHR members were highly expressed in both α- and β-cell lines, 13 receptors showed predominant expression (at least an 8-fold difference) in α- vs. β-cell lines, and 10 NHRs were not expressed in the endocrine pancreas. In addition we evaluated the relative expression of these transcription factors during hyperglycemia and found that 16 NHRs showed significantly altered mRNA levels in mouse islets. A similar survey was conducted in primary human islets to reveal several significant differences in NHR expression between mouse and man. These data identify potential therapeutic targets in the endocrine pancreas for the treatment of diabetes mellitus.

Activation of nuclear hormone receptor peroxisome proliferator–activated receptor-δ accelerates intestinal adenoma growth

10.1038/nm993 ◽  
2004 ◽  
Vol 10 (3) ◽  
pp. 245-247 ◽  
Author(s):  
Rajnish A Gupta ◽  
Dingzhi Wang ◽  
Sharada Katkuri ◽  
Haibin Wang ◽  
Sudhansu K Dey ◽  
...  
Keyword(s):  
Hormone Receptor ◽  
Nuclear Hormone Receptor ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Intestinal Adenoma

scholarly journals A role for the peroxisome proliferator-activated receptor α in T-cell physiology and ageing immunobiology

2002 ◽  
Vol 61 (3) ◽  
pp. 363-369 ◽  
Author(s):  
Dallas C. Jones ◽  
Bernadette M. Manning ◽  
Raymond A. Daynes
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Hormone Receptor ◽  
Interleukin 2 ◽  
Interferon Γ ◽  
Nuclear Hormone Receptor ◽  
Cell Physiology ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Enhanced Production

Peroxisome proliferator-activated receptor (PPAR) α represents an important member of the nuclear hormone receptor superfamily that can be activated by a variety of natural fatty acids, some of their metabolites and by commonly-used anti-lipidaemic drugs. We recently demonstrated PPARα expression in T lymphocytes, where it controls the initiation of transcription of T-box expressed in T-cells (T-bet) independent of added agonist. T-bet is an activation-inducible transcription factor regulator of interleukin 2 (suppression) and interferon γ (stimulation) synthesis. A suppressed ability to produce interleukin 2 and an enhanced production of interferon γ occurs in activated T-cells from PPARα-/- mice, as well as in T-cells from wild-type aged animals whose lymphocytes express lowered basal levels of PPARα. The dysregulated expression and/or function of cytokines, glucocorticoids or leptin that occurs with advanced age could all be responsible for the reduced expression of PPARα. Dietary supplementation of aged mice with vitamin E, or supplementation with known agonists of PPARα, was associated with elevation of lymphocyte expression of this nuclear hormone receptor, restoration of control over T-bet expression and elimination of the dysregulated production of interleukin 2 and interferon γ following lymphocyte activation. Interleukin 2 and interferon γ play very important roles in the initiation and/or regulation of immune, inflammatory and autoimmune disease states. Thus, the mechanisms that control the timing, magnitude and duration of specific cytokine production by activated T lymphocytes need clarification before appropriate nutritional or therapeutic strategies can be devised to treat disease conditions where cytokine expression and/or activities are deemed to be dysregulated and responsible.

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