scholarly journals Peroxisome Proliferator-Activated Receptor Subtype- and Cell-Type-Specific Activation of Genomic Target Genes upon Adenoviral Transgene Delivery

2006 ◽  
Vol 26 (15) ◽  
pp. 5698-5714 ◽  
Author(s):  
Ronni Nielsen ◽  
Lars Grøntved ◽  
Hendrik G. Stunnenberg ◽  
Susanne Mandrup
Keyword(s):  
Target Genes ◽  
Receptor Subtype ◽  
Peroxisome Proliferator ◽  
Cell Type ◽  
Peroxisome Proliferator Activated Receptor ◽  
Molecular Events ◽  
Adenoviral Delivery ◽  
Cell Type Specific ◽  
Peroxisome Proliferator Activated Receptors ◽  
The Individual

ABSTRACT Investigations of the molecular events involved in activation of genomic target genes by peroxisome proliferator-activated receptors (PPARs) have been hampered by the inability to establish a clean on/off state of the receptor in living cells. Here we show that the combination of adenoviral delivery and chromatin immunoprecipitation (ChIP) is ideal for dissecting these mechanisms. Adenoviral delivery of PPARs leads to a rapid and synchronous expression of the PPAR subtypes, establishment of transcriptional active complexes at genomic loci, and immediate activation of even silent target genes. We demonstrate that PPARγ2 possesses considerable ligand-dependent as well as independent transactivation potential and that agonists increase the occupancy of PPARγ2/retinoid X receptor at PPAR response elements. Intriguingly, by direct comparison of the PPARs (α, γ, and β/δ), we show that the subtypes have very different abilities to gain access to target sites and that in general the genomic occupancy correlates with the ability to activate the corresponding target gene. In addition, the specificity and potency of activation by PPAR subtypes are highly dependent on the cell type. Thus, PPAR subtype-specific activation of genomic target genes involves an intricate interplay between the properties of the subtype- and cell-type-specific settings at the individual target loci.

scholarly journals Dysregulation of the Peroxisome Proliferator-Activated Receptor Target Genes by XPD Mutations

2005 ◽  
Vol 25 (14) ◽  
pp. 6065-6076 ◽  
Author(s):  
Emmanuel Compe ◽  
Pascal Drané ◽  
Camille Laurent ◽  
Karin Diderich ◽  
Cathy Braun ◽  
...  
Keyword(s):  
Target Genes ◽  
Genetic Disorders ◽  
Peroxisome Proliferator ◽  
Wild Type ◽  
Independent Manner ◽  
Peroxisome Proliferator Activated Receptor ◽  
Pol Ii ◽  
Knowing That ◽  
Peroxisome Proliferator Activated Receptors ◽  
Ppar Ligands

ABSTRACT Mutations in the XPD subunit of TFIIH give rise to human genetic disorders initially defined as DNA repair syndromes. Nevertheless, xeroderma pigmentosum (XP) group D (XP-D) patients develop clinical features such as hypoplasia of the adipose tissue, implying a putative transcriptional defect. Knowing that peroxisome proliferator-activated receptors (PPARs) are implicated in lipid metabolism, we investigated the expression of PPAR target genes in the adipose tissues and the livers of XPD-deficient mice and found that (i) some genes are abnormally overexpressed in a ligand-independent manner which parallels an increase in the recruitment of RNA polymerase (pol) II but not PPARs on their promoter and (ii) upon treatment with PPAR ligands, other genes are much less induced compared to the wild type, which is due to a lower recruitment of both PPARs and RNA pol II. The defect in transactivation by PPARs is likely attributable to their weaker phosphorylation by the cdk7 kinase of TFIIH. Having identified the phosphorylated residues in PPAR isotypes, we demonstrate how their transactivation defect in XPD-deficient cells can be circumvented by overexpression of either a wild-type XPD or a constitutively phosphorylated PPAR S/E. This work emphasizes that underphosphorylation of PPARs affects their transactivation and consequently the expression of PPAR target genes, thus contributing in part to the XP-D phenotype.

scholarly journals The Role of PPARs in Disease

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2367
Author(s):  
Nicole Wagner ◽  
Kay-Dietrich Wagner
Keyword(s):  
Target Genes ◽  
Peroxisome Proliferator ◽  
Downstream Target ◽  
Novel Approach ◽  
Pparγ Agonists ◽  
Cell Type Specific ◽  
Peroxisome Proliferator Activated Receptors ◽  
Specific Regulation ◽  
X Receptors

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that function as ligand-activated transcription factors. They exist in three isoforms: PPARα, PPARβ/δ, and PPARγ. For all PPARs, lipids are endogenous ligands, linking them directly to metabolism. PPARs form heterodimers with retinoic X receptors, and upon ligand binding, they modulate the gene expression of downstream target genes, depending on the presence of co-repressors or co-activators. This results in a complex, cell type-specific regulation of proliferation, differentiation, and cell survival. PPARs are linked to metabolic disorders and are interesting pharmaceutical targets. PPARα and PPARγ agonists are already in clinical use for the treatment of hyperlipidemia and type 2 diabetes, respectively. More recently, PPARβ/δ activation came into focus as an interesting novel approach for the treatment of metabolic syndrome and associated cardiovascular diseases; however, this has been limited due to the highly controversial function of PPARβ/δ in cancer. This Special Issue of Cells brings together the most recent advances in understanding the various aspects of the action of PPARs, and it provides new insights into our understanding of PPARs, implying also the latest therapeutic perspectives for the utility of PPAR modulation in different disease settings.

Nuclear receptors in disease: the oestrogen receptors

2004 ◽  
Vol 40 ◽  
pp. 157-167 ◽  
Author(s):  
Maria Nilsson ◽  
Karin Dahlman-Wright ◽  
Jan-Åke Gustafsson
Keyword(s):  
Nuclear Receptors ◽  
Target Genes ◽  
Receptor Subtype ◽  
Target Tissue ◽  
Oestrogen Receptors ◽  
Nucleotide Polymorphisms ◽  
Cell Type ◽  
Single Nucleotide ◽  
Beneficial Effects ◽  
The Family

For several decades, it has been known that oestrogens are essential for human health. The discovery that there are two oestrogen receptors (ERs), ERalpha and ERbeta, has facilitated our understanding of how the hormone exerts its physiological effects. The ERs belong to the family of ligand-activated nuclear receptors, which act by modulating the expression of target genes. Studies of ER-knockout (ERKO) mice have been instrumental in defining the relevance of a given receptor subtype in a certain tissue. Phenotypes displayed by ERKO mice suggest diseases in which dysfunctional ERs might be involved in aetiology and pathology. Association between single-nucleotide polymorphisms (SNPs) in ER genes and disease have been demonstrated in several cases. Selective ER modulators (SERMs), which are selective with regard to their effects in a certain cell type, already exist. Since oestrogen has effects in many tissues, the goal with a SERM is to provide beneficial effects in one target tissue while avoiding side effects in others. Refined SERMs will, in the future, provide improved therapeutic strategies for existing and novel indications.

scholarly journals New Target Genes for the Peroxisome Proliferator-Activated Receptor-γ(PPARγ) Antitumour Activity: Perspectives from the Insulin Receptor

PPAR Research ◽  
2009 ◽  
Vol 2009 ◽  
pp. 1-8 ◽  
Author(s):  
Daniela P. Foti ◽  
Francesco Paonessa ◽  
Eusebio Chiefari ◽  
Antonio Brunetti
Keyword(s):  
Insulin Receptor ◽  
Target Genes ◽  
Tumour Progression ◽  
Antitumour Activity ◽  
Peptide Hormone ◽  
Nuclear Hormone Receptor ◽  
Peroxisome Proliferator ◽  
Preclinical Research ◽  
Peroxisome Proliferator Activated Receptor ◽  
Wide Range

The insulin receptor (IR) plays a crucial role in mediating the metabolic and proliferative functions triggered by the peptide hormone insulin. There is considerable evidence that abnormalities in both IR expression and function may account for malignant transformation and tumour progression in some human neoplasias, including breast cancer. PPARγis a ligand-activated, nuclear hormone receptor implicated in many pleiotropic biological functions related to cell survival and proliferation. In the last decade, PPARγagonists—besides their known action and clinical use as insulin sensitizers—have proved to display a wide range of antineoplastic effects in cells and tissues expressing PPARγ, leading to intensive preclinical research in oncology. PPARγand activators affect tumours by different mechanisms, involving cell proliferation and differentiation, apoptosis, antiinflammatory, and antiangiogenic effects. We recently provided evidence that PPARγand agonists inhibit IR by non canonical, DNA-independent mechanisms affecting IR gene transcription. We conclude that IR may be considered a new PPARγ“target” gene, supporting a potential use of PPARγagonists as antiproliferative agents in selected neoplastic tissues that overexpress the IR.

scholarly journals PPARgene: A Database of Experimentally Verified and Computationally Predicted PPAR Target Genes

PPAR Research ◽  
2016 ◽  
Vol 2016 ◽  
pp. 1-6 ◽  
Author(s):  
Li Fang ◽  
Man Zhang ◽  
Yanhui Li ◽  
Yan Liu ◽  
Qinghua Cui ◽  
...  
Keyword(s):  
In Silico ◽  
Target Gene ◽  
Target Genes ◽  
Prediction Method ◽  
Peroxisome Proliferator ◽  
Physiological Processes ◽  
Peroxisome Proliferator Activated Receptors ◽  
High Throughput Gene Expression ◽  
Responsive Element ◽  
Target Gene Transcription

The peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors of the nuclear receptor superfamily. Upon ligand binding, PPARs activate target gene transcription and regulate a variety of important physiological processes such as lipid metabolism, inflammation, and wound healing. Here, we describe the first database of PPAR target genes, PPARgene. Among the 225 experimentally verified PPAR target genes, 83 are for PPARα, 83 are for PPARβ/δ, and 104 are for PPARγ. Detailed information including tissue types, species, and reference PubMed IDs was also provided. In addition, we developed a machine learning method to predict novel PPAR target genes by integratingin silicoPPAR-responsive element (PPRE) analysis with high throughput gene expression data. Fivefold cross validation showed that the performance of this prediction method was significantly improved compared to thein silicoPPRE analysis method. The prediction tool is also implemented in the PPARgene database.

Clofibrate causes an upregulation of PPAR-α target genes but does not alter expression of SREBP target genes in liver and adipose tissue of pigs

2007 ◽  
Vol 293 (1) ◽  
pp. R70-R77 ◽  
Author(s):  
Sebastian Luci ◽  
Beatrice Giemsa ◽  
Holger Kluge ◽  
Klaus Eder
Keyword(s):  
Adipose Tissue ◽  
Target Genes ◽  
Regulatory Element ◽  
Control Diet ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Cholesterol Homeostasis ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Hepatic Expression

This study investigated the effect of clofibrate treatment on expression of target genes of peroxisome proliferator-activated receptor (PPAR)-α and various genes of the lipid metabolism in liver and adipose tissue of pigs. An experiment with 18 pigs was performed in which pigs were fed either a control diet or the same diet supplemented with 5 g clofibrate/kg for 28 days. Pigs treated with clofibrate had heavier livers, moderately increased mRNA concentrations of various PPAR-α target genes in liver and adipose tissue, a higher concentration of 3-hydroxybutyrate, and markedly lower concentrations of triglycerides and cholesterol in plasma and lipoproteins than control pigs ( P < 0.05). mRNA concentrations of sterol regulatory element-binding proteins (SREBP)-1 and -2, insulin-induced genes ( Insig) -1 and Insig-2, and the SREBP target genes acetyl-CoA carboxylase, 3-methyl-3-hydroxyglutaryl-CoA reductase, and low-density lipoprotein receptor in liver and adipose tissue and mRNA concentrations of apolipoproteins A-I, A-II, and C-III in the liver were not different between both groups of pigs. In conclusion, this study shows that clofibrate treatment activates PPAR-α in liver and adipose tissue and has a strong hypotriglyceridemic and hypocholesterolemic effect in pigs. The finding that mRNA concentrations of some proteins responsible for the hypolipidemic action of fibrates in humans were not altered suggests that there were certain differences in the mode of action compared with humans. It is also shown that PPAR-α activation by clofibrate does not affect hepatic expression of SREBP target genes involved in synthesis of triglycerides and cholesterol homeostasis in liver and adipose tissue of pigs.

scholarly journals RNA-bound PGC-1α controls gene expression in liquid-like nuclear condensates

2020 ◽  
Author(s):  
Joaquín Pérez-Schindler ◽  
Bastian Kohl ◽  
Konstantin Schneider-Heieck ◽  
Volkan Adak ◽  
Julien Delezie ◽  
...  
Keyword(s):  
Target Genes ◽  
Rna Binding ◽  
Protein Complexes ◽  
Transcriptional Networks ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Central Function ◽  
Skeletal Muscle Wasting ◽  
Active Transcription ◽  
Transcriptional Coregulator

AbstractThe peroxisome-proliferator-activated receptor-γ coactivator-1α (PGC-1α) integrates environmental cues by controlling complex transcriptional networks in various metabolically active tissues. However, it is unclear how a transcriptional coregulator coordinates dynamic biological programs in response to multifaceted stimuli such as endurance training or fasting. Here, we discovered a central function of the poorly understood C-terminal domain (CTD) of PGC-1α to bind RNAs and assemble multi-protein complexes. Surprisingly, in addition to controlling the coupling of transcription and processing of target genes, RNA binding is indispensable for the recruitment of PGC-1α to chromatin into liquid-like nuclear condensates, which compartmentalize and regulate active transcription. These results demonstrate a hitherto unsuspected molecular mechanism by which complexity in the regulation of large transcriptional networks by PGC-1α is achieved. These findings are not only essential for the basic understanding of transcriptional coregulator-driven control of biological programs, but will also help to devise new strategies to modulate these processes in pathological contexts in which PGC-1α function is dysregulated, such as type 2 diabetes, cardiovascular diseases or skeletal muscle wasting.

scholarly journals Thioredoxin Binding Protein-2/Thioredoxin-Interacting Protein Is a Critical Regulator of Insulin Secretion and Peroxisome Proliferator-Activated Receptor Function

Endocrinology ◽  
2008 ◽  
Vol 150 (3) ◽  
pp. 1225-1234 ◽  
Author(s):  
Shin-ichi Oka ◽  
Eiji Yoshihara ◽  
Akiko Bizen-Abe ◽  
Wenrui Liu ◽  
Mutsumi Watanabe ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Target Genes ◽  
Binding Protein ◽  
Dynamic Change ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Interacting Protein ◽  
Thioredoxin Interacting Protein ◽  
Nutritional Transition ◽  
Coordinated Regulation

The feeding-fasting nutritional transition triggers a dynamic change in metabolic pathways and is a model for understanding how these pathways are mutually organized. The targeted disruption of the thioredoxin binding protein-2 (TBP-2)/thioredoxin-interacting protein (Txnip)/VDUP1 gene in mice results in lethality with hypertriglyceridemia and hypoglycemia during fasting. To investigate the molecular mechanism of the nutritional transition and the role of TBP-2, microarray analyses were performed using the liver of TBP-2−/− mice in the fed and fasted states. We found that the fasting-induced reduction in the expression of lipogenic genes targeted by insulin (SREBP-1), such as FASN and THRSP, was abolished in TBP-2−/− mice, and the expression of lipoprotein lipase is down-regulated, which was consistent with the lipoprotein profile. TBP-2−/− mice also exhibited enhanced glucose-induced insulin secretion and sensitivity. Another feature of the hepatic gene expression in fed TBP-2−/− mice was the augmented expression of peroxisome proliferator activated receptor (PPAR) target genes, such as CD36, FABP2, ACOT1, and FGF21, to regulate fatty acid consumption. In TBP-2−/− mice, PPARα expression was elevated in the fed state, whereas the fasting-induced up-regulation of PPARα was attenuated. We also detected an increased expression of PPARγ coactivator-1α protein in fed TBP-2−/− mice. TBP-2 overexpression significantly inhibited PPARα-mediated transcriptional activity induced by a specific PPARα ligand in vitro. These results suggest that TBP-2 is a key regulator of PPARα expression and signaling, and coordinated regulation of PPARα and insulin secretion by TBP-2 is crucial in the feeding-fasting nutritional transition. TBP-2/Txnip is a key regulator of PPARα expression and signaling, and coordinated regulation of PPARα and insulin secretion by TBP-2/Txnip is crucial in fasting response.

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