The DLK gene is a transcriptional target of PPARγ

2011 ◽  
Vol 438 (1) ◽  
pp. 93-101 ◽  
Author(s):  
Jean-Philippe Couture ◽  
Richard Blouin
Keyword(s):  
Transcriptional Activation ◽  
Binding Sites ◽  
Leucine Zipper ◽  
Transcriptional Start Site ◽  
Peroxisome Proliferator ◽  
Mobility Shift ◽  
Peroxisome Proliferator Activated Receptor ◽  
Bioinformatic Tools ◽  
Pparγ Agonist ◽  
Transcriptional Target

DLK (dual leucine zipper-bearing kinase) is a key regulator of development, cell differentiation and apoptosis. Interestingly, recent studies have shown that DLK expression is up-regulated in 3T3-L1 cells induced to differentiate into adipocytes and that DLK knockdown impairs the expression of PPARγ (peroxisome-proliferator-activated receptor γ), a master regulator of adipogenesis. Because the PPARγ agonist rosiglitazone was found to increase DLK expression in 3T3-L1 cells, we hypothesized that PPARγ is required for the transcriptional activation of the DLK gene. To test this hypothesis, we first examined the effects of pharmacological inhibition or shRNA (small-hairpin RNA)-mediated depletion of PPARγ on DLK accumulation in 3T3-L1 cells undergoing differentiation. In addition to blocking adipocyte conversion of 3T3-L1 cells, inhibition of PPARγ suppressed DLK expression at both the mRNA and protein levels. Moreover, supporting a role for PPARγ in DLK regulation, two potential PPARγ-binding sites identified by bioinformatic tools at positions −611 and −767 upstream of the DLK gene transcriptional start site were shown by electrophoretic mobility-shift assay and chromatin immunoprecipitation to bind PPARγ and its essential heterodimer partner retinoid X receptor as differentiation proceeds. Collectively, these results show that DLK is a novel transcriptional target of PPARγ with functional PPARγ-binding sites in its promoter.

scholarly journals Mouse Cardiac Pde1C Is a Direct Transcriptional Target of Pparα

2018 ◽  
Vol 19 (12) ◽  
pp. 3704 ◽  
Author(s):  
Varsha Shete ◽  
Ning Liu ◽  
Yuzhi Jia ◽  
Navin Viswakarma ◽  
Janardan Reddy ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Molecular Mechanisms ◽  
Promoter Sequence ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Direct Transcriptional Target ◽  
Cardiac Functions ◽  
H9c2 Myoblasts ◽  
Camp And Cgmp ◽  
Transcriptional Target

Phosphodiesterase 1C (PDE1C) is expressed in mammalian heart and regulates cardiac functions by controlling levels of second messenger cyclic AMP and cyclic GMP (cAMP and cGMP, respectively). However, molecular mechanisms of cardiac Pde1c regulation are currently unknown. In this study, we demonstrate that treatment of wild type mice and H9c2 myoblasts with Wy-14,643, a potent ligand of nuclear receptor peroxisome-proliferator activated receptor alpha (PPARα), leads to elevated cardiac Pde1C mRNA and cardiac PDE1C protein, which correlate with reduced levels of cAMP. Furthermore, using mice lacking either Pparα or cardiomyocyte-specific Med1, the major subunit of Mediator complex, we show that Wy-14,643-mediated Pde1C induction fails to occur in the absence of Pparα and Med1 in the heart. Finally, using chromatin immunoprecipitation assays we demonstrate that PPARα binds to the upstream Pde1C promoter sequence on two sites, one of which is a palindrome sequence (agcTAGGttatcttaacctagc) that shows a robust binding. Based on these observations, we conclude that cardiac Pde1C is a direct transcriptional target of PPARα and that Med1 may be required for the PPARα mediated transcriptional activation of cardiac Pde1C.

scholarly journals Functional Analysis of Steroidogenic Factor 1 (sf-1) and 17α-Hydroxylase/Lyase (cyp17α) Promoters in Yellow Catfish Pelteobagrus fulvidraco

2020 ◽  
Vol 22 (1) ◽  
pp. 195
Author(s):  
Wu-Hong Lv ◽  
Guang-Hui Chen ◽  
Mei-Qin Zhuo ◽  
Yi-Huan Xu ◽  
Yi-Chuang Xu ◽  
...  
Keyword(s):  
Binding Sites ◽  
Promoter Activity ◽  
Pelteobagrus Fulvidraco ◽  
Peroxisome Proliferator ◽  
Yellow Catfish ◽  
Site Mutation ◽  
Promoter Regions ◽  
Mobility Shift ◽  
Peroxisome Proliferator Activated Receptor ◽  
Steroidogenic Factor 1

The present study was performed to clone and characterize the structures and functions of steroidogenic factor 1 (sf-1) and 17α-hydroxylase/lyase (cyp17α) promoters in yellow catfish Pelteobagrus fulvidraco, a widely distributed freshwater teleost. We successfully obtained 1981 and 2034 bp sequences of sf-1 and cyp17α promoters, and predicted the putative binding sites of several transcription factors, such as Peroxisome proliferator-activated receptor alpha (PPARα), Peroxisome proliferator-activated receptor gamma (PPARγ) and Signal transducer and activator of transcription 3 (STAT3), on sf-1 and cyp17α promoter regions, respectively. Overexpression of PPARγ significantly increased the activities of sf-1 and cyp17α promoters, but overexpression of PPARα significantly decreased the promoter activities of sf-1 and cyp17α. Overexpression of STAT3 reduced the activity of the sf-1 promoter but increased the activity of the cyp17α promoter. The analysis of site-mutation and electrophoretic mobility shift assay suggested that the sf-1 promoter possessed the STAT3 binding site, but did not the PPARα or PPARγ binding sites. In contrast, only the PPARγ site, not PPARα or STAT3 sites, was functional with the cyp17α promoter. Leptin significantly increased sf-1 promoter activity, but the mutation of STAT3 and PPARγ sites decreased leptin-induced activation of sf-1 promoter. Our findings offered the novel insights into the transcriptional regulation of sf-1 and cyp17α and suggested leptin regulated sf-1 promoter activity through STAT3 site in yellow catfish.

scholarly journals The effect of peroxisome-proliferator-activated receptor-α on the activity of the cholesterol 7α-hydroxylase gene

2000 ◽  
Vol 351 (3) ◽  
pp. 747-753 ◽  
Author(s):  
Dilip D. PATEL ◽  
Brian L. KNIGHT ◽  
Anne K. SOUTAR ◽  
Geoffrey F. GIBBONS ◽  
David P. WADE
Keyword(s):  
Binding Sites ◽  
Cholesterol Metabolism ◽  
Mrna Abundance ◽  
Major Influence ◽  
Dark Phase ◽  
Peroxisome Proliferator ◽  
Dependent Manner ◽  
Mobility Shift ◽  
Concentration Dependent Manner ◽  
Peroxisome Proliferator Activated Receptor

Cholesterol 7α-hydroxylase (Cyp7a1) plays a central role in the regulation of bile acid and cholesterol metabolism, and transcription of the gene is controlled by bile acids and hormones acting through a complex interaction with a number of potential steroid-hormone-binding sites. Transcriptional activity of the human CYP7A1 gene promoter transfected into HepG2 cells was decreased in a concentration-dependent manner by co-transfection with an expression vector for peroxisome-proliferator-activated receptor-α (PPARα). This effect was augmented by 9-cis-retinoic acid receptor-α (RXRα) and activators of PPARα to give a maximum inhibition of approx. 80%. The region responsible for this inhibition contained a site known to bind hepatocyte nuclear factor 4 (HNF4), and mutation of this site greatly decreased the effect. Co-expression of HNF4 increased promoter activity and decreased the effect of PPARα. Gel-mobility-shift assays failed to detect any binding of PPARα/RXRα dimers to any regions of the promoter containing potential binding sites. Also the hepatic abundance of Cyp7a1 mRNA in mice in which the PPARα gene was disrupted was the same as in normal mice, both during the dark phase, when the animals were feeding, and during the light phase, when mRNA abundance was greatly increased. Cholesterol feeding produced the same increase in hepatic Cyp7a1 mRNA abundance in PPARα-null animals as in normals. It is concluded that, whereas PPARα can affect CYP7A1 gene transcription in vitro through an indirect action, probably by competing for co-factors, this is unlikely to be a major influence on Cyp7a1 activity under normal physiological conditions.

Sp sites contribute to basal and inducible expression of the human TNIP1 (TNFα-inducible protein 3-interacting protein 1) promoter

2013 ◽  
Vol 452 (3) ◽  
pp. 519-529 ◽  
Author(s):  
Priscilla C. Encarnacao ◽  
Vincent P. Ramirez ◽  
Carmen Zhang ◽  
Brian J. Aneskievich
Keyword(s):  
Transcriptional Activation ◽  
Retinoic Acid Receptor ◽  
Membrane Receptors ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Mobility Shift ◽  
End Points ◽  
Peroxisome Proliferator Activated Receptor ◽  
Interacting Protein ◽  
Expression Levels

TNIP1 [TNFα (tumour necrosis factor α)-induced protein 3-interacting protein 1] is a co-repressor of RAR (retinoic acid receptor) and PPAR (peroxisome-proliferator-activated receptor). Additionally, it can reduce signalling stemming from cell membrane receptors such as those for TNFα and EGF (epidermal growth factor). Consequently, it influences a variety of receptor-mediated events as diverse as transcription, programmed cell death and cell cycling. Thus changes in TNIP1 expression levels are likely to affect multiple important biological end points. TNIP1 expression level changes have been linked to psoriasis and systemic sclerosis. As such, it is crucial to determine what controls its expression levels, starting with constitutive control of its promoter. Our analysis of the TNIP1 promoter revealed multiple transcription start sites in its GC-rich proximal regions along with two transcriptionally active Sp (specificity protein) sites, responsive to both Sp1 and Sp3. EMSA (electrophoretic mobility-shift assay) and ChIP (chromatin immunoprecipitation) demonstrated physical binding between Sp1 and Sp3 at these sites. A decrease in Sp1 protein levels via siRNA (short interfering RNA) or diminished Sp1 DNA binding by mithramycin decreased TNIP1 mRNA levels. This Sp-binding GC-rich region of the TNIP1 promoter also participates in transcriptional activation by ligand-bound RAR. Together, these results demonstrate newly identified regulators of TNIP1 expression and suggest possible transcription factor targets which in turn control TNIP1-related biological end points ranging from apoptosis to inflammatory diseases.

scholarly journals SUMO-1 Regulates Body Weight and Adipogenesis via PPARγ in Male and Female Mice

Endocrinology ◽  
2012 ◽  
Vol 154 (2) ◽  
pp. 698-708 ◽  
Author(s):  
Laura Mikkonen ◽  
Johanna Hirvonen ◽  
Olli A. Jänne
Keyword(s):  
Adipose Tissue ◽  
Transcriptional Activation ◽  
Cell Biology ◽  
Target Genes ◽  
The Body ◽  
Peroxisome Proliferator ◽  
Fat Cell ◽  
Peroxisome Proliferator Activated Receptor ◽  
Pparγ Agonist

Properly functioning adipose tissue is essential for normal insulin sensitivity of the body. When mice are kept on high-fat diet (HFD), adipose tissue expands, adipocytes increase in size and number, and the mice become obese. Many of these changes are mediated by the nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ), the activity of which is regulated by multiple posttranslational modifications, including SUMOylation. To address the role of small ubiquitin-like modifier-1 (SUMO-1) in PPARγ function in vivo, particularly in fat cell biology, we subjected Sumo1-knockout mice to HFD. Sumo1-null mice gained less weight and had smaller and fewer adipocytes in their gonadal fat tissue on HFD, but their glucose tolerance was similar to that of wild-type littermates. Adipogenesis was impaired in Sumo1-null cells, and expression of PPARγ target genes was attenuated. In addition, both Sumo1-null cells and Sumo1-null mice responded less efficiently to rosiglitazone, a PPARγ agonist. These findings indicate that SUMO-1 is important also for transcriptional activation by the PPARγ signaling pathway and not only for trans-repressive functions of PPARγ as previously reported.

scholarly journals Wnt/β-catenin Pathway-Mediated PPARδ Expression during Embryonic Development Differentiation and Disease

2021 ◽  
Vol 22 (4) ◽  
pp. 1854
Author(s):  
Tabinda Sidrat ◽  
Zia-Ur Rehman ◽  
Myeong-Don Joo ◽  
Kyeong-Lim Lee ◽  
Il-Keun Kong
Keyword(s):  
Embryonic Development ◽  
Transcriptional Activation ◽  
Target Gene ◽  
Developmental Stages ◽  
Embryonic Stem ◽  
Hereditary Diseases ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Stem Cell Regulation ◽  
Early Developmental

The Wnt/β-catenin signaling pathway plays a crucial role in early embryonic development. Wnt/β-catenin signaling is a major regulator of cell proliferation and keeps embryonic stem cells (ESCs) in the pluripotent state. Dysregulation of Wnt signaling in the early developmental stages causes several hereditary diseases that lead to embryonic abnormalities. Several other signaling molecules are directly or indirectly activated in response to Wnt/β-catenin stimulation. The crosstalk of these signaling factors either synergizes or opposes the transcriptional activation of β-catenin/Tcf4-mediated target gene expression. Recently, the crosstalk between the peroxisome proliferator-activated receptor delta (PPARδ), which belongs to the steroid superfamily, and Wnt/β-catenin signaling has been reported to take place during several aspects of embryonic development. However, numerous questions need to be answered regarding the function and regulation of PPARδ in coordination with the Wnt/β-catenin pathway. Here, we have summarized the functional activation of the PPARδ in co-ordination with the Wnt/β-catenin pathway during the regulation of several aspects of embryonic development, stem cell regulation and maintenance, as well as during the progression of several metabolic disorders.

scholarly journals Electron Transport Disturbances and Neurodegeneration: From Albert Szent-Györgyi’s Concept (Szeged) till Novel Approaches to Boost Mitochondrial Bioenergetics

2015 ◽  
Vol 2015 ◽  
pp. 1-19 ◽  
Author(s):  
Levente Szalárdy ◽  
Dénes Zádori ◽  
Péter Klivényi ◽  
József Toldi ◽  
László Vécsei
Keyword(s):  
Transcriptional Activation ◽  
Current Knowledge ◽  
Genetic Alterations ◽  
Cellular Respiration ◽  
Special Focus ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Disease Modifying Therapy ◽  
Mitochondrial Functions ◽  
Genes Encoding

Impaired function of certain mitochondrial respiratory complexes has long been linked to the pathogenesis of chronic neurodegenerative disorders such as Parkinson’s and Huntington’s diseases. Furthermore, genetic alterations of mitochondrial genome or nuclear genes encoding proteins playing essential roles in maintaining proper mitochondrial function can lead to the development of severe systemic diseases associated with neurodegeneration and vacuolar myelinopathy. At present, all of these diseases lack effective disease modifying therapy. Following a brief commemoration of Professor Albert Szent-Györgyi, a Nobel Prize laureate who pioneered in the field of cellular respiration, antioxidant processes, and the roles of free radicals in health and disease, the present paper overviews the current knowledge on the involvement of mitochondrial dysfunction in central nervous system diseases associated with neurodegeneration including Parkinson’s and Huntington’s disease as well as mitochondrial encephalopathies. The review puts special focus on the involvement and the potential therapeutic relevance of peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α), a nuclear-encoded master regulator of mitochondrial biogenesis and antioxidant responses in these disorders, the transcriptional activation of which may hold novel therapeutic value as a more system-based approach aiming to restore mitochondrial functions in neurodegenerative processes.

scholarly journals Activation of Peroxisome Proliferator-activated Receptor α (PPARα) Suppresses Hypoxia-inducible Factor-1α (HIF-1α) Signaling in Cancer Cells

2012 ◽  
Vol 287 (42) ◽  
pp. 35161-35169 ◽  
Author(s):  
Jundong Zhou ◽  
Shuyu Zhang ◽  
Jing Xue ◽  
Jori Avery ◽  
Jinchang Wu ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Hypoxia Inducible Factor ◽  
Proteasome Inhibitors ◽  
Tube Formation ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Hypoxia Inducible Factor 1Α ◽  
Anticancer Properties ◽  
Pparγ Agonist ◽  
Expression And Activity

Activation of peroxisome proliferator-activated receptor α (PPARα) has been demonstrated to inhibit tumor growth and angiogenesis, yet the mechanisms behind these actions remain to be characterized. In this study, we examined the effects of PPARα activation on the hypoxia-inducible factor-1α (HIF-1α) signaling pathway in human breast (MCF-7) and ovarian (A2780) cancer cells under hypoxia. Incubation of cancer cells under 1% oxygen for 16 h significantly induced HIF-1α expression and activity as assayed by Western blotting and reporter gene analysis. Treatment of the cells with PPARα agonists, but not a PPARγ agonist, prior to hypoxia diminished hypoxia-induced HIF-1α expression and activity, and addition of a PPARα antagonist attenuated the suppression of HIF-1α signaling. Activation of PPARα attenuated hypoxia-induced HA-tagged HIF-1α protein expression without affecting the HA-tagged HIF-1α mutant protein level, indicating that PPARα activation promotes HIF-1α degradation in these cells. This was further confirmed using proteasome inhibitors, which reversed PPARα-mediated suppression of HIF-1α expression under hypoxia. Using the co-immunoprecipitation technique, we found that activation of PPARα enhances the binding of HIF-1α to von Hippel-Lindau tumor suppressor (pVHL), a protein known to mediate HIF-1α degradation through the ubiquitin-proteasome pathway. Following PPARα-mediated suppression of HIF-1α signaling, VEGF secretion from the cancer cells was significantly reduced, and tube formation by endothelial cells was dramatically impaired. Taken together, these findings demonstrate for the first time that activation of PPARα suppresses hypoxia-induced HIF-1α signaling in cancer cells, providing novel insight into the anticancer properties of PPARα agonists.

scholarly journals PPARγ and TGFβ—Major Regulators of Metabolism, Inflammation, and Fibrosis in the Lungs and Kidneys

2021 ◽  
Vol 22 (19) ◽  
pp. 10431
Author(s):  
Gábor Kökény ◽  
Laurent Calvier ◽  
Georg Hansmann
Keyword(s):  
Transforming Growth Factor Beta ◽  
Kidney Failure ◽  
Transforming Growth Factor ◽  
Therapeutic Potential ◽  
Biological Effects ◽  
Critical Conditions ◽  
Peroxisome Proliferator ◽  
Lipid Uptake ◽  
Peroxisome Proliferator Activated Receptor ◽  
Pparγ Agonist

Peroxisome proliferator-activated receptor gamma (PPARγ) is a type II nuclear receptor, initially recognized in adipose tissue for its role in fatty acid storage and glucose metabolism. It promotes lipid uptake and adipogenesis by increasing insulin sensitivity and adiponectin release. Later, PPARγ was implicated in cardiac development and in critical conditions such as pulmonary arterial hypertension (PAH) and kidney failure. Recently, a cluster of different papers linked PPARγ signaling with another superfamily, the transforming growth factor beta (TGFβ), and its receptors, all of which play a major role in PAH and kidney failure. TGFβ is a multifunctional cytokine that drives inflammation, fibrosis, and cell differentiation while PPARγ activation reverses these adverse events in many models. Such opposite biological effects emphasize the delicate balance and complex crosstalk between PPARγ and TGFβ. Based on solid experimental and clinical evidence, the present review summarizes connections and their implications for PAH and kidney failure, highlighting the similarities and differences between lung and kidney mechanisms as well as discussing the therapeutic potential of PPARγ agonist pioglitazone.

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