scholarly journals Peroxisome Proliferator-Activated Receptor Gamma Exacerbates Concanavalin A-Induced Liver Injury via Suppressing the Translocation of NF-κB into the Nucleus

PPAR Research ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-5 ◽  
Author(s):  
Yuji Ogawa ◽  
Masato Yoneda ◽  
Wataru Tomeno ◽  
Kento Imajo ◽  
Yoshiyasu Shinohara ◽  
...  
Keyword(s):  
Liver Injury ◽  
Concanavalin A ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Peroxisome Proliferator ◽  
Con A ◽  
Mobility Shift ◽  
Peroxisome Proliferator Activated Receptor ◽  
Knock Out ◽  
In The Wild ◽  
Mobility Shift Assay

Peroxisome proliferator-activated receptor-γ(PPARγ) has been reported to reduce inflammation and attenuate fibrosis in the liver. In this study, we investigated the effects of PPARγon the liver injury induced by 20 mg/kg Concanavalin A (Con A). The mice were administered one of the three types of PPARγligands (pioglitazone, ciglitazone, and troglitazone) for 1 week, and the serum alanine aminotransferase (ALT) levels at 20 h after Con A injection were significantly elevated in the PPARγligand-treated mice. Furthermore, the serum ALT levels after Con A injection in the PPARγhetero-knock-out mice (PPARγ+/−mice) were lower than those in the wild-type mice (WT mice). Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) revealed extensive liver damage induced by Con A in the pioglitazone-treated mice. Electrophoresis mobility shift assay (EMSA) revealed that activation of translocation of nuclear factor- (NF-)κB, which is a suppressor of apoptosis, in the nucleus of the hepatocytes was suppressed in the pioglitazone-treated mice after Con A injection. In this study, we showed that PPARγexacerbated Con A-induced liver injury via suppressing the translocation of NF-κB into the nucleus, thereby inhibiting the suppression of liver cell apoptosis.

Contribution of PPARγ in modulation of acrolein-induced inflammatory signaling in gp91phox knock-out mice

2017 ◽  
Vol 95 (4) ◽  
pp. 482-490 ◽  
Author(s):  
Zivar Yousefipour ◽  
Neha Chug ◽  
Katarzyna Marek ◽  
Alicia Nesbary ◽  
Joseph Mathew ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Body Mass ◽  
Total Antioxidant Status ◽  
Peroxisome Proliferator ◽  
Wild Type ◽  
Peroxisome Proliferator Activated Receptor ◽  
Knock Out ◽  
Total Antioxidant ◽  
In The Wild ◽  
Knock Out Mice

Oxidative stress and inflammation are major contributors to acrolein toxicity. Peroxisome proliferator activated receptor gamma (PPARγ) has antioxidant and anti-inflammatory effects. We investigated the contribution of PPARγ ligand GW1929 to the attenuation of oxidative stress in acrolein-induced insult. Male gp91phox knock-out (KO) mice were treated with acrolein (0.5 mg·(kg body mass)–1 by intraperitoneal injection for 7 days) with or without GW1929 (GW; 0.5 mg·(kg body mass)–1·day–1, orally, for 10 days). The livers were processed for further analyses. Acrolein significantly increased 8-isoprostane and reduced PPARγ activity (P < 0.05) in the wild type (WT) and KO mice. GW1929 reduced 8-isoprostane (by 32% and 40% in WT and KO mice, respectively) and increased PPARγ activity (by 81% and 92% in WT and KO, respectively). Chemokine activity was increased (by 63%) in acrolein-treated WT mice, and was reduced by GW1929 (by 65%). KO mice exhibited higher xanthine oxidase (XO). Acrolein increased XO and COX in WT mice and XO in KO mice. GW1929 significantly reduced COX in WT and KO mice and reduced XO in KO mice. Acrolein significantly reduced the total antioxidant status in WT and KO mice (P < 0.05), which was improved by GW1929 (by 75% and 74%). The levels of NF-κB were higher in acrolein-treated WT mice. GW1929 reduced NF-κB levels (by 51%) in KO mice. Acrolein increased CD36 in KO mice (by 43%), which was blunted with GW1929. Data confirms that the generation of free radicals by acrolein is mainly through NAD(P)H, but other oxygenates play a role too. GW1929 may alleviate the toxicity of acrolein by attenuating NF-κB, COX, and CD36.

Transcriptional ERRγ2-mediated activation is regulated by sentrin-specific proteases

2009 ◽  
Vol 419 (1) ◽  
pp. 167-176 ◽  
Author(s):  
Moritz Hentschke ◽  
Ute Süsens ◽  
Uwe Borgmeyer
Keyword(s):  
Nuclear Receptor ◽  
Mutational Analysis ◽  
Activation Function ◽  
Peroxisome Proliferator ◽  
Orphan Nuclear Receptor ◽  
Mobility Shift ◽  
Peroxisome Proliferator Activated Receptor ◽  
Specific Protease ◽  
Mobility Shift Assay ◽  
Group B

Modification with SUMOs (small ubiquitin-related modifiers) has emerged as an important means of regulating the activity of transcription factors, often by repressing their activity. The ERRγ [oestrogen receptor-related receptor γ; ERR3 or NR3B3 (nuclear receptor subfamily 3, group B, gene3)] is a constitutively active orphan nuclear receptor. A PDSM, (phosphorylation-dependent sumoylation motif) is located in the close vicinity of the N-terminally located ERRγ2-specific AF-1 (activation function-1). Its function can be replaced by an NDSM (negatively charged amino acid-dependent sumoylation motif). A mutational analysis reveals that ERRγ2 activity is modulated through sumoylation of a lysine residue at position 40, which in turn is regulated by phosphorylation. Phosphorylation at the +5 position relative to the sumoylation target is directly visualized by a high-resolution EMSA (electrophoretic mobility-shift assay). Sumoylation represses the activity of ERRγ both with and without forced expression of the PGC-1β (peroxisome-proliferator-activated receptor γ co-activator-1β). Fusion proteins of a heterologous DNA-binding domain with the ERRγ2 N-terminus demonstrate the function of the PDSM as the RF-1 (repression function-1) for the neighbouring AF-1. De-repression is achieved by co-expression of sentrin/SENP (sentrin-specific protease) family members. Together, our results demonstrate reversible phosphorylation-dependent sumoylation as a means to regulate the activity of an orphan nuclear receptor.

scholarly journals Activating Effect of Benzbromarone, a Uricosuric Drug, on Peroxisome Proliferator-Activated Receptors

PPAR Research ◽  
2007 ◽  
Vol 2007 ◽  
pp. 1-5 ◽  
Author(s):  
Chiyoko Kunishima ◽  
Ikuo Inoue ◽  
Toshihiro Oikawa ◽  
Hiromu Nakajima ◽  
Tsugikazu Komoda ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Cultured Cells ◽  
Binding Activity ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferation ◽  
Mobility Shift ◽  
Peroxisome Proliferator Activated Receptor ◽  
Western Blot Method ◽  
Gene Assay ◽  
Mobility Shift Assay

Benzbromarone, a uricosuric drug, reportedly causes hepatic hypertrophy accompanied by proliferation of peroxisomes in rats. To elucidate the mechanisms underlying induction of peroxisome proliferation by benzbromarone, we examined binding affinity for peroxisome proliferator-activated receptorα(PPARα) andγ(PPARγ), and effects on the binding activity of PPARs with peroxisome proliferation-responsive element (PPRE) and expression of the PPARs target protein. Binding affinity of benzbromarone forPPARαandPPARγwas examined by reporter gene assay. Binding activity of PPARs with PPRE was determined by electric mobility shift assay, and expression of lipoprotein lipase (LPL) and acyl-CoA synthetase (ACS) by Western blot method. Benzbromarone displayed affinity forPPARαandPPARγ, and promoted binding of PPARs to PPRE. Furthermore, cultured cells with benzbromarone added showed upregulated expression of LPL and ACS. These results suggest that benzbromarone induces peroxisome proliferation in hepatocytes by binding to PPARs, and controls expression of proteins related to lipid metabolism.

Elafibranor interrupts adipose dysfunction-mediated gut and liver injury in mice with alcoholic steatohepatitis

2019 ◽  
Vol 133 (3) ◽  
pp. 531-544 ◽  
Author(s):  
Tzu-Hao Li ◽  
Ying-Ying Yang ◽  
Chia-Chang Huang ◽  
Chih-Wei Liu ◽  
Hung-Cheng Tsai ◽  
...  
Keyword(s):  
Liver Injury ◽  
Energy Homeostasis ◽  
Intestinal Barrier ◽  
Peroxisome Proliferator ◽  
Intestinal Epithelial ◽  
Peroxisome Proliferator Activated Receptor ◽  
Alcoholic Steatohepatitis ◽  
Ppar Agonists ◽  
Apoptosis And Inflammation ◽  
Adipose Dysfunction

Abstract Background: Reversal of alcohol-induced peroxisome proliferator-activated receptor (PPAR) α (PPARα) and PPARδ dysfunction has been reported to decrease the severity of alcoholic steatohepatitis (ASH). Autophagy is essential for cell survival and tissue energy homeostasis. Emerging evidence indicates that alcohol-induced adipose tissue (AT) autophagy dysfunction contributes to injury in the intestine, liver, and AT of ASH. Methods: The effects and mechanisms of dual PPARα/δ agonist elafibranor on autophagy stimulation were investigated using mice with ASH. Results: C57BL/6 mice on ethanol diet showed AT dysfunction, disrupted intestinal barrier, and ASH, which was accompanied by alcohol-mediated decrease in PPARα, PPARδ, and autophagy levels in intestine, liver, and AT. Chronic treatment with elafibranor attenuated AT apoptosis and inflammation by restoration of tissue PPARα, PPARδ, and autophagy levels. In ASH mice, alcohol-induced AT dysfunction along with increased fatty acid (FA) uptake and decreased free FA (FFA) release from AT was inhibited by elafibranor. The improvement of AT autophagy dysfunction by elafibranor alleviated inflammation and apoptosis-mediated intestinal epithelial disruption in ASH mice. Acute elafibranor incubation inhibited ethanol-induced ASH-mice-sera-enhanced autophagy dysfunction, apoptosis, barrier disruption, and intracellular steatosis in Caco-2 cells and primary hepatocytes (PHs). Conclusion: Altogether, these findings demonstrated that the PPARα/δ agonist, elafibranor, decreased the severity of liver injury by restoration of alcohol-suppressed AT autophagy function and by decreasing the release of apoptotic markers, inflammatory cytokines, and FFA, thereby reducing intestinal epithelium disruption and liver inflammation/apoptosis/steatosis in ASH mice. These data suggest that dual PPAR agonists can serve as potential therapeutic agents for the management of ASH.

scholarly journals Enhanced Therapeutic Potential of the Secretome Released from Adipose-Derived Stem Cells by PGC-1α-Driven Upregulation of Mitochondrial Proliferation

2019 ◽  
Vol 20 (22) ◽  
pp. 5589
Author(s):  
Jaeim Lee ◽  
Ok-Hee Kim ◽  
Sang Chul Lee ◽  
Kee-Hwan Kim ◽  
Jin Sun Shin ◽  
...  
Keyword(s):  
Stem Cells ◽  
Liver Injury ◽  
Therapeutic Potential ◽  
Tissue Expression ◽  
In Vitro Models ◽  
Peroxisome Proliferator ◽  
Adipose Derived Stem Cells ◽  
Peroxisome Proliferator Activated Receptor

Peroxisome proliferator activated receptor λ coactivator 1α (PGC-1α) is a potent regulator of mitochondrial biogenesis and energy metabolism. In this study, we investigated the therapeutic potential of the secretome released from the adipose-derived stem cells (ASCs) transfected with PGC-1α (PGC-secretome). We first generated PGC-1α-overexpressing ASCs by transfecting ASCs with the plasmids harboring the gene encoding PGC-1α. Secretory materials released from PGC-1α-overexpressing ASCs were collected and their therapeutic potential was determined using in vitro (thioacetamide (TAA)-treated AML12 cells) and in vivo (70% partial hepatectomized mice) models of liver injury. In the TAA-treated AML12 cells, the PGC-secretome significantly increased cell viability, promoted expression of proliferation-related markers, such as PCNA and p-STAT, and significantly reduced the levels of reactive oxygen species (ROS). In the mice, PGC-secretome injections significantly increased liver tissue expression of proliferation-related markers more than normal secretome injections did (p < 0.05). We demonstrated that the PGC-secretome does not only have higher antioxidant and anti-inflammatory properties, but also has the potential of significantly enhancing liver regeneration in both in vivo and in vitro models of liver injury. Thus, reinforcing the mitochondrial antioxidant potential by transfecting ASCs with PGC-1α could be one of the effective strategies to enhance the therapeutic potential of ASCs.

PGC-1α coactivates estrogen-related receptor-α to induce the expression of glucokinase

2010 ◽  
Vol 298 (6) ◽  
pp. E1210-E1218 ◽  
Author(s):  
Liu-Luan Zhu ◽  
Yang Liu ◽  
An-Fang Cui ◽  
Di Shao ◽  
Ji-Chao Liang ◽  
...  
Keyword(s):  
Enzyme Regulation ◽  
Regulatory Function ◽  
Acid Oxidation ◽  
Regulatory Sequence ◽  
Peroxisome Proliferator ◽  
Mobility Shift ◽  
Glucokinase Gene ◽  
Peroxisome Proliferator Activated Receptor ◽  
Insulin Dependent ◽  
Novel Target

Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a key regulator of cellular energy metabolism and regulates processes such as adaptive thermogenesis, hepatic gluconeogenesis, fatty acid oxidation, and mitochondrial biogenesis by coactivating numerous nuclear receptors and transcription factors. Here, we demonstrate the presence of the ERRα binding site in the regulatory sequence of the glucokinase gene and that PGC-1α coactivates ERRα to stimulate the transcription of glucokinase. Simultaneous overexpression of PGC-1α and ERRα potently induced the glucokinase gene expression and its enzymatic activity in primary hepatocytes; however, expression of either PGC-1α or ERRα alone had no significant effect. Electrophoretic mobility shift and chromatin immunoprecipitation assays revealed the interaction of ERRα with the glucokinase promoter. Finally, the knockdown of endogenous ERRα with specific siRNA (siERRα) or pharmacological inhibition of ERRα with XCT790 attenuated insulin-induced glucokinase expression. Taken together, this research identifies glucokinase as a novel target of PGC-1α/ERRα and underscores the regulatory function of ERRα in insulin-dependent enzyme regulation.

scholarly journals Transcriptional Regulation of Mouse μ Opioid Receptor Gene by PU.1

2004 ◽  
Vol 279 (19) ◽  
pp. 19764-19774 ◽  
Author(s):  
Cheol Kyu Hwang ◽  
Chun Sung Kim ◽  
Hack Sun Choi ◽  
Scott R. McKercher ◽  
Horace H. Loh
Keyword(s):  
Transcription Factors ◽  
Opioid Receptor ◽  
Trichostatin A ◽  
Receptor Gene ◽  
Hematopoietic Cells ◽  
Mobility Shift ◽  
Knock Out ◽  
Cis Acting ◽  
Μ Opioid Receptor ◽  
Mobility Shift Assay

We previously reported that the 34-bp cis-acting element of the mouse μ opioid receptor (MOR) gene represses transcription of the MOR gene from the distal promoter. Using a yeast one-hybrid screen to identify potential transcription factors of the MOR promoter, we have identified PU.1 as one of the candidate genes. PU.1 is a member of theetsfamily of transcription factors, expressed predominantly in hematopoietic cells and microglia of brain. PU.1 plays an essential role in the development of both lymphoid and myeloid lineages. Opioids exert neuromodulatory as well as immunomodulatory effects, which are transduced by MOR. Moreover, MOR-deficient mice exhibit increased proliferation of hematopoietic cells, suggesting a possible link between the opioid system and hematopoietic development. The PU.1 protein binds to the 34-bp element of the MOR gene in a sequence-specific manner confirmed by electrophoretic mobility shift assay and supershift assays. We have also determined endogenous PU.1 interactions with the 34-bp element of MOR promoter by chromatin immunoprecipitation assays. In co-transfection studies PU.1 represses MOR promoter reporter constructs through its PU.1 binding site. When the PU.1 gene is disrupted as in PU.1 knock-out mice and using small interfering RNA-based strategy in RAW264.7 cells, the transcription of the endogenous target MOR gene is increased significantly. This increase is probably mediated through modification of the chromatin structure, as suggested by the reversal of the PU.1-mediated repression of MOR promoter activity after trichostatin A treatment in neuroblastoma NMB cells. Our results suggest that PU.1 may be an important regulator of the MOR gene, particularly in brain and immune cells.

A downstream sequence of the rpL32 promoter competes with the glucocorticoid responsive element for a protein factor

1992 ◽  
Vol 70 (9) ◽  
pp. 787-791 ◽  
Author(s):  
Thillainathan Yoganathan ◽  
Bruce H. Sells
Keyword(s):  
Ribosomal Protein ◽  
Cross Linking ◽  
Mobility Shift ◽  
Promoter Sequences ◽  
Protein Factor ◽  
In The Wild ◽  
Glucocorticoid Responsive Element ◽  
Mobility Shift Assay ◽  
Responsive Element ◽  
Gel Mobility Shift

The murine ribosomal protein (rp) L32 gene contains essential promoter sequences located both upstream and downstream of the cap site. A combination of gel mobility shift, UV cross-linking, and cell-free transcription assays were used to analyze the interaction of factors binding to a downstream element (located at position +25 to +37). The rpL32 downstream element identified polypeptides (transcription factors) ranging in size from 45 to 25 kilodaltons (kDa). Four base pair changes in the wild-type sequence of the downstream element eliminated binding. An oligonucleotide containing the glucocorticoid responsive element sequence competed specifically for the 45-kDa protein in both the gel mobility shift assay and in the UV cross-linking studies. Our data also indicate that the downstream binding factors contribute to cell-free transcription of the rpL32 gene.Key words: ribosomal protein L32, transcription factor, glucocorticoid response element.

scholarly journals Activation of Peroxisome Proliferator-Activated Receptor Gamma by Human Cytomegalovirus for De Novo Replication Impairs Migration and Invasiveness of Cytotrophoblasts from Early Placentas

2009 ◽  
Vol 84 (6) ◽  
pp. 2946-2954 ◽  
Author(s):  
Benjamin Rauwel ◽  
Bernard Mariamé ◽  
Hélène Martin ◽  
Ronni Nielsen ◽  
Sophie Allart ◽  
...  
Keyword(s):  
Human Cytomegalovirus ◽  
De Novo ◽  
Present Report ◽  
Primary Cultures ◽  
First Trimester ◽  
Peroxisome Proliferator ◽  
Mobility Shift ◽  
Peroxisome Proliferator Activated Receptor ◽  
Human Trophoblast

ABSTRACT Human cytomegalovirus (HCMV) contributes to pathogenic processes in immunosuppressed individuals, in fetuses, and in neonates. In the present report, by using reporter gene activation assays and confocal microscopy in the presence of a specific antagonist, we show for the first time that HCMV infection induces peroxisome proliferator-activated receptor gamma (PPARγ) transcriptional activity in infected cells. We demonstrate that the PPARγ antagonist dramatically impairs virus production and that the major immediate-early promoter contains PPAR response elements able to bind PPARγ, as assessed by electrophoretic mobility shift and chromatin immunoprecipitation assays. Due to the key role of PPARγ in placentation and its specific trophoblast expression within the human placenta, we then provided evidence that by activating PPARγ human cytomegalovirus dramatically impaired early human trophoblast migration and invasiveness, as assessed by using well-established in vitro models of invasive trophoblast, i.e., primary cultures of extravillous cytotrophoblasts (EVCT) isolated from first-trimester placentas and the EVCT-derived cell line HIPEC. Our data provide new clues to explain how early infection during pregnancy could impair implantation and placentation and therefore embryonic development.

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