Transactivation of the PPAR-Responsive Enhancer Module in Chemopreventive Glutathione <b>
                     <i>S</i>
                  </b>-Transferase Gene by the Peroxisome Proliferator-Activated Receptor-γ and Retinoid X Receptor Heterodimer

Park, Eun Young; Cho, Il Je; Kim, Sang Geon

doi:10.1158/0008-5472.can-03-3924

Cited by 130 publications

(112 citation statements)

References 53 publications

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“…This indicates that PPARg could act on upstream signal pathways for Nrf2 activation. In support of this function, accumulating evidence has indicated that PPARg agonists induce antioxidant and defense genes encoding GST-a, HO-1, and CD36 through regulation of Nrf2 (43)(44)(45). The current study also supported this concept, first by showing suppressed Nrf2 expression and ARE binding activity after PPARg silencing, and then by elucidating potential PPAR binding motifs in the Nrf2 promoter.…”

Section: Discussionsupporting

confidence: 75%

“…Recent studies indicate that PPARg may control the expression of cytoprotective genes including GST-a, HO-1, and CD36 directly through their PPRE or indirectly through Nrf2 (41)(42)(43)(44)(45). To determine whether PPARg modulates these cytoprotective genes and Nrf2 in the lung, their expression was compared in wild type mice treated with si-PPARg or si-NS ( Figure 7A).…”

Section: Effect Of Pparg Inhibition On Cytoprotective Genes and Nrf2mentioning

confidence: 99%

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Nrf2-regulated PPARγ Expression Is Critical to Protection against Acute Lung Injury in Mice

Cho

Gladwell

Wang

et al. 2010

Am J Respir Crit Care Med

199

176

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Rationale: The NF-E2 related factor 2 (Nrf2)-antioxidant response element (ARE) pathway is essential for protection against oxidative injury and inflammation including hyperoxia-induced acute lung injury. Microarray expression profiling revealed that lung peroxisome proliferator activated receptor g (PPARg) induction is suppressed in hyperoxia-susceptible Nrf2-deficient (Nrf2 2/2 ) mice compared with wild-type (Nrf2 1/1 ) mice. PPARg has pleiotropic beneficial effects including antiinflammation in multiple tissues. Objectives: We tested the hypothesis that PPARg is an important determinant of pulmonary responsivity to hyperoxia regulated by Nrf2. Methods: A computational bioinformatic method was applied to screen potential AREs in the Pparg promoter for Nrf2 binding. The functional role of a potential ARE was investigated by in vitro promoter analysis. A role for PPARg in hyperoxia-induced acute lung injury was determined by temporal silencing of PPARg via intranasal delivery of PPARg-specific interference RNA and by administration of a PPARg ligand 15-deoxy-D 12,14 -prostaglandin J 2 in mice. Measurements and Main Results: Deletion or site-directed mutagenesis of a potential ARE spanning -784/-764 sequence significantly attenuated hyperoxia-increased Pparg promoter activity in airway epithelial cells overexpressing Nrf2, indicating that the -784/-764 ARE is critical for Nrf2-regulated PPARg expression. Mice with decreased lung PPARg by specific interference RNA treatment had significantly augmented hyperoxia-induced pulmonary inflammation and injury. 15 Deoxy-D 12,14 -prostaglandin J 2 administration significantly reduced hyperoxia-induced lung inflammation and edema in Nrf2 1/1 , but not in Nrf2 2/2 mice. Conclusions: Results indicate for the first time that Nrf2-driven PPARg induction has an essential protective role in pulmonary oxidant injury. Our observations provide new insights into the therapeutic potential of PPARg in airway oxidative inflammatory disorders.

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Section: Discussionsupporting

confidence: 75%

Section: Effect Of Pparg Inhibition On Cytoprotective Genes and Nrf2mentioning

confidence: 99%

Nrf2-regulated PPARγ Expression Is Critical to Protection against Acute Lung Injury in Mice

Cho

Gladwell

Wang

et al. 2010

Am J Respir Crit Care Med

199

176

View full text Add to dashboard Cite

show abstract

“…Moreover, it has been shown that the Gsta2 expression is transcriptionally regulated by NRF2 and C/EBP . In addition, functional multiple PPRE-responsive enhancer module (PPREM) was recently reported in the Gsta2 promoter, by which PPAR agonists induce the Gsta2 expression via PPREM in hepatocytes 59) . Therefore, the mechanism underlying the reduction of the Gsta2 expression induced by K-877 treatment in Ppara-null…”

Section: Conflicts Of Interestmentioning

confidence: 99%

Transcriptome Analysis of K-877 (a Novel Selective PPARα Modulator (SPPARMα))-Regulated Genes in Primary Human Hepatocytes and the Mouse Liver

Raza-Iqbal

Tanaka

Anai

et al. 2015

J Atheroscler Thromb

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Aim: Selective PPAR modulators (SPPARM ) are under development for use as next-generation lipid lowering drugs. In the current study, to predict the pharmacological and toxicological effects of a novel SPPARM K-877, comprehensive transcriptome analyses of K-877-treated primary human hepatocytes and mouse liver tissue were carried out. Methods: Total RNA was extracted from the K-877 treated primary human hepatocytes and mouse liver and adopted to the transcriptome analysis. Using a cluster analysis, commonly and species specifically regulated genes were identified. Also, the profile of genes regulated by K-877 and fenofibrate were compared to examine the influence of different SPPARM on the liver gene expression. Results: Consequently, a cell-based transactivation assay showed that K-877 activates PPAR with much greater potency and selectivity than fenofibric acid, the active metabolite of clinically used fenofibrate. K-877 upregulates the expression of several fatty acid -oxidative genes in human hepatocytes and the mouse liver. Almost all genes up-or downregulated by K-877 treatment in the mouse liver were also regulated by fenofibrate treatment. In contrast, the K-877-regulated genes in the mouse liver were not affected by K-877 treatment in the Ppara-null mouse liver. Depending on the species, the peroxisomal biogenesis-related gene expression was robustly

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“…Also, PPAR-gamma agonists trans-repress the transcription of downstream pro-inflammatory genes after ischemia (37) (Table 3). Furthermore, the administration of rosiglitazone or pioglitazone increases the translocation of PPAR-gamma to the nucleus in neurons and this is further enhanced in the presence of retinoic acid (37,38). Freshly prepared peripheral blood monocytes treated with TZDs showed decreased cytokine release after activation and 15d-PGJ2 modified target gene expression changes when administered to peritoneal macrophages (20,85).…”

Section: Ppar-gamma and Focal Cerebral Ischemiamentioning

confidence: 99%

Mechanisms of anti-inflammatory and neuroprotective actions of PPAR-gamma agonists

Kapadia

Yi²,

Vemuganti³

2008

Front Biosci

378

246

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Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors of the nuclear hormone receptor superfamily. The 3 PPAR isoforms (alpha, delta/beta and gamma) are known to control many physiological functions including glucose absorption, lipid balance, and cell growth and differentiation. Of interest, PPAR-gamma activation was recently shown to mitigate the inflammation associated with chronic and acute neurological insults. Particular attention was paid to test the therapeutic potential of PPAR agonists in acute conditions like stroke, spinal cord injury (SCI) and traumatic brain injury (TBI), in which massive inflammation plays a detrimental role. While 15d-prostaglandin J2 (15d PGJ 2 ) is the natural ligand of PPAR-gamma, the thiazolidinediones (TZDs) are potent exogenous agonists. Due to their insulin-sensitizing properties, 2 TZDs rosiglitazone and pioglitazone are currently FDA-approved for type-2 diabetes treatment. Recent studies from our laboratory and other groups have shown that TZDs induce significant neuroprotection in animal models of focal ischemia and SCI by multiple mechanisms. The beneficial actions of TZDs were observed to be both PPAR-gamma-dependent as well as -independent. The major mechanism of TZD-induced neuroprotection seems to be prevention of microglial activation and inflammatory cytokine and chemokine expression. TZDs were also shown to prevent the activation of pro-inflammatory transcription factors at the same time promoting the anti-oxidant mechanisms in the injured CNS. This review article discusses the multiple mechanisms of TZDinduced neuroprotection in various animal models of CNS injury with an emphasis on stroke. KeywordsTranscription Factor; Inflammation; Brain Damage; Nuclear Factor; Cerebral Ischemia; Stroke; Neuroprotection; Review INTRODUCTIONStroke is the leading cause of long-term disability in the adult population worldwide. A variety of pathophysiological processes contribute to the irreversible neuronal injury that eventually results in neurological dysfunction after stroke. The complex nature of these processes involves specific cell types that effect several downstream signalling pathways. In a majority of stroke patients, only a small area of the brain tissue, the ischemic core, is irreversibly damaged. A much larger volume of the brain tissue surrounding the ischemic core, called the penumbra, can potentially recover if treatment is provided in a timely manner (3). Tissue protection and regeneration are tightly regulated by cell growth, survival and cell death signals provided by the cellular microenvironment. Hence, understanding the molecular mechanisms that govern Send correspondence to: Dr. Raghu Vemuganti, Department of Neurological Surgery, K4/8 Mail code CSC 8660, 600 Highland Avenue, Madison, WI 53792, Tel:608-263-4055, Fax:608-263-1728, E-mail: vemugant@neurosurg.wisc.edu. NIH Public Access Author ManuscriptFront Biosci. Author manuscript; available in PMC 2009 August 28. Published in final edited form as:Fr...

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Transactivation of the PPAR-Responsive Enhancer Module in Chemopreventive Glutathione S -Transferase Gene by the Peroxisome Proliferator-Activated Receptor-γ and Retinoid X Receptor Heterodimer

Abstract: ABSTRACT

Cited by 130 publications

References 53 publications

Nrf2-regulated PPARγ Expression Is Critical to Protection against Acute Lung Injury in Mice

Nrf2-regulated PPARγ Expression Is Critical to Protection against Acute Lung Injury in Mice

Transcriptome Analysis of K-877 (a Novel Selective PPARα Modulator (SPPARMα))-Regulated Genes in Primary Human Hepatocytes and the Mouse Liver

Mechanisms of anti-inflammatory and neuroprotective actions of PPAR-gamma agonists

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