Differential responses of PPARα, PPARδ, and PPARγ reporter cell lines to selective PPAR synthetic ligands

Seimandi, Mathieu; Lemaire, G.; Pillon, Arnaud; Perrin, Agnès; Carlavan, Isabelle; Voegel, Johannes J.; Vignon, Françoise; Nicolas, Jean‐Claude; Balaguer, Patrick

doi:10.1016/j.ab.2005.06.010

Cited by 139 publications

(138 citation statements)

References 34 publications

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“…3C) thus confirming the increased hepatotoxicity observed in vivo in the PPARβ/δ −/− mouse model (data not shown). To further examine the role of PPARβ/δ activity on conferring resistance to 4-HNE cytotoxicity, immortalized hepatocytes (MuSH WT) were pretreated with either a PPARβ/δ agonist tetradecylthioacetic acid (TTA) or PPAR antagonist GW9662 (at concentrations known to inhibit PPARβ/δ [17]) prior to 4-HNE administration. Pretreating hepatocytes with TTA resulted in a significant protection from 4-HNE-depdendent toxicity (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…In support, we discovered that oxidized-VLDL and constituents including 13(S)-HODE and 4-HNE are PPARβ/δ agonists. In addition, modulating PPARβ/δ activity, either by activation with synthetic PPARβ/δ-selective agonist tetradecylthioacetic acid (TTA) or inhibition with PPAR pan-antagonist GW9662 [17], affects the sensitivity of hepatocytes to 4-HNE and other toxic agents. This research raises the possibility that PPARβ/δ agonists may be utilized to prevent or treat liver disease associated with the generation of ROIs.…”

Section: Introductionmentioning

confidence: 99%

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The oxidative stress mediator 4-hydroxynonenal is an intracellular agonist of the nuclear receptor peroxisome proliferator-activated receptor-β/δ (PPARβ/δ)

Coleman

Prabhu

Thompson

et al. 2007

Free Radical Biology and Medicine

104

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Liver insufficiency and damage is a major cause of death and disease worldwide and may result from exposure to environmental toxicants, specific combinations or dosages of pharmaceuticals and microbial metabolites. The generation of reactive intermediates, in particular 4-hydroxynonenal (4-HNE), is a common event in liver damage caused by a variety of hepatotoxic drugs and solvents. The peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that are involved in the transcriptional regulation of lipid metabolism as well as other biological functions. Importantly, we have observed that the PPARβ/δ −/− mouse is more susceptible to chemically-induced hepatotoxicity than its wildtype counterpart, and our objective in this study was to elucidate the mechanism(s) by which PPARβ/δ confers protection to hepatocytes. We hypothesized that PPARβ/ δ plays a protective role by responding to toxic lipids and altering gene expression accordingly. In support, oxidized-VLDL and constituents including 13-S-hydroxyoctadeca-dienoic acid (13(S)-HODE) and 4-HNE are PPARβ/δ ligands. A structure-activity relationship was established where 4-HNE and 4-hydroperoxynonenal (4-HpNE) enhanced the activity of the PPARβ/δ subtype while 4-hyroxy-hexenal (4-HHE), 4-oxo-2-Nonenal (4-ONE), and trans-4,5-epoxy-2(E)-decenal did not activate this receptor. Increasing PPARβ/δ activity with a synthetic agonist decreased sensitivity of hepatocytes to 4-HNE and other toxic agents, whereas inhibition of this receptor had the opposite result. Gene expression microarray analysis identified several important PPARβ/δ-regulated detoxification enzymes involved in 4-HNE metabolism that are regulated at the transcript level. This research established 4-HNE as an endogenous modulator of PPARβ/δ activity and raises the possibility that agonists of this nuclear receptor may be utilized to prevent or treat liver disease associated with oxidative damage.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The oxidative stress mediator 4-hydroxynonenal is an intracellular agonist of the nuclear receptor peroxisome proliferator-activated receptor-β/δ (PPARβ/δ)

Coleman

Prabhu

Thompson

et al. 2007

Free Radical Biology and Medicine

104

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“…Although useful, selective activation of PPAR isoforms by their synthetic ligands is seriously hampered by their overlapping specificity (34). These ligands have been shown to differentially induce unspecific activation of other PPAR isoforms, or even act PPAR-independent (34). In the present study, by combining PPAR subtype-selective siRNA knockdown with microarray profiling and genome-wide identification of PPREs, we determined isoformselective target gene profiles of PPARs in a cardiomyocyte-like cell type.…”

Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Peroxisome Proliferator-activated Receptor (PPAR) Gene Profiling Uncovers Insulin-like Growth Factor-1 as a PPARα Target Gene in Cardioprotection

Azzouzi

Leptidis

Bourajjaj

et al. 2011

Journal of Biological Chemistry

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Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor family of ligand-activated transcription factors and consist of the three isoforms, PPAR␣, PPAR␤/␦, and PPAR␥. Considerable evidence indicates the importance of PPARs in cardiovascular lipid homeostasis and diabetes, yet the isoform-dependent cardiac target genes remain unknown. Here, we constructed murine ventricular clones allowing stable expression of siRNAs to achieve specifically knockdown for each of the PPAR isoforms. By combining gene profiling and computational peroxisome proliferator response element analysis following PPAR isoform activation in normal versus PPAR isoform-deficient cardiomyocyte-like cells, we have, for the first time, determined PPAR isoform-specific endogenous target genes in the heart. Electromobility shift and chromatin immunoprecipitation assays demonstrated the existence of an evolutionary conserved peroxisome proliferator response element consensus-binding site in an insulin-like growth factor-1 (igf-1) enhancer. In line, Wy-14643-mediated PPAR␣ activation in the wild-type mouse heart resulted in up-regulation of igf-1 transcript abundance and provided protection against cardiomyocyte apoptosis following ischemia/reperfusion or biomechanical stress. Taken together, these data confirm igf-1 as an in vivo target of PPAR␣ and the involvement of a PPAR␣/IGF-1 signaling pathway in the protection of cardiomyocytes under ischemic and hemodynamic loading conditions.

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“…Those tested were carbaprostacyclin (cPGI 2 ), a ligand for both PTGIR and PPARD ( Forman et al 1997); cicaprost, a ligand for PTGIR but not PPARD ( Forman et al 1997); and AFP-07 a high-affinity ligand for PTGIR (Chang et al 1997) but no information available for binding to PPARD. In addition, L165041, a synthetic high-affinity ligand for PPARD without significant binding to PTGIR (Seimandi et al 2005) was used. Since PPARD heterodimerizes with RXRA upon activation, docasahexanoic acid (DHA), a ligand for RXRA (Germain et al 2006) was also included.…”

Section: Introductionmentioning

confidence: 99%

Expression patterns and role of prostaglandin-endoperoxide synthases, prostaglandin E synthases, prostacyclin synthase, prostacyclin receptor, peroxisome proliferator-activated receptor delta and retinoid x receptor alpha in rat endometrium during artificially-induced decidualization

Gillio-Meina¹,

Phang²,

Mather³

et al. 2009

Reproduction

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To determine if changes in endometrial expression of the enzymes and receptors involved in prostaglandin (PG) synthesis and action might provide insights into the PGs involved in the initiation of decidualization, ovariectomized steroid-treated rats at the equivalent of day 5 of pseudopregnancy were given a deciduogenic stimulus and killed at various times up to 32 h thereafter. The expression of PG-endoperoxide synthases (PTGS1 and PTGS2), microsomal PGE synthases (PTGES and PTGES2), cytosolic PGE synthase (PTGES3), prostacyclin synthase (PTGIS), prostacyclin receptor, peroxisome proliferator-activated receptor d (PPARD) and retinoid x receptor a (RXRA) in endometrium was assessed by semiquantitative RT-PCR, western blot analyses and immunohistochemistry. In addition, to determine which PG is involved in mediating decidualization, we compared the ability of PGE 2 , stable analogues of PGI 2 , L165041 (an agonist of PPARD), and docasahexanoic acid (an agonist of RXRA) to increase endometrial vascular permeability (EVP, an early event in decidualization), and decidualization when infused into the uterine horns of rats sensitized for the decidual cell reaction (DCR). EVP was assessed by uterine concentrations of Evans blue 10 h after initiation of infusions. DCR was assessed by the uterine mass 5 days after the initiation of the infusions. Because enzymes associated with the synthesis of PGE 2 , including PTGS2, are up-regulated in response to a deciduogenic stimulus and because PGE 2 was more effective than the PGI 2 analogues and PPARD and RXRA agonists in increasing EVP and inducing decidualization, we suggest that PGE 2 is most likely the PG involved in the initiation of decidualization in the rat.

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Differential responses of PPARα, PPARδ, and PPARγ reporter cell lines to selective PPAR synthetic ligands

Cited by 139 publications

References 34 publications

The oxidative stress mediator 4-hydroxynonenal is an intracellular agonist of the nuclear receptor peroxisome proliferator-activated receptor-β/δ (PPARβ/δ)

The oxidative stress mediator 4-hydroxynonenal is an intracellular agonist of the nuclear receptor peroxisome proliferator-activated receptor-β/δ (PPARβ/δ)

Peroxisome Proliferator-activated Receptor (PPAR) Gene Profiling Uncovers Insulin-like Growth Factor-1 as a PPARα Target Gene in Cardioprotection

Expression patterns and role of prostaglandin-endoperoxide synthases, prostaglandin E synthases, prostacyclin synthase, prostacyclin receptor, peroxisome proliferator-activated receptor delta and retinoid x receptor alpha in rat endometrium during artificially-induced decidualization

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