Binding of prostaglandins to human PPARγ: tool assessment and new natural ligands

Ferry, Gilles; Bruneau, Vincent; Beauverger, Philippe; Goussard, Marion; Rodriguez, Marianne; Lamamy, Véronique; Dromaint, Sandra; Canet, Emmanuel; Galizzi, Jean‐Pierre; Boutin, Jean A.

doi:10.1016/s0014-2999(01)00907-4

Cited by 52 publications

(34 citation statements)

References 56 publications

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“…ૺ, p Ͻ 0.05 by ANOVA with post hoc Dunnett's test. 15d-PGJ 2 has been reported to be an activator of PPAR-␦ and -␥ (Forman et al, 1995(Forman et al, , 1997Kliewer et al, 1995;Ferry et al, 2001). To assess the relative roles of PPAR-␥ and -␦ in mediating 15d-PGJ 2 effects, WISH cells were transfected with a pTK-PPREx3-luc reporter plasmid, and luciferase activity was determined after treatment with 15d-PGJ 2 (0 -10 M), the PPAR-␥ ligand rosiglitazone (0 -10 M), and the PPAR-␦ ligand GW501516 (0 -1 M).…”

Section: Resultsmentioning

confidence: 99%

Nanomolar and Micromolar Effects of 15-Deoxy-Δ^12,14-prostaglandin J₂on Amnion-Derived WISH Epithelial Cells: Differential Roles of Peroxisome Proliferator-Activated Receptors γ and δ and Nuclear Factor κB

Berry¹,

Keelan²,

Helliwell³

et al. 2005

Mol Pharmacol

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15-Deoxy ⌬12,14 -prostaglandin J 2 (15d-PGJ 2 ), an activator of peroxisome proliferator-activated receptor (PPAR)-␥ and -␦, is a prostanoid metabolite with anti-inflammatory actions. In intrauterine tissues, proinflammatory cytokines and prostaglandins have been identified as playing key roles in the maintenance of pregnancy and the onset of labor. We investigated and compared the early (Ͻ3 h) effects of 15d-PGJ 2 with rosiglitazone (PPAR-␥ ligand) and 2-methyl-4-((4-methyl-2-(4-trifluoromethylphenyl)-1,3-thiazol-5-yl)-methylsulfanyl)phenoxy-acetic acid (GW501516) (PPAR-␦ ligand) on interleukin (IL)-1␤-induced prostaglandin and cytokine production by amnion-derived WISH cells. We show that 15d-PGJ 2 exerts differential effects depending on concentration. At low concentrations (Ͻ0.1 M), 15d-PGJ 2 inhibited IL-1␤-stimulated prostaglandin E 2 (PGE 2 ) but not cytokine (IL-6/IL-8) production or cyclooxygenase-2 (COX-2) expression. This effect was attenuated by a PPAR-␥ inhibitor [2-chloro-5-nitro-N-phenylbenzamide (GW9662)], by transfection with a dominant-negative PPAR construct, and was reproduced by the PPAR-␥ ligand rosiglitazone. At higher concentrations (1-10 M), 15d-PGJ 2 inhibited IL-1␤-stimulated PGE 2 and cytokine production and COX-2 expression, and this effect was not blocked by GW9662. Rosiglitazone at high concentrations (1-10 M) stimulated PGE 2 production in the absence or presence of the dominant-negative PPAR. The PPAR-␦ ligand GW501516 also inhibited IL-1␤-stimulated PGE 2 production but only at high concentrations (1 M). IL-1␤-induced nuclear factor-B (NF-B) DNA binding activity was significantly inhibited by 15d-PGJ 2 (10 M) and GW501516 (1 M) but increased with 10 M rosiglitazone. We conclude that 1) at low concentrations, 15d-PGJ 2 acts through a PPAR-␥ signaling pathway; b) at higher concentrations, its actions are mediated most likely through other pathways such as activation of PPAR-␦ and/or inhibition of NF-B; and 3) rosiglitazone exerts PPAR-independent effects at high concentrations (Ͼ1 M).Proinflammatory cytokines have been shown to play crucial roles in the maintenance of human pregnancy and the initiation of parturition (Romero et al., 1993;Mitchell et al., 1995). The presence of intrauterine infection has been shown to result in the local expression and secretion of proinflammatory cytokines such as interleukin (IL)-1␤, tumor necrosis factor-␣, IL-6, and IL-8 (Romero et al., 1993;Dudley et al., 1996;Keelan et al., 1999a), which act locally on intrauterine cells to induce the release of inflammatory mediators, extracellular matrix-remodeling enzymes (So et al., 1992;Draper et al., 1995), and prostaglandins (PGs) through altered expression of prostanoid biosynthetic enzymes including fatty acid cyclooxygenase-2 (COX-2) Hansen et al., 1999;Kniss, 1999;Rauk and Chiao, 2000).Although most studies to date have focused on the produc- Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org. doi:10.1124/mol.104.009449.ABBREVIATIONS: IL, ...

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Section: Resultsmentioning

confidence: 99%

Nanomolar and Micromolar Effects of 15-Deoxy-Δ^12,14-prostaglandin J₂on Amnion-Derived WISH Epithelial Cells: Differential Roles of Peroxisome Proliferator-Activated Receptors γ and δ and Nuclear Factor κB

Berry¹,

Keelan²,

Helliwell³

et al. 2005

Mol Pharmacol

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“…K i values were calculated according to the equation 50 is the concentration of test compound required to inhibit 50% of the specific binding of the radioligand, [L] is the concentration of the radioligand used, and K d is the dissociation constant for the radioligand at the receptor (40). Each experiment was performed twice, and points were in triplicate.…”

Section: Methodsmentioning

confidence: 99%

S 26948

et al. 2007

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OBJECTIVE-Rosiglitazone displays powerful antidiabetes benefits but is associated with increased body weight and adipogenesis. Keeping in mind the concept of selective peroxisome proliferator-activated receptor (PPAR)␥ modulator, the aim of this study was to characterize the properties of a new PPAR␥ ligand, S 26948, with special attention in body-weight gain.RESEARCH DESIGN AND METHODS-We used transient transfection and binding assays to characterized the binding characteristics of S 26948 and GST pull-down experiments to investigate its pattern of coactivator recruitment compared with rosiglitazone. We also assessed its adipogenic capacity in vitro using the 3T3-F442A cell line and its in vivo effects in ob/ob mice (for antidiabetes and antiobesity properties), as well as the homozygous human apolipoprotein E2 knockin mice (E2-KI) (for antiatherogenic capacity).RESULTS-S 26948 displayed pharmacological features of a high selective ligand for PPAR␥ with low potency in promoting adipocyte differentiation. It also displayed a different coactivator recruitment profile compared with rosiglitazone, being unable to recruit DRIP205 or PPAR␥ coactivator-1␣. In vivo experiments showed that S 26948 was as efficient in ameliorating glucose and lipid homeostasis as rosiglitazone, but it did not increase body and white adipose tissue weights and improved lipid oxidation in liver. In addition, S 26948 represented one of the few molecules of the PPAR␥ ligand class able to decrease atherosclerotic lesions.CONCLUSIONS-These findings establish S 26948 as a selective PPAR␥ ligand with distinctive coactivator recruitment and gene expression profile, reduced adipogenic effect, and improved biological responses in vivo.

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“…As for the standard agonists, pioglitazone (pEC 50 6.0) was found to be far more active than linoleic acid (pEC 50 3.2). For pioglitazone, PPAR␥ activity was reported at concentrations approximately 5 times lower than those found here (Ferry et al, 2001;Minoura et al, 2004;Inukai et al, 2005). Hence, the sensitivity of our experimental setup may be somewhat low, and the true minimum concentrations of the drugs needed for PPAR␥ activation may be lower than found here.…”

Section: Resultsmentioning

confidence: 52%

“…For PPAR␥, several unsaturated fatty acids have been proposed as natural ligands, in particular prostaglandins such as 15-deoxy-⌬ 12,14 -prostaglandin J 2 (Ferry et al, 2001), nitrolinoleic acids such as 10-nitrolinoleic acid (Schopfer et al, 2005), and putative metabolites of docosahexaenoic acid such as 4-hydroxydocosahexaenoic acid (Yamamoto et al, 2005). A few synthetic PPAR␥ agonists are approved drugs [e.g., rosiglitazone, pioglitazone, which are members of the glitazone (thiazolidinedione) class (Willson et al, 2001)] or are under development as antidiabetics [e.g., tesaglitazar (Ericsson et al, 2004) and muraglitazar (Cox, 2005)].…”

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confidence: 99%

Sulfonylureas and Glinides Exhibit Peroxisome Proliferator-Activated Receptor γ Activity: A Combined Virtual Screening and Biological Assay Approach

Scarsi

Podvinec²,

Roth³

et al. 2006

Mol Pharmacol

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Most drugs currently employed in the treatment of type 2 diabetes either target the sulfonylurea receptor stimulating insulin release (sulfonylureas, glinides), or target the peroxisome proliferator-activated receptor (PPAR␥) improving insulin resistance (thiazolidinediones). Our work shows that sulfonylureas and glinides additionally bind to PPAR␥ and exhibit PPAR␥ agonistic activity. This activity was predicted in silico by virtual screening and confirmed in vitro in a binding assay, a transactivation assay, and by measuring the expression of PPAR␥ target genes. Among the measured compounds, gliquidone and glipizide (two sulfonylureas), as well as nateglinide (a glinide), exhibit PPAR␥ agonistic activity at concentrations comparable with those reached under pharmacological treatment. The

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Binding of prostaglandins to human PPARγ: tool assessment and new natural ligands

Cited by 52 publications

References 56 publications

Nanomolar and Micromolar Effects of 15-Deoxy-Δ^12,14-prostaglandin J₂on Amnion-Derived WISH Epithelial Cells: Differential Roles of Peroxisome Proliferator-Activated Receptors γ and δ and Nuclear Factor κB

Nanomolar and Micromolar Effects of 15-Deoxy-Δ^12,14-prostaglandin J₂on Amnion-Derived WISH Epithelial Cells: Differential Roles of Peroxisome Proliferator-Activated Receptors γ and δ and Nuclear Factor κB

S 26948

Sulfonylureas and Glinides Exhibit Peroxisome Proliferator-Activated Receptor γ Activity: A Combined Virtual Screening and Biological Assay Approach

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Binding of prostaglandins to human PPARγ: tool assessment and new natural ligands

Cited by 52 publications

References 56 publications

Nanomolar and Micromolar Effects of 15-Deoxy-Δ12,14-prostaglandin J2on Amnion-Derived WISH Epithelial Cells: Differential Roles of Peroxisome Proliferator-Activated Receptors γ and δ and Nuclear Factor κB

Nanomolar and Micromolar Effects of 15-Deoxy-Δ12,14-prostaglandin J2on Amnion-Derived WISH Epithelial Cells: Differential Roles of Peroxisome Proliferator-Activated Receptors γ and δ and Nuclear Factor κB

S 26948

Sulfonylureas and Glinides Exhibit Peroxisome Proliferator-Activated Receptor γ Activity: A Combined Virtual Screening and Biological Assay Approach

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Nanomolar and Micromolar Effects of 15-Deoxy-Δ^12,14-prostaglandin J₂on Amnion-Derived WISH Epithelial Cells: Differential Roles of Peroxisome Proliferator-Activated Receptors γ and δ and Nuclear Factor κB

Nanomolar and Micromolar Effects of 15-Deoxy-Δ^12,14-prostaglandin J₂on Amnion-Derived WISH Epithelial Cells: Differential Roles of Peroxisome Proliferator-Activated Receptors γ and δ and Nuclear Factor κB