Fatty Acids, Eicosanoids, and Hypolipidemic Agents Identified as Ligands of Peroxisome Proliferator-Activated Receptors by Coactivator-Dependent Receptor Ligand Assay

Krey, Grigorios; Braissant, Olivier; L'Horset, F; Kalkhoven, Eric; Perroud, Mai; Parker, Malcolm G.; Wahli, Walter

doi:10.1210/mend.11.6.0007

Cited by 882 publications

(299 citation statements)

References 30 publications

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“…This specificity may derive from various lipase-specific properties: different substrates (triglyceride vs. phospholipids, saturated vs. unsaturated FA), subsequent FA modifications, and͞or the lipolytic products generated. Regardless, these results argue against the assumption based on prior in vitro data that FA in general activate PPARs (38)(39)(40) or that FA generation by any means of lipolysis would do the same. Rather, our findings suggest different transcriptional responses dependent on the specific mechanism of FA generation and uptake (Fig.…”

Section: Discussioncontrasting

confidence: 63%

Lipolysis of triglyceride-rich lipoproteins generates PPAR ligands: Evidence for an antiinflammatory role for lipoprotein lipase

Ziouzenkova

Perrey

Asatryan

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

219

176

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Section: Discussioncontrasting

confidence: 63%

Lipolysis of triglyceride-rich lipoproteins generates PPAR ligands: Evidence for an antiinflammatory role for lipoprotein lipase

Ziouzenkova

Perrey

Asatryan

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

219

176

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“…Future studies should be performed to compare strategies with the wild-type and mutant systems. To date, several in vitro assays have been developed for screening ER ligands by using either purified ER␣ protein or ER isolated from cell lysates (18)(19)(20)(21). Limited fluorescence-based assays (22) have been developed to measure receptor conformational changes (23) and recruitment of coactivator peptides (22,24,25) in the full-length hER␣ within cell culture (26).…”

Section: Discussionmentioning

confidence: 99%

An intramolecular folding sensor for imaging estrogen receptor–ligand interactions

Paulmurugan

Gambhir

2006

Proc. Natl. Acad. Sci. U.S.A.

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Strategies for high-throughput analysis of interactions between various hormones and drugs with the estrogen receptor (ER) are crucial for accelerating the understanding of ER biology and pharmacology. Through careful analyses of the crystal structures of the human ER (hER) ligand-binding domain (hER-LBD) in complex with different ligands, we hypothesized that the hER-LBD intramolecular folding pattern could be used to distinguish ER agonists from selective ER modulators and pure antiestrogens. We therefore constructed and validated intramolecular folding sensors encoding various hER-LBD fusion proteins that could lead to split Renilla͞firefly luciferase reporter complementation in the presence of the appropriate ligands. A mutant hER-LBD with low affinity for circulating estradiol was also identified for imaging in living subjects. Cells stably expressing the intramolecular folding sensors expressing wild-type and mutant hER-LBD were used for imaging ligand-induced intramolecular folding in living mice. This is the first hER-LBD intramolecular folding sensor suited for high-throughput quantitative analysis of interactions between hER with hormones and drugs using cell lysates, intact cells, and molecular imaging of small living subjects. The strategies developed can also be extended to study and image other important protein intramolecular folding systems.complementation ͉ optical imaging ͉ split reporters E strogens are responsible for the growth, development, and maintenance of the reproductive, skeletal, neuronal, and immune systems as well as and other systems. The physiological effects of these hormones are mediated by the estrogen receptor (ER), which is a ligand-inducible nuclear transcription factor (1). In the classical pathway of steroid hormone action, 17␤-estradiol (E2), hormones, and a variety of other estrogens bind to the ligandbinding domain (LBD) of ER and lead to its dimerization and subsequent binding to a specific regulatory sequence in the promoters of ER target genes known as the estrogen response elements (2, 3), which then trigger activation or repression of many downstream target genes (4). The deficiency or excess of estrogens can lead to various pathological conditions including osteoporosis and breast carcinomas (5), making ER a major cellular therapeutic target.Elegant crystallographic studies with ER-LBD have shown that conformation of helix 12 (H12) is critical in responses observed with various ER ligands (4, 6, 7). The conformation of H12 behaves as a ''molecular switch'' that either prevents or enhances ER from binding to an array of coactivator proteins, which then activates transcription of many downstream estrogen-regulated genes responsible for cell growth. Given the critical role of H12 in ER signaling, we reasoned that it may be feasible to develop an intramolecular ER folding sensor with specific split reporter complementation patterns to study ligand pharmacology based directly on the conformational changes of H12 in response to different ligands (Fig. 1).We used a spli...

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“…The biological effects of 15d-PGJ 2 have attracted considerable interest in recent years. It was initially identified as a high affinity natural ligand for the peroxisome proliferator-activated receptor-␥ (PPAR␥) and shown to exert several effects through binding to this nuclear receptor (2)(3)(4)(5). More recently, several recent studies have shown that 15d-PGJ 2 exhibits a potent anti-inflammatory effect by attenuating the expression of proinflammatory mediators in activated monocytes/macrophages mainly through the inhibition of NF-B-dependent transcription of inflammatory genes (6,7).…”

Section: -mentioning

confidence: 99%

Induction of Heme Oxygenase-1 Expression in Murine Macrophages Is Essential for the Anti-inflammatory Effect of Low Dose 15-Deoxy-Δ12,14-prostaglandin J2

Lee

Tsai

Chau

2003

Journal of Biological Chemistry

205

131

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15-Deoxy-⌬ 12,14 -prostaglandin J 2 (15d-PGJ 2 ), a cyclopentenone prostaglandin, displays a potent anti-inflammatory effect at micromolar concentrations (>2 M) through direct inhibition of nuclear factor (NF)-B activation. Here we show that at submicromolar concentrations (0.1-0.5 M) 15d-PGJ 2 retains the ability to suppress the production of tumor necrosis factor-␣ (TNF-␣) and nitric oxide (NO) in lipopolysaccharide (LPS)-activated murine J774 macrophages under the conditions of a prolonged incubation (>12 h). Western blot analysis revealed that the expression of the cytoprotective enzyme, heme oxygenase-1 (HO-1), was induced and coincident with the anti-inflammatory action of 15d-PGJ 2 . Inhibition of HO-1 activity or scavenging carbon monoxide (CO), a byproduct derived from heme degradation, significantly attenuated the suppressive activity of 15d-PGJ 2 . Furthermore, LPS-induced NF-B activation assessed by the inhibitory protein of NF-B (I B) degradation and p50 nuclear translocation was diminished in cells subjected to prolonged treatment with the low concentration of 15d-PGJ 2 . Treatment of cells with the protein synthesis inhibitor, cycloheximide, or the specific p38 MAP kinase inhibitor, SB203580, blocked the induction of HO-1 and suppression of LPS-induced I B degradation mediated by 15d-PGJ 2 . Likewise, HO inhibitor and CO scavenger were effective in abolishing the inhibitory effects of 15d-PGJ 2 on NF-B activation induced by LPS. The functional role of CO was further demonstrated by the use of a CO releasing molecule, tricarbonyldichlororuthenium(II) dimer, which significantly suppressed LPS-induced nuclear translocation of p50 as assessed by confocal immunofluorescence. Collectively, these data suggest that even at submicromolar concentrations 15d-PGJ 2 can exert an anti-inflammatory effect in macrophages through a mechanism that involves the action of HO/CO.15-Deoxy-⌬ 12,14 -prostaglandin J 2 (15d-PGJ 2 ), 1 a dehydration product of prostaglandin D 2 , has been shown to be present in the inflammatory exudates and is increased during the resolution phase of inflammation (1). The biological effects of 15d-PGJ 2 have attracted considerable interest in recent years. It was initially identified as a high affinity natural ligand for the peroxisome proliferator-activated receptor-␥ (PPAR␥) and shown to exert several effects through binding to this nuclear receptor (2-5). More recently, several recent studies have shown that 15d-PGJ 2 exhibits a potent anti-inflammatory effect by attenuating the expression of proinflammatory mediators in activated monocytes/macrophages mainly through the inhibition of NF-B-dependent transcription of inflammatory genes (6, 7). In addition to antagonizing the NF-B activity through PPAR␥-dependent mechanism (6 -8), 15d-PGJ 2 can directly inhibit the signaling steps leading to NF-B activation (9 -12). It has also been shown that the ␣,␤-unsaturated carbonyl group of 15d-PGJ 2 can act as an electrophile to react covalently with specific cysteine residues located in the activa...

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Fatty Acids, Eicosanoids, and Hypolipidemic Agents Identified as Ligands of Peroxisome Proliferator-Activated Receptors by Coactivator-Dependent Receptor Ligand Assay

Cited by 882 publications

References 30 publications

Lipolysis of triglyceride-rich lipoproteins generates PPAR ligands: Evidence for an antiinflammatory role for lipoprotein lipase

Lipolysis of triglyceride-rich lipoproteins generates PPAR ligands: Evidence for an antiinflammatory role for lipoprotein lipase

An intramolecular folding sensor for imaging estrogen receptor–ligand interactions

Induction of Heme Oxygenase-1 Expression in Murine Macrophages Is Essential for the Anti-inflammatory Effect of Low Dose 15-Deoxy-Δ12,14-prostaglandin J2

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