7-Ketocholesterol Is an Endogenous Modulator for the Arylhydrocarbon Receptor

Savouret, Jean‐François; Antenos, Monica; Quesne, Monique; Xu, Jin; Milgröm, Edwin; Casper, Robert F.

doi:10.1074/jbc.m005988200

Cited by 109 publications

(75 citation statements)

References 38 publications

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“…Such data suggest that STO-609 may constitute a relatively potent AhR ligand. In contrast, much higher EC 50 s have been reported for indole-3-carbinol (60 ϫ 10 Ϫ6 M), resveratrol (6 ϫ 10 Ϫ6 M), U0126 (25 ϫ 10 Ϫ6 M), and 7-ketocholesterol (7 ϫ 10 Ϫ6 M), using the same in vitro approach (Casper et al, 1999;Savouret et al, 2001), leading to the classification of these compounds as weak AhR ligands (Andrieux et al, 2004). Moreover, it is noteworthy that the chemical structure of STO-609 reveals some similarities with that of TCDD, especially the presence of aromatic rings (Fig.…”

Section: Discussionmentioning

confidence: 86%

Activation of the Aryl Hydrocarbon Receptor by the Calcium/Calmodulin-Dependent Protein Kinase Kinase Inhibitor 7-Oxo-7H-benzimidazo[2,1-a]benz[de]isoquinoline-3-carboxylic Acid (STO-609)

Monteiro

Gilot²,

Langouët³

et al. 2008

Drug Metab Dispos

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Section: Discussionmentioning

confidence: 86%

Activation of the Aryl Hydrocarbon Receptor by the Calcium/Calmodulin-Dependent Protein Kinase Kinase Inhibitor 7-Oxo-7H-benzimidazo[2,1-a]benz[de]isoquinoline-3-carboxylic Acid (STO-609)

Monteiro

Gilot²,

Langouët³

et al. 2008

Drug Metab Dispos

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“…Interestingly, PON1 induction by curcumin was significantly counteracted (approximately 50 % inhibition at 20 mM-curcumin) due to 20 mM-7-ketocholesterol (data not shown). It has been previously shown that 7-ketocholesterol is an inhibitor of the aryl hydrocarbon receptor (16) . Thus, PON1 induction by curcumin seems to be, at least partly, mediated by an aryl hydrocarbon receptor-dependent signal transduction pathway.…”

Section: Resultsmentioning

confidence: 99%

Curcumin induces paraoxonase 1 in cultured hepatocytes in vitro but not in mouse liver in vivo

et al. 2010

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Paraoxonase 1 (PON1) is an enzyme that is mainly synthesised in the liver and protects LDL from oxidation, thereby exhibiting antiatherogenic properties. Using a luciferase reporter gene assay, we tested curcumin for its ability to induce PON1 in Huh7 hepatocytes in culture. Curcumin ($10 mmol/l) dose-dependently induced PON1 transactivation in Huh7 cells. However, dietary supplementation of female B6C3F1 mice with curcumin (500 mg/kg diet) for 2 weeks did not increase the hepatic PON1 mRNA and protein levels. No curcumin was detectable in the plasma of the 12 h fasted mice. In conclusion, curcumin may be a potent PON1 inducer in cultured cells in vitro, but not in the liver of curcumin-fed mice because of its low concentrations in vivo.

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“…23,25 Candidate endogenous ligands of the AhR include ketocholesterol, bilirubin, indigo, lipoxin A 4 , and tryptophan derivatives such as ITE. 22,[27][28][29][30][31][32] However, the AhR is betterknown for its ligation by a diverse group of xenobiotics, the most potent of which is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). 22 Agonist binding induces nuclear translocation of the AhR, which allows it to regulate expression of a variety of genes, including those of the cytochrome P450 family of drug-metabolizing enzymes.…”

mentioning

confidence: 99%

The Aryl Hydrocarbon Receptor Ligand ITE Inhibits TGFβ1-Induced Human Myofibroblast Differentiation

Lehmann

Xia

Kulkarni

et al. 2011

The American Journal of Pathology

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Fibrosis can occur in any human tissue when the normal wound healing response is amplified. Such amplification results in fibroblast proliferation, myofibroblast differentiation, and excessive extracellular matrix deposition. Occurrence of these sequelae in organs such as the eye or lung can result in severe consequences to health. Unfortunately, medical treatment of fibrosis is limited by a lack of safe and effective therapies. These therapies may be developed by identifying agents that inhibit critical steps in fibrotic progression; one such step is myofibroblast differentiation triggered by transforming growth factor-␤1 (TGF␤1). In this study, we demonstrate that TGF␤1-induced myofibroblast differentiation is blocked in human fibroblasts by a candidate endogenous aryl hydrocarbon receptor (AhR) ligand 2-(1=H-indole-3=-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE). Our data show that ITE disrupts TGF␤1 signaling by inhibiting the nuclear translocation of Smad2/3/4. Although ITE functions as an AhR agonist, and biologically persistent AhR agonists, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin, cause severe toxic effects, ITE exhibits no toxicity. Interestingly, ITE effectively inhibits TGF␤1-driven myofibroblast differentiation in AhR ؊/؊ fibroblasts: Its ability to inhibit TGF␤1 signaling is AhR independent. As supported by the results of this study, the small molecule ITE inhibits myofibroblast differentiation and may be useful clinically as an antiscarring agent.

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7-Ketocholesterol Is an Endogenous Modulator for the Arylhydrocarbon Receptor

Abstract: We have identified 7-ketocholesterol (7-KC) as an endogenous modulator that inhibits transactivation by the arylhydrocarbon receptor (

Cited by 109 publications

References 38 publications

Activation of the Aryl Hydrocarbon Receptor by the Calcium/Calmodulin-Dependent Protein Kinase Kinase Inhibitor 7-Oxo-7H-benzimidazo[2,1-a]benz[de]isoquinoline-3-carboxylic Acid (STO-609)

Activation of the Aryl Hydrocarbon Receptor by the Calcium/Calmodulin-Dependent Protein Kinase Kinase Inhibitor 7-Oxo-7H-benzimidazo[2,1-a]benz[de]isoquinoline-3-carboxylic Acid (STO-609)

Curcumin induces paraoxonase 1 in cultured hepatocytes in vitro but not in mouse liver in vivo

The Aryl Hydrocarbon Receptor Ligand ITE Inhibits TGFβ1-Induced Human Myofibroblast Differentiation

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