The pollutant diethylhexyl phthalate regulates hepatic energy metabolism via species-specific PPARalpha-dependent mechanisms.

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Etat: Public
Version: de l'auteur
ID Serval
serval:BIB_15084BA0F852
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
The pollutant diethylhexyl phthalate regulates hepatic energy metabolism via species-specific PPARalpha-dependent mechanisms.
Périodique
Environmental Health Perspectives
Auteur(s)
Feige J.N., Gerber A., Casals-Casas C., Yang Q., Winkler C., Bedu E., Bueno M., Gelman L., Auwerx J., Gonzalez F.J., Desvergne B.
ISSN
1552-9924[electronic], 0091-6765[linking]
Statut éditorial
Publié
Date de publication
2010
Peer-reviewed
Oui
Volume
118
Numéro
2
Pages
234-241
Langue
anglais
Résumé
Background: The modulation of energetic homeostasis by pollutants has recently emerged as a potential contributor to the onset of metabolic disorders. Diethylhexyl phthalate (DEHP) is a widely used industrial plasticizer to which humans are widely exposed. Phthalates can activate the three peroxisome proliferatoractivated receptor (PPAR) isotypes on cellular models and induce peroxisome proliferation in rodents.Objectives: In this study, we aimed to evaluate the systemic and metabolic consequences of DEHP exposure that have remained so far unexplored and to characterize the underlying molecular mechanisms of action.Methods: As a proof of concept and mechanism, genetically engineered mouse models of PPARs were exposed to high doses of DEHP, followed by metabolic and molecular analyses.Results: DEHP-treated mice were protected from diet-induced obesity via PPARalpha-dependent activation of hepatic fatty acid catabolism, whereas the activity of neither PPARbeta nor PPARgamma was affected. However, the lean phenotype observed in response to DEHP in wild-type mice was surprisingly abolished in PPARalpha-humanized mice. These species differences are associated with a different pattern of coregulator recruitment.Conclusion: These results demonstrate that DEHP exerts species-specific metabolic actions that rely to a large extent on PPARalpha signaling and highlight the metabolic importance of the species-specific activation of PPARalpha by xenobiotic compounds. Editor's SummaryDiethylhexyl phthalate (DEHP) is an industrial plasticizer used in cosmetics, medical devices, food packaging, and other applications. Evidence that DEHP metabolites can activate peroxisome proliferatoractivated receptors (PPARs) involved in fatty acid oxidation (PPARalpha and PPARbeta) and adiposite function and insulin resistance (PPARgamma) has raised concerns about potential effects of DEHP on metabolic homeostasis. In rodents, PPARalpha activation also induces hepatic peroxisome proliferation, but this response to PPARalpha activation is not observed in humans. Feige et al. (p. 234) evaluated systemic and metabolic consequences of high-dose oral DEHP in combination with a high-fat diet in wild-type mice and genetically engineered mouse PPAR models. The authors report that mice exposed to DEHP gained less weight than controls, without modifying their feeding behavior; they also exhibited lower triglyceride levels, smaller adipocytes, and improved glucose tolerance compared with controls. These effects, which were observed in mice fed both high-fat and standard diets, appeared to be mediated by PPARalpha-dependent activation of hepatic fatty acid catabolism without apparent involvement of PPARbeta or PPARgamma. However, mouse models that expressed human (versus mouse) PPARalpha tended to gain more weight on a high-fat diet than their DHEP-unexposed counterparts. The authors conclude that findings support species-specific metabolic effects of DEHP mediated by PPARalpha activation.
Mots-clé
Animals, Cell Line, Diethylhexyl Phthalate/pharmacology, Energy Metabolism/drug effects, Fatty Acids/metabolism, Glucose Tolerance Test, Liver/drug effects, Liver/metabolism, Mice, Mice, Inbred C57BL, Mice, Transgenic, Obesity/chemically induced, Obesity/prevention & control, Oxidation-Reduction/drug effects, PPAR alpha/metabolism, Phenotype, Plasticizers/pharmacology
Pubmed
Web of science
Création de la notice
01/03/2010 15:34
Dernière modification de la notice
20/08/2019 12:44
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