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Papers In Press, published online ahead of print April 27, 2007
J. Biol. Chem, 10.1074/jbc.M702724200
Submitted on March 30, 2007
Revised on April 25, 2007
Accepted on April 27, 2007
modulator which promotes adipogenesis
Center for Integrative Genomics, Lausanne 1015
Corresponding Author: beatrice.desvergne{at}unil.ch
The ability of pollutants to affect human health is a major concern, justified by the wide demonstration that reproductive functions are altered by endocrine disrupting chemicals (EDCs). The definition of endocrine disruption is today extended to broader endocrine regulations, and includes activation of metabolic sensors, such as the Peroxisome Proliferator-Activated Receptors (PPARs). Toxicology approaches have demonstrated that phthalate plasticizers can directly influence PPAR activity. What is now missing is a detailed molecular understanding of the fundamental basis of EDC interference with PPAR action. We thus performed structural and functional analyses that demonstrate how Mono-Ethyl-Hexyl-Phthalate (MEHP) directly activates PPARg and promotes adipogenesis, albeit to a lower extent than the full-agonist Rosiglitazone. Importantly, we demonstrate that MEHP induces a selective activation of different PPARg target genes. Chromatin immuno-precipitation and fluorescence microscopy in living cells reveal that this selective activity correlates with the recruitment of a specific subset of PPARg coregulators which includes Med1 and PGC-1a, but not p300 and SRC-1. These results highlight some key mechanisms in metabolic disruption but are also instrumental in the context of selective PPAR modulation, a promising field for new therapeutic development based on PPAR modulation.
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