Récepteur activé par les proliférateurs de peroxysomes

Le récepteur activé par les proliférateurs de peroxysomes (peroxisome proliferator-activated receptor, PPAR) est une protéine de la superfamille des récepteurs nucléaires liant naturellement les lipides et agissant comme facteur de transcription des gènes cibles impliqués notamment dans le métabolisme et l'adipogenèse. Nomenclature Trois types de PPAR ont été identifiés : alpha, gamma et delta (bêta).

PPAR α : exprimé dans le foie, les reins, le cœur, les muscles, le tissu adipeux, et autres.
PPAR γ : bien que transcrit par le même gêne, ce PPAR existe sous trois formes : ** PPAR γ1 : exprimé pratiquement dans tous les tissus, comme le cœur, les muscles, le côlon, les reins, le pancréas et la rate. ** PPAR γ2 : exprimé principalement dans le tissu adipeux (30 acides aminés). ** PPAR γ3 : exprimé dans les macrophages.
PPAR β/δ : exprimé dans plusieurs tissus mais de façon plus importante dans le cerveau, le tissu adipeux et la peau.

Structure Comme tou

International Union of Pharmacology. LXI. Peroxisome proliferator-activated receptors.

Johan Auwerx, Liliane Michalik, Walter Wahli

The three peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors of the nuclear hormone receptor superfamily. They share a high degree of structural homology with all members of the superfamily, particularly in the DNA-binding domain and ligand- and cofactor-binding domain. Many cellular and systemic roles have been attributed to these receptors, reaching far beyond the stimulation of peroxisome proliferation in rodents after which they were initially named. PPARs exhibit broad, isotype-specific tissue expression patterns. PPARalpha is expressed at high levels in organs with significant catabolism of fatty acids. PPARbeta/delta has the broadest expression pattern, and the levels of expression in certain tissues depend on the extent of cell proliferation and differentiation. PPARgamma is expressed as two isoforms, of which PPARgamma2 is found at high levels in the adipose tissues, whereas PPARgamma1 has a broader expression pattern. Transcriptional regulation by PPARs requires heterodimerization with the retinoid X receptor (RXR). When activated by a ligand, the dimer modulates transcription via binding to a specific DNA sequence element called a peroxisome proliferator response element (PPRE) in the promoter region of target genes. A wide variety of natural or synthetic compounds was identified as PPAR ligands. Among the synthetic ligands, the lipid-lowering drugs, fibrates, and the insulin sensitizers, thiazolidinediones, are PPARalpha and PPARgamma agonists, respectively, which underscores the important role of PPARs as therapeutic targets. Transcriptional control by PPAR/RXR heterodimers also requires interaction with coregulator complexes. Thus, selective action of PPARs in vivo results from the interplay at a given time point between expression levels of each of the three PPAR and RXR isotypes, affinity for a specific promoter PPRE, and ligand and cofactor availabilities.

2006

The Pollutant Diethylhexyl Phthalate Regulates Hepatic Energy Metabolism via Species-Specific PPAR alpha-Dependent Mechanisms

Johan Auwerx

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 proliferator-activated receptor (PPAR) isotypes on cellular models and induce peroxisome proliferation in rodents.

2010

IL-13 induces expression of CD36 in human monocytes through PPARgamma activation

Johan Auwerx, Walter Wahli

The class B scavenger receptor CD36 is a component of the pattern recognition receptors on monocytes that recognizes a variety of molecules. CD36 expression in monocytes depends on exposure to soluble mediators. We demonstrate here that CD36 expression is induced in human monocytes following exposure to IL-13, a Th2 cytokine, via the peroxisome proliferator-activated receptor (PPAR)gamma pathway. Induction of CD36 protein was paralleled by an increase in CD36 mRNA. The PPARgamma pathway was demonstrated using transfection of a PPARgamma expression plasmid into the murine macrophage cell line RAW264.7, expressing very low levels of PPARgamma, and in peritoneal macrophages from PPARgamma-conditional null mice. We also show that CD36 induction by IL-13 via PPARgamma is dependent on phospholipase A2 activation and that IL-13 induces the production of endogenous 15-deoxy-Delta12,14-prostaglandin J2, an endogenous PPARgamma ligand, and its nuclear localization in human monocytes. Finally, we demonstrate that CD36 and PPARgamma are involved in IL-13-mediated phagocytosis of Plasmodium falciparum-parasitized erythrocytes. These results reveal a novel role for PPARgamma in the alternative activation of monocytes by IL-13, suggesting that endogenous PPARgamma ligands, produced by phospholipase A2 activation, could contribute to the biochemical and cellular functions of CD36.

2007

International Union of Pharmacology. LXI. Peroxisome proliferator-activated receptors.

Johan Auwerx, Liliane Michalik, Walter Wahli

2006