RT Journal Article SR Electronic T1 International Union of Pharmacology. LXI. Peroxisome Proliferator-Activated Receptors JF Pharmacological Reviews JO Pharmacol Rev FD American Society for Pharmacology and Experimental Therapeutics SP 726 OP 741 DO 10.1124/pr.58.4.5 VO 58 IS 4 A1 Liliane Michalik A1 Johan Auwerx A1 Joel P. Berger A1 V. Krishna Chatterjee A1 Christopher K. Glass A1 Frank J. Gonzalez A1 Paul A. Grimaldi A1 Takashi Kadowaki A1 Mitchell A. Lazar A1 Stephen O'Rahilly A1 Colin N. A. Palmer A1 Jorge Plutzky A1 Janardan K. Reddy A1 Bruce M. Spiegelman A1 Bart Staels A1 Walter Wahli YR 2006 UL http://pharmrev.aspetjournals.org/content/58/4/726.abstract AB 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. PPARα is expressed at high levels in organs with significant catabolism of fatty acids. PPARβ/δ has the broadest expression pattern, and the levels of expression in certain tissues depend on the extent of cell proliferation and differentiation. PPARγ is expressed as two isoforms, of which PPARγ2 is found at high levels in the adipose tissues, whereas PPARγ1 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 PPARα and PPARγ 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.