title: International Union of Pharmacology. LXI. Peroxisome proliferator-activated receptors.
abstract: 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.
authors.affiliation: Center for Integrative Genomics, National Research Centre "Frontiers in Genetics," University of Lausanne, Lausanne, Switzerland.
authors.forename: Liliane
authors.initials: L
authors.lastname: Michalik
authors.forename: Johan
authors.initials: J
authors.lastname: Auwerx
authors.forename: Joel P
authors.initials: JP
authors.lastname: Berger
authors.forename: V Krishna
authors.initials: VK
authors.lastname: Chatterjee
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Glass
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.forename: Paul A
authors.initials: PA
authors.lastname: Grimaldi
authors.forename: Takashi
authors.initials: T
authors.lastname: Kadowaki
authors.forename: Mitchell A
authors.initials: MA
authors.lastname: Lazar
authors.forename: Stephen
authors.initials: S
authors.lastname: O'Rahilly
authors.forename: Colin N A
authors.initials: CN
authors.lastname: Palmer
authors.forename: Jorge
authors.initials: J
authors.lastname: Plutzky
authors.forename: Janardan K
authors.initials: JK
authors.lastname: Reddy
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Spiegelman
authors.forename: Bart
authors.initials: B
authors.lastname: Staels
authors.forename: Walter
authors.initials: W
authors.lastname: Wahli
mesh_terms: D000818:Animals; D001665:Binding Sites; D005231:Fatty Acids, Unsaturated / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008024:Ligands; D009154:Mutation; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D000077205:Pioglitazone; D020033:Protein Isoforms / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology
chemical_list: D005231:Fatty Acids, Unsaturated; D007004:Hypoglycemic Agents; D008024:Ligands; D047492:Peroxisome Proliferator-Activated Receptors; D020033:Protein Isoforms; D045162:Thiazolidinediones; D000077205:Pioglitazone