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Center for Integrative Genomics, National Research Centre "Frontiers in Genetics," University of Lausanne, Lausanne, Switzerland (L.M., W.W.); Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France (J.A.); Merck Research Laboratories, Rahway, New Jersey (J.P.B.); Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom (V.K.C., S.O.); Division of Endocrinology, Diabetes and Hypertension, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California (C.K.G.); Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland (F.J.G.); Institut National de la Santé et de la Recherche Médicale U636, Centre de Biochimie, l'Unité de Formation et de Recherche Sciences, Université de Nice-Sophia Antipolis, Nice, France (P.A.G.); Graduate School of Medicine, University of Tokyo, Tokyo, Japan (T.K.); Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, and the Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania (M.A.L.); Biomedical Research Centre, Ninewells Hospital and Medical School, University of Dundee, Dundee, United Kingdom (C.N.A.P.); Cardiovascular Division, Harvard Medical School, and Brigham and Women's Hospital, Boston, Massachusetts (J.P.); Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois (J.A.R.); Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts (B.M.S.); and Unité de Recherche 545, Institut National de la Santé et de la Recherche Médicale, Institut Pasteur de Lille, Lille, France (B.S.)
Abstract
Abstract Introduction Classification of PPARs in the Nuclear Receptor Family Chromosomal Distribution Functional Roles Structural Features of the Ligand-Binding Domain Endogenous Ligands Synthetic Modulators and Pharmacology of PPARs
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. PPAR
is expressed at high levels in organs with significant catabolism of fatty acids. PPAR
/
has the broadest expression pattern, and the levels of expression in certain tissues depend on the extent of cell proliferation and differentiation. PPAR
is expressed as two isoforms, of which PPAR2 is found at high levels in the adipose tissues, whereas PPAR1 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 PPAR and PPAR 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.
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