International Union of Pharmacology. LXI. Peroxisome Proliferator-Activated Receptors
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-b...
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Published in | Pharmacological reviews Vol. 58; no. 4; pp. 726 - 741 |
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Main Authors | , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Society for Pharmacology and Experimental Therapeutics
01.12.2006
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Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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Bibliography: | ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-3 content type line 23 ObjectType-Review-1 |
ISSN: | 0031-6997 1521-0081 |
DOI: | 10.1124/pr.58.4.5 |