Peroxisome proliferator-activated receptors and the regulation of mammalian lipid metabolism

Peroxisome proliferator-activated receptors (PPARs) are members of the superfamily of ligand-activated nuclear transcription factors. Three PPAR subtypes, PPARalpha, PPARdelta (PPARbeta) and PPARgamma, have been described in mammals. The tissue distribution of PPARs is heterogeneous: PPARalpha is highly expressed in liver and skeletal muscle, PPARgamma is preferentially expressed in adipose tissues, and PPARdelta is expressed in most cell types with relative abundance. Unlike most receptors, PPARs show low ligand specificity, being activated by many long-chain saturated and unsaturated fatty acids, or by eicosanoids. PPARs are transcriptionally active as heterodimeric complexes with the retinoid X receptor and bind to specific recognition sequences in the regulatory region of target genes. Many PPAR-regulated genes encode proteins that regulate fatty acid oxidation and storage. Elucidation of the biological functions of PPARs has been aided by the development of PPAR-null mice and the identification of humans bearing PPAR mutations, together with the discovery of synthetic small-molecule ligands that selectively activate individual PPAR subtypes. Using these genetic and pharmacological approaches, it has been shown that PPARalpha predominantly regulates pathways of fatty acid oxidation, whereas PPARgamma modifies fatty acid synthesis and storage in adipose tissues. By reducing systemic fatty acid availability, thiazolidinedione PPARgamma activators regulate glucose metabolism and are now used clinically in the treatment of Type II diabetes. In summary, PPARs play a central role in the mechanisms that balance fatty acid oxidation and storage in the face of fluctuations of dietary fat intake and energy expenditure.