PPARs in Cellular and Whole Body Energy Metabolism by Walter Wahli
English | PDF | 2019 | 584 Pages | ISBN : N/A | 62.22 MB
English | PDF | 2019 | 584 Pages | ISBN : N/A | 62.22 MB
Peroxisome Proliferator-Activated Receptors (PPARs) are transcription factors that belong to the nuclear hormone receptor superfamily. Nuclear receptors are one of the best described classes of regulatory factors that directly control gene expression. Humans and mice have 48 and 49 nuclear receptors, respectively, which modulate many functions such as reproduction, development, metabolism, and whole body homeostasis. They function as ligand-activated factors, and thus convert signalling by small molecules (hormones, vitamins, fatty acids), which control these processes, into appropriate gene responses.
PPARs were first identified in the early 1990s as nuclear receptors for compounds that induce peroxisome proliferation in rodents, which explains their name. Soon thereafter it became clear that fatty acids and many fatty acid derivatives can also directly regulate gene expression through PPARs. The molecular mode of action of PPARs is similar to that of other nuclear hormone receptors. They bind to a short specific response element, called the Peroxisome Proliferator Response Element (PPRE) in the regulatory region of target genes, as heterodimers with the receptor for 9-cis retinoic acid, RXR (retinoid X receptor). As mentioned above, their activity depends on binding ligands, agonists, or antagonists. Three PPAR isotypes have been identified: PPARα, PPARβ (also called δ or now more commonly β/δ), and PPARγ. Some ligands are shared by the three isotypes, while others are more isotype-specific. Drugs bind to and activate PPARα (fibrates) and PPARγ (thiazolidinediones), resulting in different but complementary effects, with the fibrates acting mainly as hypolipidemic agents and the thiazolididiones as insulin sensitizers. These initial findings have instigated an uncommon research activity to unveil the multifaceted roles of PPARs, which has resulted in thousands of publications. In fact, PubMed from the US National Library of Medicine, National Institutes of Health, features more the 30,000 publications in response to a search with the term "peroxisome proliferator-activated receptor". PPARs appear to be highly interesting and sophisticated modulators of a myriad of cellular, organ, and systemic processes, which renders their study especially challenging. For example, their key roles in lipid and carbohydrate metabolism are central for maintaining body homeostasis, particularly under the complex influences of nutrition and physical activity.
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