ReviewPeroxisome proliferator-activated receptors and the metabolic syndrome
Introduction
There is an increasing incidence of diet-related diseases, such as cardiovascular diseases (CVD) and type II diabetes mellitus (T2D). Obesity is a major risk factor for developing these metabolic diseases, and the incidence has reached global epidemic proportions [1]. CVD and T2D are often linked with the metabolic syndrome (MS), which refers to a cluster of metabolic disturbances, such as abnormal lipid and carbohydrate metabolism and a pro-inflammatory state of the body [2].
Potential molecular targets to treat and prevent these metabolic disturbances are peroxisome proliferator-activated receptors (PPARs). PPARs are one of the central regulators of nutrient–gene interactions and are able to regulate lipid, carbohydrate, and inflammatory pathways, hereby maintaining homeostasis [3], [4], [5]. In fact, PPARα agonists (fibrates) and PPARγ agonists (thiazolidinediones) are already used to improve serum lipoprotein profiles and glucose metabolism, respectively [6], [7]. PPARs are able to sense the presence of fatty acids [8]. Upon binding with fatty acids or a synthetic agonist, PPARs bind as a heterodimer with the retinoid X receptor (RXR) to a PPAR response element (PPRE) in enhancer sites of regulated genes to increase gene transcription [9]. Furthermore, phosphorylation status and the presence of co-factors are important in regulating PPAR-dependent gene transcription [10], [11].
Fatty acids derived from the diet can modulate the activity of PPARs, but the type of fatty acid differs in its capacity to activate PPAR-dependent gene transcription [12], [13], [14]. Activation of PPARs by fatty acids has been investigated in previous studies, which almost exclusively focused on ligand-binding assays [14], [15]. Ligand binding, however, does not necessarily mean transcriptional activation. Here we will present an overview of the current knowledge of PPARs and their ability to sense fatty acids, their synthetic agonists, and their ability to modify gene transcription in light of the metabolic syndrome. First, we elaborate on the role and function of PPAR isotypes and their tissue distribution. Second, the ability of natural and synthetic ligands to transactivate PPARs is discussed. Finally, the influences of PPARs on lipid metabolism, glucose metabolism and inflammation are described and the importance of these effects in relation to the metabolic syndrome is discussed.
Section snippets
PPAR isotypes, chromosomal location and tissue distribution in humans
PPARs form a subclass of the nuclear hormone receptor superfamily. First, the PPAR subclasses are described, followed by the general structure of PPARs, their chromosomal localization, and their variation in tissue-specific expression. So far, three PPAR isotypes are identified in vertebrates: PPARα, PPARβ (also designated as PPARδ) and PPARγ. These isotypes were first discovered as a group in Xenopus laevis [16]. Based on sequence homology, the mammalian PPARα and -γ were easily identified,
PPAR ligands
Fatty acids are important dietary components and participate in the regulation of gene expression upon nutritional changes. Hereby, fatty acids influence transport, mobilization, utilization and the availability of lipids and glucose. Many effects of fatty acids are regulated via PPARs, as these receptors are lipid-sensing transcription factors [8]. Fatty acids are only one class of compounds that are known to activate PPARs. PPARs can also be activated by the hypolipidemic drugs (e.g.
Lipid and lipoprotein metabolism
Dyslipidemia in the metabolic syndrome is characterized by elevated triglyceride levels and reduced HDL cholesterol levels and associated with increased LDL cholesterol levels [53], [54]. In addition, obesity, diabetes, CVD, and fasting are associated with elevated levels of plasma free fatty acids [55], [56], [57]. PPARs are thought to play a prominent role to prevent dyslipidemia and maintain metabolic homeostasis as PPARs are the major regulators of lipid and fatty acid metabolism that
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2014, Reproductive ToxicologyCitation Excerpt :Immunocytochemistry and CHIP-qPCR results showed that PPARα was transferred to the nucleus after 24 h of DBP exposure and activated the PPRE transcription factor, which demonstrated the activation of PPARα. Besides the transportation to nucleus and promotion of the transcription of target genes, PPARα is also associated with kinase-dependent processes in the cytoplasm (non-genomic effects) [61,62]. PPARα is involved in many of the kinase-dependent processes, such as the mitogen-activated protein kinase (MAPKs) signal cascade [63,64], transforming growth factor (TGF)-β pathway [65], and the protein kinase C (PKC) signal pathway [66].
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2014, Biochemical PharmacologyCitation Excerpt :PPARs regulate distinct biochemical events required for lipid homeostasis. After binding of their ligand, they mediate transcriptional activation of genes carrying the PPAR response element [18]. The effects of FAs as signaling molecules can also be explained by receptor binding at the cell surface.