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PPAR Research  2010 

The Role of Peroxisome Proliferator-Activated Receptor β/δ on the Inflammatory Basis of Metabolic Disease

DOI: 10.1155/2010/368467

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Abstract:

The pathophysiology underlying several metabolic diseases, such as obesity, type 2 diabetes mellitus, and atherosclerosis, involves a state of chronic low-level inflammation. Evidence is now emerging that the nuclear receptor Peroxisome Proliferator-Activated Receptor (PPAR) ameliorates these pathologies partly through its anti-inflammatory effects. PPAR activation prevents the production of inflammatory cytokines by adipocytes, and it is involved in the acquisition of the anti-inflammatory phenotype of macrophages infiltrated in adipose tissue. Furthermore, PPAR ligands prevent fatty acid-induced inflammation in skeletal muscle cells, avoid the development of cardiac hypertrophy, and suppress macrophage-derived inflammation in atherosclerosis. These data are promising and suggest that PPAR ligands may become a therapeutic option for preventing the inflammatory basis of metabolic diseases. 1. Introduction Over the last decade, an abundance of evidence has shown a close link between a state of chronic low-level inflammation and metabolic dysfunction. In fact, excessive nutrition consumption or storage has the capacity to activate both inflammatory and metabolic signaling networks since they are linked and interdependent [1]. Peroxisome Proliferator-Activated Receptors (PPARs), which are members of the nuclear receptor family, have emerged as important regulators of metabolic and inflammatory signaling, particularly in the context of metabolic disease [2–4]. The ability of these receptors to connect metabolism and inflammation makes them interesting targets for the treatment of metabolic diseases, such as atherosclerosis and diabetes, through modulation of the inflammatory process. Here, we will focus on recent advances in our understanding of the role of one of these PPAR members, the PPAR / , as an integrator of metabolic and inflammatory signaling networks. 2. Peroxisome Proliferator-Activated Receptors (PPARs) PPARs are members of the nuclear receptor superfamily of ligand-activated transcription factors that regulate the expression of genes involved in fatty acid uptake and oxidation, lipid metabolism, and inflammation [2]. To be transcriptionally active, PPARs need to heterodimerize with the 9-cis retinoic acid receptor (RXR) (NR2B) (Figure 1). PPAR-RXR heterodimers bind to DNA-specific sequences called peroxisome proliferator-response elements (PPREs), which consist of an imperfect direct repeat of the consensus binding site for nuclear hormone receptors (AGGTCA), separated by one nucleotide (Direct Repeat 1, DR-1). These sequences have been

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