Peroxisome proliferator-activated receptor targets for the treatment of metabolic diseases

Abstract

Metabolic syndrome is estimated to affect more than one in five adults, and its prevalence is growing in the adult and pediatric populations. The most widely recognized metabolic risk factors are atherogenic dyslipidemia, elevated blood pressure, and elevated plasma glucose. Individuals with these characteristics commonly manifest a prothrombotic state and a proinflammatory state as well. Peroxisome proliferator-activated receptors (PPARs) may serve as potential therapeutic targets for treating the metabolic syndrome and its related risk factors. The PPARs are transcriptional factors belonging to the ligand-activated nuclear receptor superfamily. So far, three isoforms of PPARs have been identified, namely, PPAR- α, PPAR-β/δ, and PPAR-γ. Various endogenous and exogenous ligands of PPARs have been identified. PPAR- α and PPAR- γ are mainly involved in regulating lipid metabolism, insulin sensitivity, and glucose homeostasis, and their agonists are used in the treatment of hyperlipidemia and T2DM. Whereas PPAR- β / δ function is to regulate lipid metabolism, glucose homeostasis, anti-inflammation, and fatty acid oxidation and its agonists are used in the treatment of metabolic syndrome and cardiovascular diseases. This review mainly focuses on the biological role of PPARs in gene regulation and metabolic diseases, with particular focus on the therapeutic potential of PPAR modulators in the treatment of thrombosis.

Figure 1

Schematic representation of the functional domains of PPARs. The PPARs are composed of four different domains. The A/B domain is located in the N-terminal region with AF-1 which is responsible for phosphorylation, C domain is involved in DNA binding domain, the D domain is the region of cofactors coupling and E/F domain is the specific domain for the ligands, associated with E/F domain is AF-2, which promotes the recruitment of cofactors necessary for the process of gene transcription.

Figure 2

Gene transcription mechanisms of PPAR. In inactivated state, PPAR interacts with the corepressor, and this complex has Histone deacetylase activity, thus inhibiting the transcription process. After the binding of the exogenous ligand (drug) or endogenous ligand (fatty acids, prostaglandins, etc.), with the PPAR it is activated and it heterodimerizes with RXR and recruits coactivators, which have histone acetylase activity facilitating the transcription of several genes.

Figure 3

Mechanism of transcription and biological effects in different organs. (a) PPAR-γ exhibits anti-diabetic and atherosclerotic effects in adipocytes and skeletal muscle. (b) PPAR-α has multiple effects on liver, heart, and vascular wall. (c) PPAR-δ is expressed widely throughout the body and its gene expression is involved with the metabolism of lipids and glucose, as well as in decreasing the platelet activation. (Modified from [87].)