PPARs and Lipid Ligands in Inflammation and Metabolism

Peroxisome proliferator-activated receptors (PPARs) belong to a family of ligand-activated nuclear receptors that includes the estrogen, thyroid hormone, and glucocorticoid receptors1. The PPAR family consists of three subtypes encoded by three separate genes: PPAR-α (NR1C1), PPAR-β/δ (NR1C2), and PPAR-γ (NR1C3). Distinct PPAR subtype tissue distributions2,3 and unique ligand-binding pockets drive separate but often complementary patterns of gene expression in response to PPAR ligands4. PPAR activation occurs upon cognate synthetic or endogenous ligand binding to the ligand-binding domain (LBD). Activated PPARs heterodimerize with retinoid X receptors (RXRs), another class of nuclear receptor, which subsequently bind to the hexameric direct repeat peroxisome proliferator response elements (PPRE)5,6 and recruit co-activator protein complexes to positively regulate expression of target genes (Figure 1A). PPARs also mediate ligand-dependent repression of inflammatory gene expression through the association with co-repressor protein complexes7. Figure 1 PPAR transcriptional regulation and the production of endogenous ligands. A) Endogenous lipid ligand precursors undergo enzymatic conversion to active lipids, leading to their binding to PPAR/RXR heterodimers on target genes and recruitment of co-activator ... Nearly all nuclear receptors share structural similarity consisting of a conserved DNA-binding domain (DBD) and LBD1. The PPAR subtype structural similarities contribute to the partial overlapping function of PPARs across different tissues. In hepatocytes, PPAR-α positively regulates fatty acid β-oxidation, ketogenesis, and gluconeogenesis, while suppressing amino acid catabolism and inflammatory responses8. PPAR-α plays anti-inflammatory roles in smooth muscle cells and vascular endothelial cells9,10. PPAR-β/δ (PPAR-δ) plays roles in lipid metabolism11, fatty acid oxidation and energy dissipation12, anti-inflammation13, and colon cancer14. PPAR-γ is an essential modulator of fat cell differentiation15-17 and lipid storage and plays important anti-inflammatory roles in macrophages18,19 and other tissues such as the colon20. PPAR-γ also contributes to insulin sensitivity21, in part through the regulation of adiponectin, an adipo(cyto)kine that enhances insulin sensitivity22. PPAR-γ is activated by synthetic ligand thiazolidinediones (TZDs)7. TZDs, including rosiglitazone and pioglitazone, are potent insulin sensitizers that have a myriad of potential benefits for patients with cardiovascular disease including improvements in endothelial function, lipid profiles and atherosclerosis23-25. TZDs, however, augment renal sodium reabsorption, leading to fluid retention that can exacerbate heart failure26-28. Recent meta-analyses have raised questions surrounding the safety of TZDs, linking the drugs to the occurrence of myocardial infarction and death29,30. While some studies suggest that the relative risks of rosiglitazone are higher than pioglitazone, the possibility that all TZDs may have adverse risk profiles has not been excluded. The unwanted side effects of TZDs have raised the prospects for the development of newer and safer PPAR ligands, such as the therapeutic usage of natural PPAR ligands. Recent studies have identified physiologically relevant endogenous PPAR ligands linked to the expression of their endogenous synthetic enzymes in specific tissues. Examples include 15-keto-prostaglandin E2 produced by 15-hydroxyprostaglandin dehydrogenase (15-PGDH) in colonic epithelial cells and 15-deoxy-Δ12,14-prostaglandin J2 produced by prostaglandin D2 synthase (PGD2S) in macrophages (Figure 1B). Further study of the effectiveness of natural PPAR ligands or synthetic molecules that mimic the actions of natural ligands is needed to determine their potential as clinical therapeutics. This review will characterize the structural and functional relationships of PPARs, define the regulatory mechanisms that control PPAR activities, and review the candidate natural ligands of PPARs to provide a framework for understanding the roles of PPARs as anti-inflammatory therapeutics.