Lipids, Lipoproteins, and Peroxisome Proliferator Activated Receptor–δ

Peroxisome proliferator activated receptors (PPARs) are nuclear receptors activated by small, lipophilic compounds. Typically resident on nuclear DNA, full activation requires heterodimer formation with retinoid X receptor and ligand binding, leading to modulation in the expression of hundreds of genes. Of the 3 described forms, (PPAR-α, PPAR-γ, and PPAR-δ), PPAR-δ has been the least investigated. Preclinical in vitro data show that activation of PPAR-δ, like PPAR-α, results in enhancement of fatty acid oxidation, leading to increased energy production in the form of adenosine triphosphate and of energy uncoupling. Microarray data in preclinical models suggest substantial PPAR-δ expression in skeletal muscle. Exercise, which induces upregulation of PPAR-δ in muscle tissue, leads to an increased requirement for an external or serum derived triacylglycerol energy source. This suggests that upregulation of skeletal muscle PPAR-δ would influence lipoprotein composition, this being the major source of combustible substrate. In the first human study using a PPAR-δ agonist, experimental data obtained with GW 501516 (a highly specific PPAR-δ agonist) suggested that upregulated enzymes critical to fatty acid oxidation in human cells enhanced fatty acid and β-oxidation in skeletal muscle.