PPARβ/δ at the crossroads of energy metabolism, mitochondrial quality control and redox balance

Peroxisome proliferator-activated receptor β/δ (PPARβ/δ), member of the PPAR subfamily of nuclear receptors, is highly expressed in tissues with high rates of oxidative metabolism, such as the heart, skeletal muscle and liver. PPARβ/δ exerts its transcriptional control by direct binding on specific response elements on target genes promoters with the help of cofactors resulting in transactivation or transrepression of multiple genes involved in energy metabolism, mitochondrial biogenesis, or antioxidant defense. Several pre-clinical studies have shown that reduced PPARβ/δ expression in the heart is associated with diminished cardiac performance, impaired contractility and relaxation and even decreased survival in cardiomyopathies with distinct aetiologies while ligand-mediated activation or overexpression of PPARβ/δ has been shown to be protective in the setting of ischemia/reperfusion injury and several types of cardiomyopathies (dilated, hypertrophic or diabetic). PPARβ/δ stimulates fatty acid and glucose uptake as well as fatty acid oxidation but does not control triglyceride synthesis. In parallel, PPARβ/δ upregulates PGC1α, which is the critical regulator of mitochondrial biogenesis, and is also associated with mediators of mitochondrial fusion/fission and components of mitochondrial respiration. In addition, PPARβ/δ has been linked to multiple antioxidant defense mechanisms in the heart, including SOD1 and 2, Catalase, ALDH2 or NF-κB related pathways. Overall, this review summarizes the research data on the role of PPARβ/δ in the regulation of cardiac energy metabolism, antioxidant defense systems and mitochondrial quality control. Those data suggest the potential of PPARβ/δ activation as a therapeutic target for patients with cardiometabolic disorders.