Peroxisome Proliferator-Activated Receptor Delta (PPARD) Molecular studies of regulation and activation

The peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors involved in energy homeostasis. Their natural ligands are fatty acids and there are three different PPAR isoforms; PPARA, PPARG and PPARD. They are encoded by separate genes and have distinct functions, due to different tissue expression and affinity for ligands. PPARA controls genes involved in fatty acid oxidation, PPARG regulates genes important for fatty acid storage, and PPARD controls genes implicated in lipid oxidation and lipoprotein metabolism. Primates and humans treated with a PPARD agonist (GW501516) resulted in improved insulin sensitivity, increased HDL and decreased LDL cholesterol levels, making it a putative drug candidate for treatment of metabolic disease. PPARD has recently been assigned a beneficial role in macrophages, by inducing a switch from proinflammatory (M1) to antiinflammatory (M2) macrophages. To characterize additional target genes of PPARD involved in the lipoprotein metabolism, the effect of PPARD activation on the apolipoprotein A-II (apoA-II) gene was investigated in human hepatoma cells. ApoA-II is one of the major proteins in the HDL particles. Treatment with GW501516 increased apoA-II promoter activity and mRNA levels in hepatoma cell lines. A site located at -737/-717 in the promoter was identified as the functional PPAR response element (PPRE). These results suggest that increased expression of the apoA-II gene is one of the reasons for the beneficial effects on lipoprotein metabolism after treatment with