4-Hydroxyalkenal-activated PPARδ mediates hormetic interactions in diabetes

Activated peroxisome proliferator-activated receptor-δ (PPARδ) induces the expression of genes encoding enzymes that metabolize fatty acids and carbohydrate. Attempts to identify cellular activators of PPARδ produced large lists of various fatty acids and their metabolic derivatives; however, there is no consensus on specific and selective binding interactions of natural ligands with PPARδ. Most models on binding interactions within the ligand binding domain (LBD) of PPARδ have been derived from analyses of PPARδ-LBD crystals formed with synthetic low molecular weight ligands. Nonetheless, crystals of the whole receptor with natural ligands or of its heterodimer with its cognate retinoid X receptor (RXR) are not yet available for analysis. We have found that 4-hydroxyalkenals, non-enzymatic peroxidation products of polyunsaturated fatty acids (PUFA), namely, 4-hydroxy-2E,6Z-dodecadienal (4-HDDE) and 4-hydroxy-2E-nonenal (4-HNE), activate PPARδ in vascular endothelial cells and insulin-secreting beta cells, respectively. In both cases activated PPARδ induced adaptive responses that allowed the cells to adjust to ambient stressful metabolic conditions. This review article addresses the interactions of 4-hydroxyalkenals with PPARδ and the resulting hormetic interactions in cells exposed to nutrient overload conditions.