Leukotriene B4 Is a Physiologically Relevant Endogenous Peroxisome Proliferator-activated Receptor-α Agonist

Peroxisome proliferator-activated receptors (PPARs) are nuclear transcription factors that play central roles in metabolism and inflammation. Although a variety of compounds have been shown to activate PPARs, identification of physiologically relevant ligands has proven difficult. In silico studies of lipid derivatives reported here identify specific 5-lipoxygenase products as candidate physiologically relevant PPAR-alpha activators. Subsequent studies show both in vitro and in a murine model of inflammation that 5-lipoxygenase stimulation induces PPAR-alpha signaling and that this results specifically from production of the inflammatory mediator and chemoattractant leukotriene B-4 (LTB4). Activation of PPAR-alpha is a direct effect of intracellularly generated LTB4 binding to the nuclear receptor and not of secreted LTB4 acting via its cell-surface receptors. Activation of PPAR-alpha reduces secretion of LTB4 by stimulating degradation of this fatty acid derivative. We also show that the LTB4 precursors leukotriene A(4) (LTA(4)) and 5-hydroperoxyeicosatetrenoic acid (5-HPETE) activate PPAR-alpha but have no significant endogenous effect independent of conversion to LTB4. We conclude that LTB4 is a physiologically relevant PPAR-alpha activator in cells of the immune system. This, together with previous findings, demonstrates that different types of lipids serve as endogenous PPAR-alpha ligands, with the relevant ligand varying between functionally different cell types. Our results also support the suggestion that regulation of inflammation may involve balancing proinflammatory effects of LTB4, exerted through cell-surface receptors, and anti-inflammatory effects exerted through PPAR-alpha activation.