Epidermal lipoxygenase products of the hepoxilin pathway selectively activate the nuclear receptor PPAR alpha

Arachidonic acid can be transformed into a specific epoxyalcohol product via the sequential action of two epidermal lipoxygenases, 12R-LOX and eLOX3. Functional impairment of either lipoxygenase gene (ALOX12B or ALOXE3) results in ichthyosis, suggesting a role for the common epoxyalcohol product or its metabolites in the differentiation of normal human skin. Here we tested the ability of products derived from the epidermal LOX pathway to activate the peroxisome proliferator-activated receptors PPAR alpha, gamma, and delta, which have been implicated in epidermal differentiation. Using a dual luciferase reporter assay in PC3 cells, the 12R-LOX/ eLOX3-derived epoxyalcohol, 8R-hydroxy-11R, 12R-epoxyeicosa-5Z,9E,14Z-trienoic acid, activated PPAR alpha with similar in potency to the known natural ligand, 8S-hydroxyeicosatetraenoic acid (8S-HETE) (both at 10 mu M concentration). In contrast, the PPAR gamma and PPAR delta receptor isoforms were not activated by the epoxyalcohol. Activation of PPAR alpha was also observed using the trihydroxy hydrolysis products (trioxilins) of the unstable epoxyalcohol. Of the four trioxilins isolated and characterized, the highest activation was observed with the isomer that is also formed by enzymatic hydrolysis of the epoxyalcohol. Formation of a ligand for the nuclear receptor PPAR alpha may be one possibility by which 12R-LOX and eLOX3 contribute to epidermal differentiation.