Аннотация:Abstract Arachidonic acid can be transformed into a specific epoxyalcohol product via the sequential action of two epidermal lipoxygenases, 12 R ‐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 PPARα, γ, and δ, which have been implicated in epidermal differentiation. Using a dual luciferase reporter assay in PC3 cells, the 12 R ‐LOX/eLOX3‐derived epoxyalcohol, 8 R ‐hydroxy‐11 R ,12 R ‐epoxyeicosa‐5 Z ,9 E ,14 Z ‐trienoic acid, activated PPARα with similar in potency to the known natural ligand, 8 S ‐hydroxyeicosatetraenoic acid (8 S ‐HETE) (both at 10 μM concentration). In contrast, the PPARγ and PPARδ receptor isoforms were not activated by the epoxyalcohol. Activation of PPARα 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 PPARα may be one possibility by which 12 R ‐LOX and eLOX3 contribute to epidermal differentiation.
