Aloxe3 Knockout Mice Reveal a Function of Epidermal Lipoxygenase-3 as Hepoxilin Synthase and Its Pivotal Role in Barrier Formation

Abstract

Loss-of-function mutations in the lipoxygenase (LOX) genes ALOX12B and ALOXE3 are the second most common cause of autosomal recessive congenital ichthyosis. The encoded proteins, 12R-LOX and epidermal LOX-3 (eLOX-3), act in sequence to convert fatty acid substrates via R-hydroperoxides to specific epoxyalcohol derivatives and have been proposed to operate in the same metabolic pathway during epidermal barrier formation. Here, we show that eLOX-3 deficiency in mice results in early postnatal death, associated with similar but somewhat less severe barrier defects and morphological changes than reported earlier for the 12R-LOX-knockout mice. Skin lipid analysis demonstrated that the severity of barrier failure is related to the loss of covalently bound ceramides in both 12R-LOX- and eLOX-3-null mice, confirming a proposed functional linkage of the LOX pathway to ceramide processing and formation of the corneocyte lipid envelope. Furthermore, analysis of free oxygenated fatty acid metabolites revealed strongly reduced levels of hepoxilin metabolites in eLOX-3-deficient epidermis, indicating an additional function of eLOX-3 in mammalian skin as a hepoxilin synthase linked to the 12S-LOX pathway.

Evolutionary alteration of ALOX15 specificity optimizes the biosynthesis of antiinflammatory and proresolving lipoxins

“…Similarly, the distances between C 10 and the iron bound hydroxyl [d(C 10 -OH)] vary between 3.28 to 3.67 Å (SI Appendix, Table S5). For structures XI to XX, which represent arachidonic acid conformers for 15-lipoxygenation, C 13 is also located at reactive distances (SI Appendix, Table S5). These data indicate that, if one considers only the geometric distances, hydrogen abstraction from both C 10 and C 13 is possible.…”

Essential role of the cytochrome P450 CYP4F22 in the production of acylceramide, the key lipid for skin permeability barrier formation

“…Furthermore, recent findings have demonstrated that ALOX12B and ALOXE3 are involved in the reactions necessary for conversion of acylceramide to proteinbound ceramide, i.e., peroxidation of the linoleate moiety and subsequent epoxyalcohol derivatization (13). In addition, ALOX12B was proven not to be involved in hepoxilin/trioxilin production (30). These findings suggest that, although hepoxilin/ trioxilin metabolism may not be relevant to the pathogenesis of ichthyosis, the impairment of acylceramide/protein-bound ceramide formation causes ichthyosis.…”

Phospho‐ΔNp63α regulates AQP3, ALOX12B, CASP14 and CLDN1 expression through transcription and microRNA modulation

“…Alterations in Alox12b expression were shown to be often associated with the defective skin barrier functions subsequently resulting in epidermal hyper-proliferation [19,27]. CLDN1 was shown to act as a signal mediator to regulate gene expression and cell migration in human oral and lung cancer cells [11,28].…”

“…Arachidonate 12R-lipoxygenase (Alox12b) shown to be involved in mouse epidermal differentiation and skin barrier formation is induced in epidermoid carcinomas contributing to the tumor cell proliferation [18]. Genetic inactivation of Alox12b leads to thickening of the epidermis, hyper-proliferation of epidermal cells, and severe hyperkeratosis in mice [19], while the ALOX12B inhibition enhances human tumor cell death [20].…”