title: 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.
authors: Genome Modifications and Carcinogenesis, German Cancer Research Center, Heidelberg, Germany. p.krieg@dkfz.de
authors: Peter
authors: P
authors: Krieg
authors: Sabine
authors: S
authors: Rosenberger
authors: Silvia
authors: S
authors: de Juanes
authors: Susanne
authors: S
authors: Latzko
authors: Jin
authors: J
authors: Hou
authors: Angela
authors: A
authors: Dick
authors: Ulrich
authors: U
authors: Kloz
authors: Frank
authors: F
authors: van der Hoeven
authors: Ingrid
authors: I
authors: Hausser
authors: Irene
authors: I
authors: Esposito
authors: Manfred
authors: M
authors: Rauh
authors: Holm
authors: H
authors: Schneider
mesh_terms: D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000235:genetics / Q000502:physiology*; D002518:Ceramides / Q000032:analysis / Q000378:metabolism; D004195:Disease Models, Animal; D004817:Epidermis / Q000737:chemistry / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D005230:Fatty Acids, Nonesterified / Q000032:analysis / Q000378:metabolism; D007057:Ichthyosis / Q000235:genetics / Q000378:metabolism; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000502:physiology*; D008055:Lipids / Q000032:analysis; D008084:Lipoxygenase / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D012720:Severity of Illness Index
chemical_list: D002518:Ceramides; D005230:Fatty Acids, Nonesterified; D008055:Lipids; D008084:Lipoxygenase; C518403:eLOX3 protein, mouse; D001092:Arachidonate 12-Lipoxygenase; D019746:Intramolecular Oxidoreductases; C473385:hepoxilin synthase