Document Detail


Lipoxygenases mediate the effect of essential fatty acid in skin barrier formation: a proposed role in releasing omega-hydroxyceramide for construction of the corneocyte lipid envelope.
MedLine Citation:
PMID:  21558561     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
A barrier to water loss is vital to maintaining life on dry land. Formation of the mammalian skin barrier requires both the essential fatty acid linoleate and the two lipoxygenases 12R-lipoxygenase (12R-LOX) and epidermal lipoxygenase-3 (eLOX3), although their roles are poorly understood. Linoleate occurs in O-linoleoyl-ω-hydroxyceramide, which, after hydrolysis of the linoleate moiety, is covalently attached to protein via the free ω-hydroxyl of the ceramide, forming the corneocyte lipid envelope, a scaffold between lipid and protein that helps seal the barrier. Here we show using HPLC-UV, LC-MS, GC-MS, and (1)H NMR that O-linoleoyl-ω-hydroxyceramide is oxygenated in a regio- and stereospecific fashion by the consecutive actions of 12R-LOX and eLOX3 and that these products occur naturally in pig and mouse epidermis. 12R-LOX forms 9R-hydroperoxy-linoleoyl-ω-hydroxyceramide, further converted by eLOX3 to specific epoxyalcohol (9R,10R-trans-epoxy-11E-13R-hydroxy) and 9-keto-10E,12Z esters of the ceramide; an epoxy-ketone derivative (9R,10R-trans-epoxy-11E-13-keto) is the most prominent oxidized ceramide in mouse skin. These products are absent in 12R-LOX-deficient mice, which crucially display a near total absence of protein-bound ω-hydroxyceramides and of the corneocyte lipid envelope and die shortly after birth from transepidermal water loss. We conclude that oxygenation of O-linoleoyl-ω-hydroxyceramide is required to facilitate the ester hydrolysis and allow bonding of the ω-hydroxyceramide to protein, providing a coherent explanation for the roles of multiple components in epidermal barrier function. Our study uncovers a hitherto unknown biochemical pathway in which the enzymic oxygenation of ceramides is involved in building a crucial structure of the epidermal barrier.
Authors:
Yuxiang Zheng; Huiyong Yin; William E Boeglin; Peter M Elias; Debra Crumrine; David R Beier; Alan R Brash
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2011-05-10
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  286     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2011 Jul 
Date Detail:
Created Date:  2011-07-04     Completed Date:  2011-09-08     Revised Date:  2014-01-16    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  24046-56     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Arachidonate 12-Lipoxygenase / genetics,  metabolism*
Ceramides / genetics,  metabolism*
Epidermis / metabolism*
Fatty Acids, Essential / genetics,  metabolism*
Lipoxygenase / genetics,  metabolism*
Mice
Oxidation-Reduction
Swine
Grant Support
ID/Acronym/Agency:
AR019098/AR/NIAMS NIH HHS; AR051968/AR/NIAMS NIH HHS; HD36404/HD/NICHD NIH HHS; R01 AR061106/AR/NIAMS NIH HHS
Chemical
Reg. No./Substance:
0/Ceramides; 0/Fatty Acids, Essential; EC 1.13.11.12/Lipoxygenase; EC 1.13.11.12/eLOX3 protein, mouse; EC 1.13.11.31/12R-LOX protein, mouse; EC 1.13.11.31/Arachidonate 12-Lipoxygenase
Comments/Corrections

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