Edin_2021_J.Biol.Chem_296_100198

Reference

Title : Epoxide hydrolase 3 (Ephx3) gene disruption reduces ceramide linoleate epoxide hydrolysis and impairs skin barrier function - Edin_2021_J.Biol.Chem_296_100198
Author(s) : Edin ML , Yamanashi H , Boeglin WE , Graves JP , DeGraff LM , Lih FB , Zeldin DC , Brash AR
Ref : Journal of Biological Chemistry , 296 :100198 , 2021
Abstract :

The mammalian epoxide hydrolase (EPHX)3 is known from in vitro experiments to efficiently hydrolyze the linoleate epoxides 9,10-epoxyoctadecamonoenoic acid (EpOME) and epoxyalcohol 9R,10R-trans-epoxy-11E-13R-hydroxy-octadecenoate to corresponding diols and triols, respectively. Herein we examined the physiological relevance of EPHX3 to hydrolysis of both substrates in vivo. Ephx3(-)(/)(-) mice show no deficiency in EpOME-derived plasma diols, discounting a role for EPHX3 in their formation, whereas epoxyalcohol-derived triols esterified in acylceramides of the epidermal 12R-lipoxygenase pathway are reduced. Although the Ephx3(-)(/)(-) pups appear normal, measurements of transepidermal water loss detected a modest and statistically significant increase compared with the wild-type or heterozygote mice, reflecting a skin barrier impairment that was not evident in the knockouts of mouse microsomal (EPHX1/microsomal epoxide hydrolase) or soluble (EPHX2/sEH). This barrier phenotype in the Ephx3(-)(/)(-) pups was associated with a significant decrease in the covalently bound ceramides in the epidermis (40% reduction, p < 0.05), indicating a corresponding structural impairment in the integrity of the water barrier. Quantitative LC-MS analysis of the esterified linoleate-derived triols in the murine epidermis revealed a marked and isomer-specific reduction (-85%) in the Ephx3(-)(/)(-) epidermis of the major trihydroxy isomer 9R,10S,13R-trihydroxy-11E-octadecenoate. We conclude that EPHX3 (and not EPHX1 or EPHX2) catalyzes hydrolysis of the 12R-LOX/eLOX3-derived epoxyalcohol esterified in acylceramide and may function to control flux through the alternative and crucial route of metabolism via the dehydrogenation pathway of SDR9C7. Importantly, our findings also identify a functional role for EPHX3 in transformation of a naturally esterified epoxide substrate, pointing to its potential contribution in other tissues.

PubMedSearch : Edin_2021_J.Biol.Chem_296_100198
PubMedID: 33334892
Gene_locus related to this paper: human-EPHX3 , mouse-ephx3

Related information

Substrate Linoleic-acid    Coronaric-acid
Gene_locus Linoleic-acid    Coronaric-acid    human-EPHX3    mouse-ephx3

Citations formats

Edin ML, Yamanashi H, Boeglin WE, Graves JP, DeGraff LM, Lih FB, Zeldin DC, Brash AR (2021)
Epoxide hydrolase 3 (Ephx3) gene disruption reduces ceramide linoleate epoxide hydrolysis and impairs skin barrier function
Journal of Biological Chemistry 296 :100198

Edin ML, Yamanashi H, Boeglin WE, Graves JP, DeGraff LM, Lih FB, Zeldin DC, Brash AR (2021)
Journal of Biological Chemistry 296 :100198