The importance of the lipoxygenase-hepoxilin pathway in the mammalian epidermal barrier

Abstract

Summary This review covers the background to discovery of the two key lipoxygenases (LOX) involved in epidermal barrier function, 12R-LOX and eLOX3, and our current views on their functioning. In the outer epidermis, their consecutive actions oxidize linoleic acid esterified in ω-hydroxy-ceramide to a hepoxilin-related derivative. The relevant background to hepoxilin and trioxilin biochemistry is briefly reviewed. We outline the evidence that linoleate in the ceramide is the natural substrate of the two LOX enzymes and our proposal for its importance in construction of the epidermal water barrier. Our hypothesis is that the oxidation promotes hydrolysis of the oxidized linoleate moiety from the ceramide. The resulting free ω-hydroxyl of the ω-hydroxyceramide is covalently bound to proteins on the surface of the corneocytes to form the corneocyte lipid envelope, a key barrier component. Understanding the role of the LOX enzymes and their hepoxilin products should provide rational approaches to ameliorative therapy for a number of the congenital ichthyoses involving compromised barrier function.

Pathophysiology of the hepoxilins

“…Two excellent recent reviews on the properties of skin lipoxygenases and their potential role in the activity of the water permeability barrier have recently appeared [4,12]. In these reviews, the potential formation of hepoxilins derived from arachidonic acid or of 'hepoxilin-like' compounds derived from linoleic acid, the main PUFA esterified to omega-hydroxylated acyl ceramides, is discussed.…”

“…In these reviews, the potential formation of hepoxilins derived from arachidonic acid or of 'hepoxilin-like' compounds derived from linoleic acid, the main PUFA esterified to omega-hydroxylated acyl ceramides, is discussed. It is of interest that normal murine skin expresses both leukocyte-type and platelet-type 12-LOX although 12R-LOX is in low amount [11,41]; once activated through inflammation (psoriasis [42,43]) or in tumors [41], or in ichthyosis [4,34], skin expresses 8(R)-and 12(R)-lipoxygenase activity [9]. Interestingly, it was recently shown through the use of 12R-LOX −/− , or eLOX-3 −/− mice that formation of dermal hepoxilins derived from 12S-HPETE was unchanged in the former model, while they were totally abolished in the eLOX-3 −/− mice, suggesting that hepoxilins are NOT formed from 12R-LOX (the precursor HPETE is) but that eLOX-3 is essential for their formation.…”

“…The enzymatic nature of the isomerization reaction to form the hepoxilins was later confirmed through two important findings 1) cloning experiments using rat insulinoma cells, RINm5F, demonstrated that the responsible isomerization activity was an intrinsic component of the 12(S)-lipoxygenase activity of the 12/15-lipoxygenase enzyme [10], and 2) demonstration that eLOX3, a protein which possesses no 12-LOX activity originally found in skin, acts in concert with 12(R)-LOX to convert the 12-LOX product, 12(R)-HPETE into 11R, 12R-hepoxilins [4,11,12] (see section on Control of hepoxilin/12-HETE formation).…”

“…Analogous hepoxilin-like compounds derived from linoleic acid from skin have been reported [4]. The hepoxilin compounds possess both hydroxyl and epoxide groups formed from an intramolecular rearrangement of the hydroperoxy oxygen atoms of 12(S)-HPETE [5] (Scheme 2).…”

Catalytic Multiplicity of 15-Lipoxygenase-1 Orthologs (ALOX15) of Different Species

“…In vitro, the recombinant enzyme is capable of decomposing lipohydroperoxides to secondary products such as epoxy hydroxy compounds (hepoxilins). This catalytic activity is of in vivo relevance since the hepoxilin synthase activity of ALOXE3 has been implicated in the formation of the water barrier of the skin [150].…”