The role of lipoxygenases in epidermis

doi:10.1016/j.bbalip.2013.08.005

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids

Volume 1841, Issue 3, March 2014, Pages 390-400

https://doi.org/10.1016/j.bbalip.2013.08.005 Get rights and content

Highlights

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Distinct LOX isoforms in skin play roles in differentiation, inflammation and cancer.
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12R-LOX and eLOX-3 play a key role in epidermal barrier function.
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Loss of 12R-LOX and eLOX-3 causes ARCI and results in neonatal death in mice.
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Ceramide 1 is oxygenated by the consecutive actions of 12R-LOX and eLOX-3.
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LOX catalyzed oxygenation of ceramides is essential for the formation of CLE.

Abstract

Lipoxygenases (LOX) are key enzymes in the biosynthesis of a variety of highly active oxylipins which act as signaling molecules involved in the regulation of many biological processes. LOX are also able to oxidize complex lipids and modify membrane structures leading to structural changes that play a role in the maturation and terminal differentiation of various cell types. The mammalian skin represents a tissue with highly abundant and diverse LOX metabolism. Individual LOX isozymes are thought to play a role in the modulation of epithelial proliferation and/or differentiation as well as in inflammation, wound healing, inflammatory skin diseases and cancer. Emerging evidence indicates a structural function of a particular LOX pathway in the maintenance of skin permeability barrier. Loss-of-function mutations in the LOX genes ALOX12B and ALOXE3 have been found to represent the second most common cause of autosomal recessive congenital ichthyosis and targeted disruption of the corresponding LOX genes in mice resulted in neonatal death due to a severely impaired permeability barrier function. Recent data indicate that LOX action in barrier function can be traced back to the oxygenation of linoleate-containing ceramides which constitutes an important step in the formation of the corneocyte lipid envelope. This article is part of a Special Issue entitled The Important Role of Lipids in the Epidermis and their Role in the Formation and Maintenance of the Cutaneous Barrier. Guest Editors: Kenneth R. Feingold and Peter Elias.

Introduction

An important role of fatty acid (FA) metabolism in skin has been suggested since the discovery that essential fatty acids (EFA) and their products are involved in the normal process of forming the water-impermeable barrier in skin. Dietary deficiency of EFA results in characteristic scaly skin disorder and excessive water loss [1]. The addition of certain FA such as linoleic acid to the diet could reverse some of the cutaneous symptoms of EFA deficiency and several lines of evidence suggested that the curative effects of EFA in the EFA deficient animal involve the lipoxygenase (LOX)-catalyzed conversion of polyunsaturated fatty acids (PUFA) to oxygenated products [2], [3].

Shortly after the discovery of the first mammalian LOX [4] LOX activities and LOX products have been found in human and murine skin and epidermal cells as well [5]. Since then, a plethora of findings characterized the mammalian epidermis as a tissue with highly abundant and diverse LOX metabolism. LOX products identified in skin include a variety of oxidized free PUFA, arachidonic acid metabolites such as 12-hydroxyeicosatetraenoic acid (12-HETE), 15-hydroxyeicosatetraenoic acid (15-HETE), hepoxilins, trioxilins, and leukotrienes, and linoleic acid products such as 13-hydroxyoctadecadienoic acid (13-HODE) and 9-hydroxyoctadecadienoic acid (9-HODE) as well as docosahexaenoic acid-derived metabolites. LOX are also known to oxidize esterified structural lipids such as ceramides which in particular play an essential role in barrier function.

Section snippets

Mammalian lipoxygenases

LOX are a class of widely distributed non-heme iron containing dioxygenases that catalyze the stereo- and regio-specific incorporation of molecular oxygen into PUFA containing a (cis,cis)-1,4-pentadiene system. The primary products of LOX reactions are hydroperoxides which are rapidly transformed into their reduced hydroxyl analogs and products of subsequent enzymatic reactions (for reviews, see [6], [7]). The members of the LOX multigene family exhibit highly conserved gene and protein

Lipoxygenases in human and mouse skin: cloning, expression, activity and function

All LOX are expressed in skin of both humans and mice as detected by activity, immunohistochemistry and/or polymerase chain reaction (PCR) of the corresponding mRNA.

As key enzymes in the production of a variety of signaling lipid metabolites individual LOX isozymes are thought to play a role in the modulation of epithelial proliferation and/or differentiation as well as in inflammation, wound healing, inflammatory skin diseases and cancer. Emerging evidence furthermore indicates a structural

12R-LOX/eLOX-3 pathway in permeability barrier function

The discovery of two previously unknown LOX isoforms in skin that exhibit unconventional enzymatic features has paved the way to new insights into the role of LOX metabolism in epithelial tissue homeostasis demonstrating a pivotal role of a unique LOX pathway in the establishment and maintenance of the epidermal permeability barrier.

Acknowledgments

This work was supported by grants from the Deutsche Forschungsgemeinschaft (KR 905/6-2, KR 905/7-1).

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^☆: This article is part of a Special Issue entitled The Important Role of Lipids in the Epidermis and their Role in the Formation and Maintenance of the Cutaneous Barrier. Guest Editors: Kenneth R. Feingold and Peter Elias.

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ReviewThe role of lipoxygenases in epidermis☆

Highlights

Abstract

Introduction

Section snippets

Mammalian lipoxygenases

Lipoxygenases in human and mouse skin: cloning, expression, activity and function

12R-LOX/eLOX-3 pathway in permeability barrier function

Acknowledgments

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Review
The role of lipoxygenases in epidermis☆