Alterations of Ultra Long-Chain Fatty Acids in Hereditary Skin Diseases-Review Article

Abstract

The skin is a flexible organ that forms a barrier between the environment and the body's interior; it is involved in the immune response, in protection and regulation, and is a dynamic environment in which skin lipids play an important role in maintaining homeostasis. The different layers of the skin differ in both the composition and amount of lipids. The epidermis displays the best characteristics in this respect. The main lipids in this layer are cholesterol, fatty acids (FAs) and ceramides. FAs can occur in free form and as components of complex molecules. The most poorly characterized FAs are very long-chain fatty acids (VLCFAs) and ultra long-chain fatty acids (ULCFAs). VLCFAs and ULCFAs are among the main components of ceramides and are part of the free fatty acid (FFA) fraction. They are most abundant in the brain, liver, kidneys, and skin. VLCFAs and ULCFAs are responsible for the rigidity and impermeability of membranes, forming the mechanically and chemically strong outer layer of cell membranes. Any changes in the composition and length of the carbon chains of FAs result in a change in their melting point and therefore a change in membrane permeability. One of the factors causing a decrease in the amount of VLCFAs and ULCFAs is an improper diet. Another much more important factor is mutations in the genes which code proteins involved in the metabolism of VLCFAs and ULCFAs-regarding their elongation, their attachment to ceramides and their transformation. These mutations have their clinical consequences in the form of inborn errors in metabolism and neurodegenerative disorders, among others. Some of them are accompanied by skin symptoms such as ichthyosis and ichthyosiform erythroderma. In the following review, the structure of the skin is briefly characterized and the most important lipid components of the skin are presented. The focus is also on providing an overview of selected proteins involved in the metabolism of VLCFAs and ULCFAs in the skin.

Keywords: ceramides; cholesterol; dermis; epidermis; fatty acids; lipids; skin.

Figure 1

FA elongation cycle with involved enzymes in each step (5). ELOVL1-7-fatty acid elongase 1-7 (ELOVL1 elongates SFA with chain lengths of 18–24 carbons, ELOVL2 elongates PUFA with 20–22 carbon and SFA with 18–20 carbon chains; ELOVL3 elongates SFA with chain lengths of 18–24 carbons; ELOVL4 elongates long-chain PUFA and long-chain SFA of 24 carbon length to VLC-PUFA and VLC-SFA (≥26 carbons; ELOVL5 mediates elongation of long-chain PUFA and long-chain SFA between 18 and 22 carbons in length; ELOVL6 elongates SFA, MUFA and PUFA with 12–18 carbon chains; ELOVL7 elongates SFA with chain lengths of 18–22 carbons); KAR, 3-ketoacyl-CoA reductase; HACD 1-4, 3-hydroxyacyl-CoA dehydratase; TER, trans-2-enoyl-CoA reductase.

Figure 2

Components and biosynthetic steps of fatty acid modification in the skin. FASN1 catalyzes de novo synthesis of fatty acids from acetyl-CoA and malonyl-CoA. After activation to acyl-CoA esters, the acyl chain is elongated to VLCFA-CoA esters. CYP4F22 catalyzes ω-hydroxylation ULCFA-CoA to ω-OH ULCFA and FATP4 synthesize ω-OH ULCFA-CoA. CerS3 enables the synthesis of ω-OH ULC-ceramide. In the same time in lipid droplet TAG is hydrolyzed by ATGL activated by the ABHD5 to linoleic acid, which is synthesize with CoA-SH by receiving Linoleoyl-CoA. PNPLA1 catalyzes as a transacylase the formation of an ester bond between ω-hydroxyceramide and linoleoyl-CoA, so that we get ω-O-acylceramide. ALOX12B and ALOXE3 are responsible for oxidizing linoleic acid when it is attached to acylceramide. FASN1, fatty acid synthase 1; VLCFA-CoA, very long-chain fatty acid CoA; ELOVL, fatty acid elongase; ULCFA-CoA, ultra long-chain fatty acid CoA; CYP4F22, Cytochrome P450 Family 4 Subfamily F Member 22; FATP4, fatty acid transporter 4; CerS3, ceramide synthase 3; ABHD5, abhydrolase domain containing 5; PNPLA1, patatin like phospholipase domain containing 1; ALOX12B, arachidonate 12-lipoxygenase, 12R type; ALOXE3, arachidonate lipoxygenase 3; TAG, triacylglycerol; DAG, diacylglycerol.