Ceramides are important for skin health, with a multitude of species found in both dermis and epidermis. The epidermis contains linoleic acid-Ester-linked Omega-hydroxylated ceramides of 6-Hydroxy-sphingosine, Sphingosine and Phytosphingosine bases (CER[EOH], CER[EOS] and CER[EOP], respectively), that are crucial for the formation of the epidermal barrier, conferring protection from environmental factors and preventing trans-epidermal water loss. Furthermore, a large number of ceramides, derivatives of the same sphingoid bases and various fatty acids, are produced by dermal and epidermal cells and perform signalling roles in cell functions ranging from differentiation to apoptosis.Supplementation with the n-3 polyunsaturated fatty acids (PUFA) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have shown promise as therapeutic agents in a number of inflammatory skin conditions, altering the lipid profile of the skin and production of bioactive lipids such as the eicosanoids, docosanoids and endocannabinoids. In this study we wished to investigate whether EPA and DHA could also affect the ceramide profile in epidermis and dermis, and, in this way, contribute to formation of a robust lipid barrier and ceramide-mediated regulation of skin functions.Ex vivo skin explants were cultured for 6 days, and supplemented with EPA or DHA (50 μM). Liquid chromatography coupled to tandem mass spectrometry with electrospray ionisation was used to assess the prevalence of 321 individual ceramide species, and a number of sphingoid bases, phosphorylated sphingoid bases, and phosphorylated ceramides, within the dermis and epidermis.EPA augmented dermal production of members of the ceramide families containing Non-hydroxy fatty acids and Sphingosine or Dihydrosphingosine bases (CER[NS] and CER[NDS], respectively), while epidermal CER[EOH], CER[EOS] and CER[EOP] ceramides were not affected. DHA did not significantly affect ceramide production. Ceramide-1-phosphate levels in the epidermis, but not the dermis, increased in response to EPA, but not DHA.This ex vivo study shows that dietary supplementation with EPA has the potential to alter the ceramide profile of the skin, and this may contribute to its anti-inflammatory profile. This has implications for formation of the epidermal lipid barrier, and signalling pathways within the skin mediated by ceramides and other sphingolipid species. This article is part of a Special Issue entitled: Membrane Lipid Therapy: Drugs Targeting Biomembranes edited by Pablo V. Escribá.

Nutritional supplementation with fish oil or ω‐3 (n‐3) polyunsaturated fatty acids (PUFAs) has potential benefits for skin inflammation. Although the differential metabolism of the main n‐3PUFA eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) could lead to distinct activities, there are no clinical studies comparing their relative efficacy in human skin. Following a 10‐wk oral supplementation of healthy volunteers and using mass spectrometry‐based lipidomics, we found that n‐3PUFA mainly affected the epidermal mediator lipidome. EPA was more efficient than DHA in reducing production of arachidonic acid–derived lipids, and both n‐3PUFA lowered N‐acyl ethanolamines. In UV radiation–challenged skin (3 times the minimum erythemal dose), EPA attenuated the production of proinflammatory lipids, whereas DHA abrogated the migration of Langerhans cells, as assessed by immunohistochemistry. Interestingly, n‐3PUFA increased the infiltration of CD4+ and CD8+ T cells but did not alter the erythemal response, either the sunburn threshold or the resolution of erythema, as assessed by spectrophotometric hemoglobin index readings. As EPA and DHA differentially impact cutaneous inflammation through changes in the network of epidermal lipids and dendritic and infiltrating immune cells, they should be considered separately when designing interventions for cutaneous disease.—Kendall, A. C., Pilkington, S. M., Murphy, S. A., Del Carratore, F., Sunarwidhi, A. L., Kiezel‐Tsugunova, M., Urquhart, P., Watson, R. E. B., Breitling, R., Rhodes, L. E., Nicolaou, A. Dynamics of the human skin mediator lipidome in response to dietary ω‐3 fatty acid supplementation. FASEB J. 33, 13014–13027 (2019). http://www.fasebj.org

Human skin has a distinct profile of fatty acids and related bioactive lipid mediators that regulate many aspects of epidermal and dermal homeostasis, including immune and inflammatory reactions. Sebum lipids act as effective antimicrobial agents, shape immune cell communications and contribute to the epidermal lipidome. The essential fatty acid linoleic acid is crucial for the structure of the epidermal barrier, while polyunsaturated fatty acids act as precursors to eicosanoids, octadecanoids and docosanoids through cyclooxygenase, lipoxygenase and cytochrome P450 monooxygenase-mediated reactions, and endocannabinoids and -acyl ethanolamines. Cross-communication between these families of bioactive lipids suggests that their cutaneous activities should be considered as part of a wider metabolic network that can be targeted to maintain skin health, control inflammation and improve skin pathologies.