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Lipidomic and transcriptional analysis of the Linoleoyl-omega-Hydroxyceramide biosynthetic pathway in human psoriatic lesions

Tyrrell, Victoria J., Ali, Faraz, Boeglin, William E., Andrews, Robert, Burston, James, Birchall, James C. ORCID:, Ingram, John R., Murphy, Robert C., Piguet, Vincent, Brash, Alan R., O'Donnell, Valerie B. ORCID: and Thomas, Christopher P. ORCID: 2021. Lipidomic and transcriptional analysis of the Linoleoyl-omega-Hydroxyceramide biosynthetic pathway in human psoriatic lesions. Journal of Lipid Research 62 , 100094. 10.1016/j.jlr.2021.100094

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A complex assembly of lipids including fatty acids, cholesterol and ceramides is vital to the integrity of the mammalian epidermal barrier. The formation of this barrier requires oxidation of the substrate fatty acid, linoleate (LA), which is initiated by the enzyme 12R-lipoxygenase (LOX). In the epidermis, unoxidized LA is primarily found in long chain acylceramides termed esterified omega-hydroxy sphingosine/phytosphingosine/hydroxysphingosine (EOS/EOP/EOH, collectively EOx). The precise structure and localization of LOX-oxidised EOx in the human epidermis is unknown, as is their regulation in diseases such as psoriasis, one of the most common inflammatory diseases affecting the skin. Here, using precursor LC/MS/MS, we characterized multiple intermediates of EOx, including 9-HODE, 9,10-epoxy-13-HOME, and 9,10,13-TriHOME in healthy human epidermis likely to be formed via the epidermal LOX pathways. The top layers of the skin contained more LA, 9-HODE, and 9,10,13-TriHOME EOSs, while 9,10-epoxy-13-HOME EOS was more prevalent deeper in the stratum corneum. In psoriatic lesions, levels of native EOx and free HODEs and HOMEs were significantly elevated, while oxidized species were generally reduced. A transcriptional network analysis of human psoriatic lesions identified significantly elevated expression of the entire biosynthetic/metabolic pathway for oxygenated ceramides, suggesting a regulatory function for EOx lipids in reconstituting epidermal integrity. The role of these new lipids in progression or resolution of psoriasis is currently unknown. We also discovered the central coordinated role of the zinc finger protein transcription factor, ZIC1, in driving the phenotype of this disease. In summary, long-chain oxygenated ceramide metabolism is dysregulated at the lipidomic level in psoriasis, likely driven by the transcriptional differences also observed, and we identified ZIC1 as a potential regulatory target for future therapeutic interventions.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: American Society for Biochemistry and Molecular Biology
ISSN: 0022-2275
Date of First Compliant Deposit: 20 July 2021
Date of Acceptance: 18 June 2021
Last Modified: 04 May 2023 01:29

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