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.

中文翻译：

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人银屑病病变中亚油酰-ω-羟基神经酰胺生物合成途径的脂质组学和转录分析。

包括脂肪酸、胆固醇和神经酰胺在内的复杂脂质组合对哺乳动物表皮屏障的完整性至关重要。这种屏障的形成需要底物脂肪酸亚油酸 (LA) 的氧化，其由酶 12R-脂氧合酶 (LOX) 引发。在表皮中，未氧化的 LA 主要存在于长链酰基神经酰胺中，称为酯化 ω-羟基鞘氨醇/植物鞘氨醇/羟基鞘氨醇 (EOS/EOP/EOH，统称为 EOx)。LOX 氧化的 EOx 在人类表皮中的精确结构和定位是未知的，它们在牛皮癣等疾病中的调节也是未知的，牛皮癣是影响皮肤的最常见的炎症性疾病之一。在这里，我们使用前体 LC/MS/MS 表征了 EOx 的多种中间体，包括 9-HODE、9,10-epoxy-13-HOME 和 9,10，健康人表皮中的 13-TriHOME 可能通过表皮 LOX 途径形成。皮肤的顶层含有更多的 LA、9-HODE 和 9,10,13-TriHOME EOS，而 9,10-epoxy-13-HOME EOS 在角质层更深处更为普遍。在银屑病病变中，天然 EOx 和游离 HODEs 和 HOMEs 水平显着升高，而氧化物质普遍减少。对人类银屑病病变的转录网络分析发现，氧化神经酰胺的整个生物合成/代谢途径的表达显着升高，表明 EOx 脂质在重建表皮完整性中具有调节功能。这些新脂质在银屑病进展或消退中的作用目前尚不清楚。我们还发现了锌指蛋白转录因子 ZIC1 的中枢协调作用，在驱动这种疾病的表型。总之，长链含氧神经酰胺代谢在银屑病的脂质组水平上失调，可能是由还观察到的转录差异驱动的，我们将 ZIC1 确定为未来治疗干预的潜在调节靶点。