Institute of Infection and Immunity and Systems Immunity Research Institute, School of Medicine, Cardiff University, Nashville, TN, USA.
Department of Dermatology and Wound Healing, University Hospital of Wales, Nashville, TN, USA.
J Lipid Res. 2021;62:100094. doi: 10.1016/j.jlr.2021.100094. Epub 2021 Jun 22.
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, linoleic acid (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 (EOS)/phytosphingosine/hydroxysphingosine (collectively EOx). The precise structure and localization of LOX-oxidized 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, whereas 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, whereas 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.
一种包含脂肪酸、胆固醇和神经酰胺的复杂脂质组装体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，而这种氧化是由酶 12R-脂氧合酶（LOX）启动的。在表皮中，未氧化的 LA 主要存在于长链酰神经酰胺中，称为酯化ω-羟基神经酰胺（EOS）/植物神经酰胺/羟基神经酰胺（统称为 EOx）。LOX 氧化的 EOx 在人表皮中的精确结构和定位尚不清楚，其在银屑病等疾病中的调节也不清楚，银屑病是最常见的影响皮肤的炎症性疾病之一。在这里，我们使用前体 LC/MS/MS 鉴定了 EOx 的多种中间体，包括 9-HODE、9,10-环氧-13-HOME 和 9,10,13-TriHOME，这些中间体可能是通过表皮 LOX 途径在健康人表皮中形成的。皮肤的顶层含有更多的 LA、9-HODE 和 9,10,13-TriHOME EOS，而 9,10-环氧-13-HOME EOS 在角质层较深的部位更为普遍。在银屑病病变中，天然 EOx 和游离 HODEs 和 HOMEs 的水平显著升高，而氧化物种通常减少。对人银屑病病变的转录网络分析表明，含氧神经酰胺的整个生物合成/代谢途径的表达显著升高，表明 EOx 脂质在重建表皮完整性方面具有调节作用。这些新脂质在银屑病的进展或缓解中的作用目前尚不清楚。我们还发现锌指蛋白转录因子 ZIC1 在驱动这种疾病表型方面具有中心协调作用。总之，在银屑病中，长链含氧神经酰胺代谢在脂质组学水平上失调，可能是由也观察到的转录差异驱动的，我们确定 ZIC1 是未来治疗干预的潜在调节靶点。
Zotero 插件
