Lipidomic and transcriptional analysis of the linoleoyl-omega-hydroxyceramide biosynthetic pathway in human psoriatic lesions.
Lipidomic and transcriptional analysis of the linoleoyl-omega-hydroxyceramide biosynthetic pathway in human psoriatic lesions.
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DOI：
10.1016/j.jlr.2021.100094
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发表时间：
2021
影响因子：
6.5
通讯作者：
Thomas CP
中科院分区：
文献类型：
--
作者：
Tyrrell VJ;Ali F;Boeglin WE;Andrews R;Burston J;Birchall JC;Ingram JR;Murphy RC;Piguet V;Brash AR;O'Donnell VB;Thomas CP
包括脂肪酸、胆固醇和神经酰胺在内的脂质的复杂组合对于哺乳动物表皮屏障的完整性至关重要。该屏障的形成需要底物脂肪酸亚油酸 (LA) 的氧化，这是由 12R-脂氧合酶 (LOX) 引发的。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 omega-羟基鞘氨醇 (EOS)/植物鞘氨醇/羟基鞘氨醇（统称为 EOx）。 LOX 氧化的 EOx 在人类表皮中的精确结构和定位尚不清楚，它们在银屑病（影响皮肤的最常见炎症性疾病之一）等疾病中的调节也是未知的。在这里，我们使用前体 LC/MS/MS 表征了健康人表皮中可能通过表皮 LOX 途径形成的多种 EOx 中间体，包括 9-HODE、9,10-epoxy-13-HOME 和 9,10,13-TriHOME。皮肤表层含有更多的 LA、9-HODE 和 9,10,13-TriHOME EOS，而 9,10-epoxy-13-HOME EOS 在角质层深处更为普遍。在银屑病皮损中，天然 EOx 以及游离 HODE 和 HOME 的水平显着升高，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，含氧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 在驱动这种疾病表型中的中心协调作用。总之，长链含氧神经酰胺代谢在银屑病的脂质组学水平上失调，可能是由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。
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.
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影响因子：
3.7
作者：
Leong, J;HughesFulford, M;Goldyne, ME
通讯作者：
Goldyne, ME
影响因子：
11.2
作者：
Brill E;Gobble R;Angeles C;Lagos-Quintana M;Crago A;Laxa B;Decarolis P;Zhang L;Antonescu C;Socci ND;Taylor BS;Sander C;Koff A;Singer S
通讯作者：
Singer S
DOI：
10.1016/j.bbalip.2020.158611
发表时间：
2020-04-01
影响因子：
4.8
作者：
Fuchs, David;Tang, Xiao;Wheelock, Craig E.
通讯作者：
Wheelock, Craig E.
影响因子：
6.5
作者：
de Juanes, Silvia;Epp, Nikolas;Krieg, Peter
通讯作者：
Krieg, Peter
影响因子：
64.8
作者：
Huttlin EL;Bruckner RJ;Paulo JA;Cannon JR;Ting L;Baltier K;Colby G;Gebreab F;Gygi MP;Parzen H;Szpyt J;Tam S;Zarraga G;Pontano-Vaites L;Swarup S;White AE;Schweppe DK;Rad R;Erickson BK;Obar RA;Guruharsha KG;Li K;Artavanis-Tsakonas S;Gygi SP;Harper JW
通讯作者：
Harper JW