Department of Biological Sciences, The University of Memphis, Memphis, Tennessee, USA.
Department of Biological Sciences, The University of Memphis, Memphis, Tennessee, USA; Department of Surgery, School of Medicine, University of Maryland, Baltimore, Maryland, USA.
J Invest Dermatol. 2023 Oct;143(10):1964-1972.e4. doi: 10.1016/j.jid.2023.03.1662. Epub 2023 Mar 31.
Ligand activation of the aryl hydrocarbon receptor (AHR) accelerates keratinocyte differentiation and the formation of the epidermal permeability barrier. Several classes of lipids, including ceramides, are critical to the epidermal permeability barrier. In normal human epidermal keratinocytes, the AHR ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin, increased RNA levels of ceramide metabolism and transport genes: uridine diphosphate glucose ceramide glucosyltransferase (UGCG), ABCA12, GBA1, and SMPD1. Levels of abundant skin ceramides were also increased by 2,3,7,8-tetrachlorodibenzo-p-dioxin. These included the metabolites synthesized by UGCG, glucosylceramides, and acyl glucosylceramides. Chromatin immunoprecipitation-sequence analysis and luciferase reporter assays identified UGCG as a direct AHR target. The AHR antagonist, GNF351, inhibited the 2,3,7,8-tetrachlorodibenzo-p-dioxin-mediated RNA and transcriptional increases. Tapinarof, an AHR ligand approved for the treatment of psoriasis, increased UGCG RNA, protein, and its lipid metabolites hexosylceramides as well as increased the RNA expression of ABCA12, GBA1, and SMPD1. In Ahr-null mice, Ugcg RNA and hexosylceramides were lower than those in the wild type. These results indicate that the AHR regulates the expression of UGCG, a ceramide-metabolizing enzyme required for ceramide trafficking, keratinocyte differentiation, and epidermal permeability barrier formation.
配体激活芳香烃受体 (AHR) 可加速角质形成细胞分化和表皮渗透屏障的形成。包括神经酰胺在内的几类脂质对表皮渗透屏障至关重要。在正常的人类表皮角质形成细胞中，AHR 配体 2,3,7,8-四氯二苯并对二恶英增加了神经酰胺代谢和转运基因的 RNA 水平：尿苷二磷酸葡萄糖神经酰胺葡萄糖基转移酶 (UGCG)、ABCA12、GBA1 和 SMPD1。2,3,7,8-四氯二苯并对二恶英还增加了大量皮肤神经酰胺的水平。这些包括由 UGCG 合成的代谢物、葡萄糖神经酰胺和酰基葡萄糖神经酰胺。染色质免疫沉淀-序列分析和荧光素酶报告基因检测鉴定 UGCG 为 AHR 的直接靶标。AHR 拮抗剂 GNF351 抑制了 2,3,7,8-四氯二苯并对二恶英介导的 RNA 和转录增加。批准用于治疗银屑病的 AHR 配体 Tapinarof 增加了 UGCG 的 RNA、蛋白质及其脂质代谢物己糖神经酰胺，以及 ABCA12、GBA1 和 SMPD1 的 RNA 表达。在 Ahr 基因敲除小鼠中，Ugcg RNA 和己糖神经酰胺的水平低于野生型。这些结果表明 AHR 调节 UGCG 的表达，UGCG 是一种神经酰胺代谢酶，对于神经酰胺转运、角质形成细胞分化和表皮渗透屏障形成是必需的。
