Differentiation of epidermal keratinocytes is dependent on glucosylceramide:ceramide processing
Differentiation of epidermal keratinocytes is dependent on glucosylceramide:ceramide processing
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DOI：
10.1093/hmg/ddt264
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发表时间：
2013-10-15
影响因子：
3.5
通讯作者：
Jennemann, Richard
中科院分区：
文献类型：
--
作者：
Amen, Nicole;Mathow, Daniel;Jennemann, Richard
皮肤屏障功能主要分布在外层的角质层(SC)，主要由角质细胞和富含脂质的细胞外基质组成。表皮神经酰胺(CERs)是一种必需的屏障脂类，含有超长链(ULC)脂肪酸(FAs)，具有独特的？-羟基，是与角质细胞蛋白结合所必需的。在SC中，CERs被认为来自糖基化的中间产物，即葡萄糖神经酰胺(GlcCers)，推测来自人类Gauchers病和相关的小鼠模型。三苯氧胺()诱导角蛋白K14阳性细胞内源性GlcCer合成酶UDP-葡萄糖：神经酰胺葡萄糖基转移酶(UGCG)的缺失，导致表皮GlcCer耗竭。尽管可自由提取的CER在总表皮和SC中升高，但在UGCG(f/fK14CreERT2)小鼠中，蛋白质结合的CER显著降低，表明正常的CER加工以及脂层的排列和挤出都需要糖基化。蛋白质结合CERs的几乎完全丧失导致了水渗透屏障(WPB)的破坏。UGCG基因缺陷的小鼠出现了鱼鳞病样皮肤表型，其特征是角质形成细胞分化受损，与伤口愈合延迟有关。UGCG突变皮肤的基因表达谱揭示了一组差异表达的基因，这些基因涉及脂质信号和表皮分化/增殖，与银屑病和特应性皮炎等人类皮肤病相关。过氧化物酶体增殖物激活受体β/增量(PPAR/)是一种Cer敏感的转录因子，被认为是改变基因集的潜在介体。
Skin barrier function is primarily assigned to the outer epidermal layer, the stratum corneum (SC), mainly composed of corneocytes and lipid-enriched extracellular matrix. Epidermal ceramides (Cers) are essential barrier lipids, containing ultra-long-chain (ULC) fatty acids (FAs) with a unique ?-hydroxy group, which is necessary for binding to corneocyte proteins. In the SC, Cers are believed to derive from glucosylated intermediates, namely glucosylceramides (GlcCers), as surmised from human Gauchers disease and related mouse models. Tamoxifen (TAM)-induced deletion of the endogenous GlcCer-synthesizing enzyme UDP-glucose:ceramide glucosyltransferase (UGCG) in keratin K14-positive cells resulted in epidermal GlcCer depletion. Although free extractable Cers were elevated in total epidermis and as well in SC, protein-bound Cers decreased significantly in Ugcg(f/fK14CreERT2) mice, indicating glucosylation to be required for regular Cer processing as well as arrangement and extrusion of lipid lamellae. The almost complete loss of protein-bound Cers led to a disruption of the water permeability barrier (WPB). UGCG-deficient mice developed an ichthyosis-like skin phenotype marked by impaired keratinocyte differentiation associated with delayed wound healing. Gene expression profiling of Ugcg-mutant skin revealed a subset of differentially expressed genes involved in lipid signaling and epidermal differentiation/proliferation, correlating to human skin diseases such as psoriasis and atopic dermatitis. Peroxisome proliferator-activated receptor beta/delta (PPAR/), a Cer-sensitive transcription factor was identified as potential mediator of the altered gene sets.