Holleran W M, Man M Q, Gao W N, Menon G K, Elias P M, Feingold K R
Department of Dermatology, University of California School of Medicine, San Francisco.
J Clin Invest. 1991 Oct;88(4):1338-45. doi: 10.1172/JCI115439.
Stratum corneum lipids comprise an approximately equimolar mixture of sphingolipids, cholesterol, and free fatty acids, arranged as intercellular membrane bilayers that are presumed to mediate the epidermal permeability barrier. Prior studies have shown that alterations in epidermal barrier function lead to a rapid increase in cholesterol and fatty acid synthesis which parallels the early stages of the repair process. Despite an abundance of indirect evidence for their role in the barrier, the importance of sphingolipids has yet to be demonstrated directly. Whereas sphingolipid synthesis also increases during barrier repair, this response is delayed in comparison to cholesterol and fatty acid synthesis (Holleran, W.M., et al. 1991. J. Lipid Res. 32:1151-1158). To further delineate the role of sphingolipids in barrier homeostasis, we assessed the impact of inhibition of sphingolipid synthesis on epidermal barrier recovery. A single topical application of beta-chloro-L-alanine (beta-CA), an irreversible inhibitor of serine-palmitoyl transferase (SPT), applied to acetone-treated skin of hairless mice resulted in: (a) greater than 75% inhibition of SPT activity at 30 min (P less than 0.001); (b) a global decrease in sphingolipid synthesis between 1 and 3 h (P less than 0.02); (c) reduction of epidermal sphingolipid content at 18 h (P less than 0.01); (d) delayed reaccumulation of histochemical staining for sphingolipids in the stratum corneum; and (e) reduced numbers and contents of lamellar bodies in the stratum granulosum. Finally, despite its immediate, marked diminution of sphingolipid synthesis, beta-CA slowed barrier recovery only at late time points (greater than 6 h) after acetone treatment. This inhibition was overridden by coapplications of ceramides (the distal SPT product), indicating that the delay in repair was not due to non-specific toxicity. These studies demonstrate a distinctive role for epidermal sphingolipids in permeability barrier homeostasis.
角质层脂质由鞘脂、胆固醇和游离脂肪酸组成，其摩尔比大致相等，排列成细胞间膜双层结构，推测该结构介导了表皮通透屏障。先前的研究表明，表皮屏障功能的改变会导致胆固醇和脂肪酸合成迅速增加，这与修复过程的早期阶段相似。尽管有大量间接证据表明鞘脂在屏障中发挥作用，但其重要性尚未得到直接证实。虽然在屏障修复过程中鞘脂合成也会增加，但与胆固醇和脂肪酸合成相比，这种反应延迟了（霍勒兰，W.M.等人，1991年。《脂质研究杂志》32:1151 - 1158）。为了进一步阐明鞘脂在屏障稳态中的作用，我们评估了抑制鞘脂合成对表皮屏障恢复的影响。将β - 氯 - L - 丙氨酸（β - CA），一种丝氨酸 - 棕榈酰转移酶（SPT）的不可逆抑制剂，单次局部应用于无毛小鼠经丙酮处理的皮肤，结果导致：（a）30分钟时SPT活性抑制超过75%（P小于0.001）；（b）1至3小时内鞘脂合成总体下降（P小于0.02）；（c）18小时时表皮鞘脂含量降低（P小于0.01）；（d）角质层中鞘脂的组织化学染色再积累延迟；以及（e）颗粒层中板层小体的数量和含量减少。最后，尽管β - CA立即显著减少了鞘脂合成，但它仅在丙酮处理后的后期时间点（大于6小时）减缓了屏障恢复。这种抑制作用被同时应用神经酰胺（SPT的末端产物）所克服，表明修复延迟并非由于非特异性毒性。这些研究证明了表皮鞘脂在通透屏障稳态中具有独特作用。
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