Hara J, Higuchi K, Okamoto R, Kawashima M, Imokawa G
Department of Dermatology, Tokyo Women's Medical University, Tokyo, Japan.
J Invest Dermatol. 2000 Sep;115(3):406-13. doi: 10.1046/j.1523-1747.2000.00072.x.
We have previously demonstrated that there is abnormal expression of sphingomyelin (SM) deacylase-like enzyme in the epidermis of patients with atopic dermatitis (AD), which results in decreased levels of ceramides in their involved and uninvolved stratum corneum. For quantitation of the expression of SM deacylase in AD, we synthesized 16-(9-anthroyloxy) hexadecanoylsphingosylphosphorylcholine or [palmitic acid-14C] SM and used them as substrates to directly measure the activity of SM deacylase by detecting the release of labeled free fatty acid. Direct enzymatic measurements demonstrated that stratum corneum from lesional forearm skin (volar side) of AD patients has an extremely high SM deacylase activity that is at least five times higher than in the stratum corneum from healthy controls. In stratum corneum from nonlesional skin of AD patients, SM deacylase activity is still at least three times higher than in healthy controls. In contrast, stratum corneum from contact dermatitis patients shows levels of SM deacylase similar to healthy controls. In extracts of whole epidermis biopsies from AD patients, SM deacylase activities are significantly (3-fold) increased over healthy controls in the particulate fraction, whereas there is no significant difference in the activity of sphingomyelinase between AD and healthy control. In peripheral blood lymphocytes of AD patients, there is no increase in activity compared with healthy controls, indicating a possibility that the high expression of SM deacylase is highly associated with the skin of AD patients. These findings suggest that, in contrast to changes in sphingolipid metabolism due to aging, the hitherto undiscovered enzyme SM deacylase, is highly expressed in the epidermis of AD patients, and competes with sphingomyelinase or beta-glucocerebrosidase for the common substrate SM or glucosylceramide, which leads to the ceramide deficiency of the stratum corneum in AD.
我们之前已经证明，特应性皮炎（AD）患者的表皮中鞘磷脂（SM）脱酰基酶样酶存在异常表达，这导致其受累和未受累角质层中的神经酰胺水平降低。为了定量AD中SM脱酰基酶的表达，我们合成了16-（9-蒽氧基）十六烷酰鞘氨醇磷酸胆碱或[棕榈酸-14C]SM，并将它们用作底物，通过检测标记的游离脂肪酸的释放来直接测量SM脱酰基酶的活性。直接酶活性测定表明，AD患者病变前臂皮肤（掌侧）的角质层具有极高的SM脱酰基酶活性，至少比健康对照者角质层中的活性高五倍。在AD患者非病变皮肤的角质层中，SM脱酰基酶活性仍至少比健康对照者高两倍。相比之下，接触性皮炎患者的角质层显示出与健康对照者相似的SM脱酰基酶水平。在AD患者全表皮活检组织的提取物中，颗粒部分的SM脱酰基酶活性比健康对照者显著增加（3倍），而AD患者与健康对照者之间鞘磷脂酶的活性没有显著差异。在AD患者的外周血淋巴细胞中，与健康对照者相比活性没有增加，这表明SM脱酰基酶的高表达很可能与AD患者的皮肤高度相关。这些发现表明，与衰老引起的鞘脂代谢变化不同，迄今未被发现的酶SM脱酰基酶在AD患者的表皮中高度表达，并与鞘磷脂酶或β-葡萄糖脑苷脂酶竞争共同底物SM或葡萄糖神经酰胺，这导致AD患者角质层中神经酰胺缺乏。
