PNPLA1 has a crucial role in skin barrier function by directing acylceramide biosynthesis.
PNPLA1 has a crucial role in skin barrier function by directing acylceramide biosynthesis.
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DOI：
10.1038/ncomms14609
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发表时间：
2017-03-01
影响因子：
16.6
通讯作者：
Murakami M
中科院分区：
文献类型：
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作者：
Hirabayashi T;Anjo T;Kaneko A;Senoo Y;Shibata A;Takama H;Yokoyama K;Nishito Y;Ono T;Taya C;Muramatsu K;Fukami K;Muñoz-Garcia A;Brash AR;Ikeda K;Arita M;Akiyama M;Murakami M
patatin-like phospholipase domain-containing 1（PNPLA 1）基因突变导致常染色体隐性遗传性先天性鱼鳞病，但其机制尚不清楚。在这里，我们表明PNPLA 1，一种在分化的角质形成细胞中表达的酶，在ω-O-酰基神经酰胺的生物合成中起着至关重要的作用，ω-O-酰基神经酰胺是皮肤屏障所必需的脂质成分。全球或角质形成细胞特异性Pnpla 1缺陷的新生儿死亡，由于表皮通透性屏障缺陷与严重的经表皮水分流失，减少细胞间的脂质laminates在角质层，和异常的角质形成细胞分化。在PNPLA 1 −/−表皮中，独特的含亚油酸酯的脂质，包括酰基神经酰胺、酰基葡萄糖基神经酰胺和（O-酰基）-ω-羟基脂肪酸几乎不存在，而它们的推定前体则相反增加，这表明PNPLA 1催化亚油酸的ω-O-酯化反应形成酰基神经酰胺。此外，酰基神经酰胺补充部分挽救了Pnpla 1 −/−角质形成细胞的分化改变。我们的研究结果为皮肤屏障形成和鱼鳞病的发展提供了有价值的见解，并可能有助于治疗表皮屏障缺陷的新的治疗策略。PNPLA 1是一种编码功能未知的酶的基因，其功能缺失突变会导致人类皮肤干燥和脱皮。使用PNPLA 1缺陷的小鼠模型，作者表明PNPLA 1参与酰基神经酰胺的生物合成，酰基神经酰胺是皮肤屏障功能所必需的脂质成分。
Mutations in patatin-like phospholipase domain-containing 1 (PNPLA1) cause autosomal recessive congenital ichthyosis, but the mechanism involved remains unclear. Here we show that PNPLA1, an enzyme expressed in differentiated keratinocytes, plays a crucial role in the biosynthesis of ω-O-acylceramide, a lipid component essential for skin barrier. Global or keratinocyte-specific Pnpla1-deficient neonates die due to epidermal permeability barrier defects with severe transepidermal water loss, decreased intercellular lipid lamellae in the stratum corneum, and aberrant keratinocyte differentiation. In Pnpla1−/− epidermis, unique linoleate-containing lipids including acylceramides, acylglucosylceramides and (O-acyl)-ω-hydroxy fatty acids are almost absent with reciprocal increases in their putative precursors, indicating that PNPLA1 catalyses the ω-O-esterification with linoleic acid to form acylceramides. Moreover, acylceramide supplementation partially rescues the altered differentiation of Pnpla1−/− keratinocytes. Our findings provide valuable insight into the skin barrier formation and ichthyosis development, and may contribute to novel therapeutic strategies for treatment of epidermal barrier defects. Loss-of-function mutations in PNPLA1, a gene encoding an enzyme with unknown function, cause dry and scaling skin in humans. Using mouse models with PNPLA1 deficiency, the authors show that PNPLA1 participates in the biosynthesis of acylceramide, a lipid component essential for skin barrier function.