Skin permeability barrier formation by the ichthyosis-causative gene FATP4 through formation of the barrier lipid ω-O-acylceramide
Skin permeability barrier formation by the ichthyosis-causative gene FATP4 through formation of the barrier lipid ω-O-acylceramide
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DOI：
10.1073/pnas.1917525117
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发表时间：
2020-02-11
影响因子：
11.1
通讯作者：
Kihara, Akio
中科院分区：
文献类型：
--
作者：
Yamamoto, Haruka;Hattori, Miku;Kihara, Akio
表皮特异性脂质酰基神经酰胺在皮肤渗透性屏障的形成中发挥着关键作用；其合成的破坏会导致皮肤病鱼鳞病。然而，酰基神经酰胺合成途径尚未完全阐明：即参与该途径的酰基辅酶A合成酶(ACS)仍有待鉴定。在这里，我们假设它是由 FATP4/ACSVL4 编码的，FATP4/ACSVL4 是鱼鳞病早产综合征 (IPS) 的致病基因。体外实验表明，FATP4 对 omega-羟基脂肪酸 (FA)（酰基神经酰胺合成途径的中间体）表现出 ACS 活性。 Fatp4 基因敲除 (KO) 小鼠表现出严重的皮肤屏障功能障碍和表皮形态异常。 Fatp4 KO 小鼠中的酰基神经酰胺总量减少至与野生型小鼠相似的 10%。在饱和的非酰化神经酰胺中观察到水平降低和链长度缩短。 Fatp4 KO 小鼠表皮中的 FA 水平没有降低。 Fatp4 KO 表皮中 FA 延长酶 Elovl1 的表达水平降低，部分原因是饱和非酰化神经酰胺的减少和缩短。在 FATP4 敲低的人角质形成细胞中也观察到酰基神经酰胺水平下降。从这些结果中，我们得出结论，在 IPS 患者和 Fatp4 KO 小鼠中观察到的皮肤屏障功能障碍主要是由酰基神经酰胺产生减少引起的。我们的研究结果进一步阐明了控制酰基神经酰胺合成和 IPS 病理学的分子机制。
The epidermis-specific lipid acylceramide plays a pivotal role in the formation of the permeability barrier in the skin; abrogation of its synthesis causes the skin disorder ichthyosis. However, the acylceramide synthetic pathway has not yet been fully elucidated: Namely, the acyl-CoA synthetase (ACS) involved in this pathway remains to be identified. Here, we hypothesized it to be encoded by FATP4/ACSVL4, the causative gene of ichthyosis prematurity syndrome (IPS). In vitro experiments revealed that FATP4 exhibits ACS activity toward an omega-hydroxy fatty acid (FA), an intermediate of the acylceramide synthetic pathway. Fatp4 knockout (KO) mice exhibited severe skin barrier dysfunction and morphological abnormalities in the epidermis. The total amount of acylceramide in Fatp4 KO mice was reduced to similar to 10% of wild-type mice. Decreased levels and shortening of chain lengths were observed in the saturated, nonacylated ceramides. FA levels were not decreased in the epidermis of Fatp4 KO mice. The expression levels of the FA elongase Elovl1 were reduced in Fatp4 KO epidermis, partly accounting for the reduction and shortening of saturated, nonacylated ceramides. A decrease in acylceramide levels was also observed in human keratinocytes with FATP4 knockdown. From these results, we conclude that skin barrier dysfunction observed in IPS patients and Fatp4 KO mice is caused mainly by reduced acylceramide production. Our findings further elucidate the molecular mechanism governing acylceramide synthesis and IPS pathology.