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 ω-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 ∼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.

中文翻译：

---

鱼鳞病致病基因FATP4通过形成屏障脂质ω-O-酰基神经酰胺形成皮肤通透性屏障。

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起着关键作用。其合成的废除引起皮肤病鱼鳞病。但是，酰基神经酰胺的合成途径尚未完全阐明：即，该途径中涉及的酰基辅酶A合成酶（ACS）仍有待确定。在这里，我们假设它由鱼鳞病早熟综合征（IPS）的致病基因FATP4 / ACSVL4编码。体外实验表明，FATP4对ω-羟基脂肪酸（FA）（酰基神经酰胺合成途径的中间体）具有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野生型小鼠的约10％。在饱和的，未酰化的神经酰胺中观察到水平降低和链长缩短。FA水平在Fatp4 KO小鼠的表皮中没有降低。FA延长酶Elovl1在Fatp4 KO表皮中的表达水平降低，部分解释了饱和，未酰化的神经酰胺的减少和缩短。在具有FATP4敲低的人角质形成细胞中也观察到了酰基神经酰胺水平的降低。从这些结果，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于酰基神经酰胺生成减少所致。我们的发现进一步阐明了控制酰基神经酰胺合成和IPS病理的分子机制。FA延长酶Elovl1在Fatp4 KO表皮中的表达水平降低，部分解释了饱和，未酰化的神经酰胺的减少和缩短。在具有FATP4敲低的人角质形成细胞中也观察到了酰基神经酰胺水平的降低。从这些结果，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于酰基神经酰胺生成减少所致。我们的发现进一步阐明了控制酰基神经酰胺合成和IPS病理的分子机制。FA延长酶Elovl1在Fatp4 KO表皮中的表达水平降低，部分解释了饱和，未酰化的神经酰胺的减少和缩短。在具有FATP4敲低的人角质形成细胞中也观察到了酰基神经酰胺水平的降低。从这些结果，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于酰基神经酰胺生成减少所致。我们的发现进一步阐明了控制酰基神经酰胺合成和IPS病理的分子机制。我们得出的结论是，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于酰基神经酰胺生成减少所致。我们的发现进一步阐明了控制酰基神经酰胺合成和IPS病理的分子机制。我们得出的结论是，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于酰基神经酰胺生成减少所致。我们的发现进一步阐明了控制酰基神经酰胺合成和IPS病理的分子机制。