Lipids are the primary components of the skin permeability barrier, which is the body's most powerful defensive mechanism against pathogens. Acylceramide (ω-O-acylceramide) is a specialized lipid essential for skin barrier formation. Here, we identify PNPLA1 as the long-sought gene involved in the final step of acylceramide synthesis, esterification of ω-hydroxyceramide with linoleic acid, by cell-based assays. We show that increasing triglyceride levels by overproduction of the diacylglycerol acyltransferase DGAT2 stimulates acylceramide production, suggesting that triglyceride may act as a linoleic acid donor. Indeed, the in vitro analyses confirm that PNPLA1 catalyses acylceramide synthesis using triglyceride as a substrate. Mutant forms of PNPLA1 found in patients with ichthyosis exhibit reduced or no enzyme activity in either cell-based or in vitro assays. Altogether, our results indicate that PNPLA1 is directly involved in acylceramide synthesis as a transacylase, and provide important insights into the molecular mechanisms of skin barrier formation and of ichthyosis pathogenesis.

中文翻译：

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PNPLA1是产生皮肤屏障脂质ω-O-酰基神经酰胺必不可少的转酰基酶。

脂质是皮肤渗透性屏障的主要成分，它是人体抵抗病原体的最强大防御机制。酰基神经酰胺（ω-O-酰基神经酰胺）是皮肤屏障形成必不可少的特殊脂质。在这里，我们确定PNPLA1是参与酰基神经酰胺合成的最后一步的长期寻找的基因，通过基于细胞的分析，ω-羟基神经酰胺与亚油酸的酯化反应。我们表明，通过过量生产二酰基甘油酰基转移酶DGAT2来增加甘油三酸酯水平会刺激酰基神经酰胺的产生，表明甘油三酸酯可能充当亚油酸供体。实际上，体外分析证实了使用甘油三酸酯为底物的PNPLA1催化酰基神经酰胺的合成。在鱼鳞病患者中发现的PNPLA1突变形式在基于细胞的方法或体外试验中均显示酶活性降低或无酶活性。总而言之，我们的结果表明PNPLA1作为转酰基酶直接参与了酰基神经酰胺的合成，并为皮肤屏障形成和鱼鳞病发病机理的分子机制提供了重要的见识。