Skin permeability barrier formation by the ichthyosis-causative gene <i>FATP4</i> through formation of the barrier lipid ω-<i>O</i>-acylceramide.

Abstract

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 <i>FATP4</i>/<i>ACSVL4</i>, 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. <i>Fatp4</i> knockout (KO) mice exhibited severe skin barrier dysfunction and morphological abnormalities in the epidermis. The total amount of acylceramide in <i>Fatp4</i> 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 <i>Fatp4</i> KO mice. The expression levels of the FA elongase <i>Elovl1</i> were reduced in <i>Fatp4</i> 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 <i>FATP4</i> knockdown. From these results, we conclude that skin barrier dysfunction observed in IPS patients and <i>Fatp4</i> KO mice is caused mainly by reduced acylceramide production. Our findings further elucidate the molecular mechanism governing acylceramide synthesis and IPS pathology.