Skin permeability barrier formation by the ichthyosis-causative gene FATP4 through formation of the barrier lipid [omega]-O-acylceramide

• Verfasst von: Yamamoto, Haruka [VerfasserIn]
• Verfasst von: Chamulitrat, Walee [VerfasserIn]
• Titel: Skin permeability barrier formation by the ichthyosis-causative gene FATP4 through formation of the barrier lipid [omega]-O-acylceramide
• Verf.angabe: Haruka Yamamoto, Miku Hattori, Walee Chamulitrat, Yusuke Ohno, and Akio Kihara
• E-Jahr: 2020
• Jahr: February 11, 2020
• Umfang: 9 S.
• Fussnoten: Gesehen am 24.03.2020
• Titel Quelle: Enthalten in: National Academy of Sciences (Washington, DC)Proceedings of the National Academy of Sciences of the United States of America
• Ort Quelle: Washington, DC : National Acad. of Sciences, 1915
• Jahr Quelle: 2020
• Band/Heft Quelle: 117(2020), 6, Seite 2914-2922
• ISSN Quelle: 1091-6490
• DOI: doi:10.1073/pnas.1917525117
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1693198703

Abstract

<p>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.</p>