Skin permeability barrier formation by the ichthyosis-causative gene FATP4 through formation of the barrier lipid [omega]-O-acylceramide
<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 synth...
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| Main Authors: | , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
February 11, 2020
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| In: |
Proceedings of the National Academy of Sciences of the United States of America
Year: 2020, Volume: 117, Issue: 6, Pages: 2914-2922 |
| ISSN: | 1091-6490 |
| DOI: | 10.1073/pnas.1917525117 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1073/pnas.1917525117 Verlag, lizenzpflichtig, Volltext: https://www.pnas.org/content/117/6/2914 
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| Author Notes: | Haruka Yamamoto, Miku Hattori, Walee Chamulitrat, Yusuke Ohno, and Akio Kihara |
| Summary: | <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> |
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| Item Description: | Gesehen am 24.03.2020 |
| Physical Description: | Online Resource |
| ISSN: | 1091-6490 |
| DOI: | 10.1073/pnas.1917525117 |