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Impaired Skin Barrier Function Due to Reduced omega-O-Acylceramide Levels in a Mouse Model of Sjogren-Larsson Syndrome
| Title: | Impaired Skin Barrier Function Due to Reduced omega-O-Acylceramide Levels in a Mouse Model of Sjogren-Larsson Syndrome |
| Authors: | Nojiri, Koki Browse this author | | Fudetani, Shuhei Browse this author | | Arai, Ayami Browse this author | | Kitamura, Takuya Browse this author | | Sassa, Takayuki Browse this author | | Kihara, Akio Browse this author |
| Keywords: | aldehyde dehydrogenase | | ceramide | | ichthyosis | | lipid | | long-chain base | | Sjogren-Larsson syndrome | | skin | | sphingolipid |
| Issue Date: | Oct-2021 |
| Publisher: | American Society for Microbiology |
| Journal Title: | Molecular and cellular biology |
| Volume: | 41 |
| Issue: | 10 |
| Start Page: | e00352-21 |
| Publisher DOI: | 10.1128/MCB.00352-21 |
| Abstract: | Sjogren-Larsson syndrome (SLS) is an inherited neurocutaneous disorder whose causative gene encodes the fatty aldehyde dehydrogenase ALDH3A2. To date, the detailed molecular mechanism of the skin pathology of SLS has remained largely unclear. We generated double-knockout (DKO) mice for Aldh3a2 and its homolog Aldh3b2 (a pseudogene in humans). These mice showed hyperkeratosis and reduced fatty aldehyde dehydrogenase activity and skin barrier function. The levels of w-O-acylceramides (acylceramides), which are specialized ceramides essential for skin barrier function, in the epidermis of DKO mice were about 60% of those in wild-type mice. In the DKO mice, levels of acylceramide precursors (w-hydroxy ceramides and triglycerides) were increased, suggesting that the final step of acylceramide production was inhibited. A decrease in acylceramide levels was also observed in human immortalized keratinocytes lacking ALDH3A2. Differentiated keratinocytes prepared from the DKO mice exhibited impaired long-chain base metabolism. Based on these results, we propose that the long-chain-base-derived fatty aldehydes that accumulate in DKO mice and SLS patients attack and inhibit the enzyme involved in the final step of acylceramide production. Our findings provide insight into the pathogenesis of the skin symptoms of SLS, i.e., decreased acylceramide production, and its molecular mechanism. |
| Rights: | © 2021 American Society for Microbiology. |
| Type: | article |
| URI: | http://hdl.handle.net/2115/86651 |
| Appears in Collections: | 薬学研究院 (Faculty of Pharmaceutical Sciences) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)
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Submitter: 木原 章雄
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