Metabolism
Disruption of the Sjögren-Larsson Syndrome Gene Aldh3a2 in Mice Increases Keratinocyte Growth and Retards Skin Barrier RecoveryDisruption of Aldh3a2 Gene

https://doi.org/10.1074/jbc.M116.714030Get rights and content
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The fatty aldehyde dehydrogenase (FALDH) ALDH3A2 is the causative gene of Sjögren Larsson syndrome (SLS). To date, the molecular mechanism underlying the symptoms characterizing SLS has been poorly understood. Using Aldh3a2−/− mice, we found here that Aldh3a2 was the major FALDH active in undifferentiated keratinocytes. Long-chain base metabolism was greatly impaired in Aldh3a2−/− keratinocytes. Phenotypically, the intercellular spaces were widened in the basal layer of the Aldh3a2−/− epidermis due to hyperproliferation of keratinocytes. Furthermore, oxidative stress-induced genes were up-regulated in Aldh3a2−/− keratinocytes. Upon keratinocyte differentiation, the activity of another FALDH, Aldh3b2, surpassed that of Aldh3a2. As a result, Aldh3a2−/− mice were indistinguishable from wild-type mice in terms of their whole epidermis FALDH activity, and their skin barrier function was uncompromised under normal conditions. However, perturbation of the stratum corneum caused increased transepidermal water loss and delayed barrier recovery in Aldh3a2−/− mice. In conclusion, Aldh3a2−/− mice replicated some aspects of SLS symptoms, especially at the basal layer of the epidermis. Our results suggest that hyperproliferation of keratinocytes via oxidative stress responses may partly contribute to the ichthyosis symptoms of SLS.

ceramide
epidermis
gene knockout
genetic disease
keratinocyte
lipid
lipid ether
lipid metabolism
oxidative stress
sphingolipid

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This work was supported by Advanced Research and Development Programs for Medical Innovation (AMED-CREST) (to A. K.) from the Japan Agency for Medical Research and Development (AMED), by Grant-in-Aid for Scientific Research (A) 26251010 (to A. K.) from the Japan Society for the Promotion of Science (JSPS), and by Grant-in-aid for JSPS Fellows 25744 (to T. N.) from JSPS. The authors declare that they have no conflicts of interest with the contents of this article.

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The abbreviations used are:

    SLS

    Sjögren-Larsson syndrome

    FALDH

    fatty aldehyde dehydrogenase

    MC

    medium-chain

    LC

    long-chain

    FA

    fatty acid

    LCB

    long-chain base

    EOS

    esterified ω-hydroxyacylsphingosine

    DHS

    dihydrosphingosine

    ALDH

    aldehyde dehydrogenase

    TEWL

    transepidermal water loss

    PC

    phosphatidylcholine

    PE

    phosphatidylethanolamine

    PlsC

    plasmanyl/plasmenylcholine

    PlsE

    plasmanyl/plasmenylethanolamine

    d7

    deuterium.