SDR9C7 catalyzes critical dehydrogenation of acylceramides for skin barrier formation

J Clin Invest. 2020 Feb 3;130(2):890-903. doi: 10.1172/JCI130675.


The corneocyte lipid envelope, composed of covalently bound ceramides and fatty acids, is important to the integrity of the permeability barrier in the stratum corneum, and its absence is a prime structural defect in various skin diseases associated with defective skin barrier function. SDR9C7 encodes a short-chain dehydrogenase/reductase family 9C member 7 (SDR9C7) recently found mutated in ichthyosis. In a patient with SDR9C7 mutation and a mouse Sdr9c7-KO model, we show loss of covalent binding of epidermal ceramides to protein, a structural fault in the barrier. For reasons unresolved, protein binding requires lipoxygenase-catalyzed transformations of linoleic acid (18:2) esterified in ω-O-acylceramides. In Sdr9c7-/- epidermis, quantitative liquid chromatography-mass spectometry (LC-MS) assays revealed almost complete loss of a species of ω-O-acylceramide esterified with linoleate-9,10-trans-epoxy-11E-13-ketone; other acylceramides related to the lipoxygenase pathway were in higher abundance. Recombinant SDR9C7 catalyzed NAD+-dependent dehydrogenation of linoleate 9,10-trans-epoxy-11E-13-alcohol to the corresponding 13-ketone, while ichthyosis mutants were inactive. We propose, therefore, that the critical requirement for lipoxygenases and SDR9C7 is in producing acylceramide containing the 9,10-epoxy-11E-13-ketone, a reactive moiety known for its nonenzymatic coupling to protein. This suggests a mechanism for coupling of ceramide to protein and provides important insights into skin barrier formation and pathogenesis.

Keywords: Dermatology; Genetic diseases; Mouse models; Skin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Catalysis
  • Ceramides / genetics
  • Ceramides / metabolism*
  • Disease Models, Animal
  • Epidermis / enzymology*
  • Genetic Diseases, Inborn / enzymology
  • Genetic Diseases, Inborn / genetics
  • Humans
  • Ichthyosis / enzymology
  • Ichthyosis / genetics
  • Mice
  • Mice, Knockout
  • Oxidoreductases / genetics
  • Oxidoreductases / metabolism*


  • Ceramides
  • Oxidoreductases