Corneocyte lipid envelope (CLE), the key structure for skin barrier function and ichthyosis pathogenesis.

Research on the genetic abnormalities and pathogenetic processes of ichthyoses has progressed remarkably, and many causative genes and molecules have been identified in ichthyoses and ichthyosis syndromes. Most of the genes/molecules causative of ichthyosis are associated with the barrier function of the stratum corneum, and defects in the skin barrier play important roles in the pathogenesis of various ichthyosis phenotypes. It has been elucidated that, of the ichthyosis-causative genes, ABCA12, ALOXE3, ALOX12B, CYP4F22, CERS3, ABHD5, PNPLA1 and ELOVL4 work in the formation of the corneocyte lipid envelope (CLE), a structure that is essential to sound skin barrier function. The CLE mostly consists of ultra-long-chain (ULC) ceramides derived from ULC-acylceramide (EOS; a combination of esterified ω-hydroxy fatty acids and sphingosines). In this review, I shed light on the synthesis, metabolism and transport of epidermal ceramides, especially on ULC-acylceramide and the processes of CLE formation. In addition, I summarize the pathogeneses of various ichthyoses and ichthyosis syndromes from the aspects of abnormal synthesis of ULC-acylceramide and malformation of the CLE. Investigations on the pathomechanisms of ichthyoses have provided novel knowledge on the synthesis and metabolism of ceramides in the epidermis. Conversely, research on the dynamics of epidermal ceramides has contributed to the elucidation of the pathogenesis of ichthyoses. Advances in our understanding of the biology of epidermal lipids and the disease pathogeneses of ichthyoses and ichthyosis syndromes promise to provide clues for the development of effective therapies for ichthyosis patients in the near future.