Severe Skin Permeability Barrier Dysfunction in Knockout Mice Deficient in a Fatty Acid ω-Hydroxylase Crucial to Acylceramide Production

Abstract

The skin permeability barrier is indispensable for maintaining water inside the body and preventing the invasion of pathogens and allergens; abnormalities lead to skin disorders such as atopic dermatitis and ichthyosis. Acylceramide is an essential lipid for skin barrier formation, and CYP4F22 is a fatty acid u-hydroxylase involved in its synthesis. Mutations in CYP4F22 cause autosomal recessive congenital ichthyosis, although the symptoms vary among mutation sites and types. Here, we generated knockout mice deficient in Cyp4f39, the mouse ortholog of human CYP4F22, to investigate the effects of completely abrogating the function of the fatty acid u-hydroxylase involved in acylceramide production on skin barrier formation. Cyp4f39 knockout mice died within 8 hours of birth. Large increases in transepidermal water loss and penetration of a dye from outside the body were observed, indicating severe skin barrier dysfunction. Histologic analyses of the epidermis revealed impairment of lipid lamella formation, accumulation of corneodesmosomes in the stratum corneum, and persistence of periderm. In addition, lipid analyses by mass spectrometry showed almost complete loss of acylceramide and its precursor u-hydroxy ceramide. In conclusion, our findings provide clues to the molecular mechanisms of skin barrier abnormalities and the pathogenesis of ichthyosis caused by Cyp4f39 and CYP4F22 by association.

Comparative profiling and comprehensive quantification of stratum corneum ceramides in humans and mice by LC/MS/MS

“…1B), which are connected to cross-linked proteins constituting the cornified envelope; a structure located beneath the surface of corneocytes (20)(21)(22). Impairment of either EO-or P-O-ceramide production causes ichthyosis (1,2,8,(21)(22)(23)(24)(25)(26).…”

“…Several KO mouse models, lacking genes responsible for the production of ceramides involved in skin barrier formation, have been produced and analyzed (8,32,33). In particular, KO mice lacking the genes responsible for EO-ceramide production [e.g., the FA elongases, Elovl1 and Elovl4 (34,35); the FA ωhydroxylase, Cyp4f39 (the mouse orthologue of human CYP4F22) (26); the ceramide synthase, Cers3 (36); and the transacylase, Pnpla1 (24)] have been used as ichthyosis mouse models to elucidate the pathogenesis of ichthyosis. In addition, the atopic dermatitis mouse model has been used for investigating the correlation between skin barrier function and ceramide composition (37,38).…”

Gene expression profiling of skeletal muscles

“…Genes involved in pathways downstream of FA biosynthesis were also present among the study’s highest expressed genes. One of the highest FC genes in this study at 269-fold higher expression in Ta was Cyp4f39 , which encodes for a FA ω-hydroxylase involved in acyl-ceramide synthesis [20] (Fig 2, Table 1). Cyp4f39 is involved in cell surface protection, cell recognition, signaling, membrane transportation, increased rigidity, hydrolyzation of very long-chain FAs, and steroid hormone synthesis [20].…”

“…One of the highest FC genes in this study at 269-fold higher expression in Ta was Cyp4f39 , which encodes for a FA ω-hydroxylase involved in acyl-ceramide synthesis [20] (Fig 2, Table 1). Cyp4f39 is involved in cell surface protection, cell recognition, signaling, membrane transportation, increased rigidity, hydrolyzation of very long-chain FAs, and steroid hormone synthesis [20]. Ceramides have been linked to insulin resistance in type II diabetes [26].…”

Molecular Mechanism of Epidermal Barrier Dysfunction as Primary Abnormalities

“…Loss-of-function mutations in CYP4F22 cause autosomal recessive congenital ichthyosis. Impaired lipid lamella formation with almost complete loss of acylceramide and its precursor ω-hydroxyceramide have been demonstrated in knockout mice [78]. Loss-of-function mutations in ALOX12B and ALOXE3, which are essential for the generation of ω-hydroxyceramide, can cause autosomal recessive congenital ichthyosis [79,80].…”