PNPLA1 has a crucial role in skin barrier function by directing acylceramide biosynthesis. Mus musculus

Mutations in PNPLA1 (patatin-like phospholipase domain containing 1) cause autosomal recessive congenital ichthyosis, but the mechanism involved remains unclear. Here we show that PNPLA1, an enzyme expressed in highly differentiated keratinocytes, plays a crucial role in the biosynthesis of acylceramide, a lipid component essential for skin barrier function. Pnpla1-deficient mice showed neonatal lethality due to epidermal permeability barrier defects with severe transepidermal water loss, decreased intercellular lipid lamellae in the stratum corneum, and impaired terminal differentiation of keratinocytes. In Pnpla1–/– epidermis, three unique linoleate-containing lipids, including acylceramides, acylglucosylceramides and (O-acyl)-ω-hydroxy fatty acids, were almost absent with reciprocal increases in their precursors ω-hydroxy (glucosyl)ceramides and ω-hydroxy fatty acids, indicating that PNPLA1 catalyzes the ω-O-esterification step with linoleic acid to form acylceramides. Our results suggest that PNPLA1 represents the missing piece in the process of acylceramide biosynthesis required for establishment of a permeability barrier. Overall design: We compared gene expression in Pnpla1-/- (knockout) epidermis at P0 with Pnpla1+/+ (wild type) controls. Individual array samples were generated by pooling equal amounts of total RNA derived from skins of 6 animals.