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

Abstract

Abstract Mutations in patatin-like phospholipase domain-containing 1 (PNPLA1) cause autosomal recessive congenital ichthyosis, but the mechanism involved remains unclear. Here we show that PNPLA1, an enzyme expressed in differentiated keratinocytes, plays a crucial role in the biosynthesis of ω- O -acylceramide, a lipid component essential for skin barrier. Global or keratinocyte-specific Pnpla1 -deficient neonates die due to epidermal permeability barrier defects with severe transepidermal water loss, decreased intercellular lipid lamellae in the stratum corneum , and aberrant keratinocyte differentiation. In Pnpla1 −/− epidermis, unique linoleate-containing lipids including acylceramides, acylglucosylceramides and ( O -acyl)-ω-hydroxy fatty acids are almost absent with reciprocal increases in their putative precursors, indicating that PNPLA1 catalyses the ω- O -esterification with linoleic acid to form acylceramides. Moreover, acylceramide supplementation partially rescues the altered differentiation of Pnpla1 −/− keratinocytes. Our findings provide valuable insight into the skin barrier formation and ichthyosis development, and may contribute to novel therapeutic strategies for treatment of epidermal barrier defects.