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

Tetsuya Hirabayashi,Alan R Brash,Yuuya Senoo,Kazutaka Ikeda,Arisa Kaneko,Kazuaki Muramatsu,Kohei Yokoyama,Kiyoko Fukami,Akitaka Shibata,Agustí Muñoz-Garcia,Tomio Ono,Choji Taya,Masashi Akiyama,Hiroyuki Takama,Makoto Murakami,Yasumasa Nishito,Makoto Arita,Tatsuki Anjo

doi:10.1038/ncomms14609

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.

Highlights

Mutations in patatin-like phospholipase domain-containing 1 (PNPLA1) cause autosomal recessive congenital ichthyosis, but the mechanism involved remains unclear
A marked increase of PNPLA1 expression was observed in human keratinocytes after Ca2 þ -induced differentiation, an event that occurred in parallel with induced expression of the keratinocyte differentiation markers KRT1 and FLG, but not with constitutive expression of the stratum basale (SB) marker KRT5 (Supplementary Fig. 1e)
These results suggest that PNPLA1 has a specific role in highly differentiated keratinocytes in the uppermost layer of the stratum granulosum (SG), where lipids required for epidermal barrier function are processed and secreted into the intercellular space to form lipid lamellae and cornified lipid envelope (CLE)

Summary

Introduction

Mutations in patatin-like phospholipase domain-containing 1 (PNPLA1) cause autosomal recessive congenital ichthyosis, but the mechanism involved remains unclear. We show that PNPLA1, an enzyme expressed in differentiated keratinocytes, plays a crucial role in the biosynthesis of o-O-acylceramide, a lipid component essential for skin barrier. Several important steps for acyceramide biosynthesis and processing in the epidermis have been identified from studies of autosomal recessive congenital ichthyosis (ARCI) in humans and corresponding mouse disease models with genetic knockouts: the synthesis of ULCFAs by the FA elongase ELOVL4, o-hydroxylation of ULCFAs by the FA o-hydroxylase CYP4F22 (or CYP4F39 in mice), and formation of ceramides with ULCFAs by the ceramide synthase CERS3 (refs 18–20). Ichthyosis features and decreased acylceramide levels in the skin have been observed in patients and mice with defective ABHD5 function, but not in those with ATGL mutations or deletion, leading to the proposal that ABHD5 could activate a different lipase that regulates epidermal TG hydrolysis[21,25]. The molecular entity of o-O-acyltransferase or transacylase responsible for the linoleoyl o-O-esterification of ULCFAceramides has not yet been identified

Methods

Results

Conclusion