The human genome encodes nine
enzymes belonging to the patatin-like
phospholipase domain-containing
lipase (PNPLA)/Ca2+-independent
phospholipase A2 (iPLA2) family. Although most PNPLA/iPLA2
enzymes are widely distributed and act on
phospholipids or neutral
lipids as (phospho)lipases to play homeostatic roles in lipid metabolism, the function of PNPLA1 remained a mystery until a few years ago. However, the recent finding that mutations in the human PNPLA1 gene are linked to autosomal recessive congenital
ichthyosis (ARCI), as well as evidence obtained from biochemical and gene knockout studies, has shed light on the function of this
enzyme in skin-specific
sphingolipid metabolism rather than
glycerophospholipid metabolism. PNPLA1 is specifically expressed in differentiated keratinocytes and plays a crucial role in the biosynthesis of ω-O-acylceramide, a particular class of
sphingolipids that is essential for skin barrier function. PNPLA1 acts as a unique transacylase that specifically transfers
linoleic acid from
triglyceride to ω-hydroxy
fatty acid in
ceramide, thus giving rise to ω-O-acylceramide. In this review, we overview the biosynthetic route and
biological role of epidermal ω-O-acylceramide, highlight the function of PNPLA1 as a bona fide acylceramide synthase required for proper skin barrier function and keratinocyte differentiation, and summarize the mutations of PNPLA1 currently identified in ARCI patients. This article is part of a Special Issue entitled Novel functions of
phospholipase A2 Guest Editors: Makoto Murakami and Gerard Lambeau.