Lipids are the primary components of the skin permeability barrier, which is the body’s most
powerful defensive mechanism against pathogens. Acylceramide (o-O-acylceramide) is a
specialized lipid essential for skin barrier formation. Here, we identify PNPLA1 as the
long-sought gene involved in the final step of acylceramide synthesis, esterification of
o-hydroxyceramide with linoleic acid, by cell-based assays. We show that increasing
triglyceride levels by overproduction of the diacylglycerol acyltransferase DGAT2 stimulates
acylceramide production, suggesting that triglyceride may act as a linoleic acid donor. Indeed,
the in vitro analyses confirm that PNPLA1 catalyses acylceramide synthesis using triglyceride
as a substrate. Mutant forms of PNPLA1 found in patients with ichthyosis exhibit reduced or
no enzyme activity in either cell-based or in vitro assays. Altogether, our results indicate that
PNPLA1 is directly involved in acylceramide synthesis as a transacylase, and provide
important insights into the molecular mechanisms of skin barrier formation and of ichthyosis
pathogenesis.
DOI: 10.1038/ncomms14610 OPEN
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