PNPLA1 Is a Transacylase Essential for the Generation of the Skin Barrier Lipid ω-O-acylceramide

Nat Commun. 2017 Mar 1;8:14610. doi: 10.1038/ncomms14610.


Lipids are the primary components of the skin permeability barrier, which is the body's most powerful defensive mechanism against pathogens. Acylceramide (ω-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 ω-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acylation
  • Biocatalysis
  • Ceramides / biosynthesis*
  • Diacylglycerol O-Acyltransferase / metabolism
  • HEK293 Cells
  • Humans
  • Linoleic Acid / metabolism
  • Lipase / metabolism*
  • Sjogren-Larsson Syndrome / metabolism
  • Sjogren-Larsson Syndrome / pathology
  • Skin / metabolism*
  • Substrate Specificity
  • Triglycerides / metabolism


  • Ceramides
  • Triglycerides
  • Linoleic Acid
  • Diacylglycerol O-Acyltransferase
  • Lipase
  • PNPLA1 protein, human