PNPLA1 is a transacylase essential for the generation of the skin barrier lipid ω-O-acylceramide

Yusuke Ohno, Nozomi Kamiyama, Shota Nakamichi and Akio Kihara ()
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Yusuke Ohno: Laboratory of Biochemistry, Faculty of Pharmaceutical Sciences, Hokkaido University
Nozomi Kamiyama: Laboratory of Biochemistry, Faculty of Pharmaceutical Sciences, Hokkaido University
Shota Nakamichi: Laboratory of Biochemistry, Faculty of Pharmaceutical Sciences, Hokkaido University
Akio Kihara: Laboratory of Biochemistry, Faculty of Pharmaceutical Sciences, Hokkaido University

Nature Communications, 2017, vol. 8, issue 1, 1-8

Abstract: Abstract 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.

Date: 2017
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DOI: 10.1038/ncomms14610

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