title: PNPLA1 is a transacylase essential for the generation of the skin barrier lipid ω-O-acylceramide.
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.
authors.affiliation: Laboratory of Biochemistry, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12-jo, Nishi 6-chome, Kita-ku, Sapporo 060-0812, Japan.
authors.forename: Yusuke
authors.identifier: 0000-0003-3702-1043
authors.initials: Y
authors.lastname: Ohno
authors.affiliation: Laboratory of Biochemistry, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12-jo, Nishi 6-chome, Kita-ku, Sapporo 060-0812, Japan.
authors.forename: Nozomi
authors.initials: N
authors.lastname: Kamiyama
authors.affiliation: Laboratory of Biochemistry, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12-jo, Nishi 6-chome, Kita-ku, Sapporo 060-0812, Japan.
authors.forename: Shota
authors.initials: S
authors.lastname: Nakamichi
authors.affiliation: Laboratory of Biochemistry, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12-jo, Nishi 6-chome, Kita-ku, Sapporo 060-0812, Japan.
authors.forename: Akio
authors.identifier: 0000-0001-5889-0788
authors.initials: A
authors.lastname: Kihara
mesh_terms: D000215:Acylation; D055162:Biocatalysis; D002518:Ceramides / Q000096:biosynthesis*; D051048:Diacylglycerol O-Acyltransferase / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D019787:Linoleic Acid / Q000378:metabolism; D008049:Lipase / Q000378:metabolism*; D016111:Sjogren-Larsson Syndrome / Q000378:metabolism / Q000473:pathology; D012867:Skin / Q000378:metabolism*; D013379:Substrate Specificity; D014280:Triglycerides / Q000378:metabolism; D000217:Acyltransferases; D010740:Phospholipases
chemical_list: D002518:Ceramides; D051048:Diacylglycerol O-Acyltransferase; D019787:Linoleic Acid; D008049:Lipase; D014280:Triglycerides; C549684:PNPLA1 protein, human; D000217:Acyltransferases; D010740:Phospholipases