title: PNPLA1 has a crucial role in skin barrier function by directing acylceramide biosynthesis.
abstract: Mutations in patatin-like phospholipase domain-containing 1 (PNPLA1) cause autosomal recessive congenital ichthyosis, but the mechanism involved remains unclear. Here we show that PNPLA1, an enzyme expressed in differentiated keratinocytes, plays a crucial role in the biosynthesis of ω-O-acylceramide, a lipid component essential for skin barrier. Global or keratinocyte-specific Pnpla1-deficient neonates die due to epidermal permeability barrier defects with severe transepidermal water loss, decreased intercellular lipid lamellae in the stratum corneum, and aberrant keratinocyte differentiation. In Pnpla1-/-epidermis, unique linoleate-containing lipids including acylceramides, acylglucosylceramides and (O-acyl)-ω-hydroxy fatty acids are almost absent with reciprocal increases in their putative precursors, indicating that PNPLA1 catalyses the ω-O-esterification with linoleic acid to form acylceramides. Moreover, acylceramide supplementation partially rescues the altered differentiation of Pnpla1-/-keratinocytes. Our findings provide valuable insight into the skin barrier formation and ichthyosis development, and may contribute to novel therapeutic strategies for treatment of epidermal barrier defects.
authors.affiliation: Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.|AMED-CREST, Japan Agency for Medical Research and Development, Tokyo 100-0004, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Hirabayashi
authors.affiliation: Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.|Division of Life Science and Engineering, School of Science and Engineering, Tokyo Denki University, Saitama 350-0394, Japan.
authors.forename: Tatsuki
authors.initials: T
authors.lastname: Anjo
authors.affiliation: Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.|Laboratory of Genome and Biosignals, Tokyo University of Pharmacy and Life Sciences, Tokyo 192-0392, Japan.
authors.forename: Arisa
authors.initials: A
authors.lastname: Kaneko
authors.affiliation: Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences, Kanagawa 230-0045, Japan.
authors.forename: Yuuya
authors.initials: Y
authors.lastname: Senoo
authors.affiliation: Department of Dermatology, Nagoya University Graduate School of Medicine, Aichi 466-8550, Japan.
authors.forename: Akitaka
authors.initials: A
authors.lastname: Shibata
authors.affiliation: Department of Dermatology, Nagoya University Graduate School of Medicine, Aichi 466-8550, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Takama
authors.affiliation: Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Yokoyama
authors.affiliation: Center for Basic Technology Research, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Nishito
authors.affiliation: Center for Basic Technology Research, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
authors.forename: Tomio
authors.initials: T
authors.lastname: Ono
authors.affiliation: Center for Basic Technology Research, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
authors.forename: Choji
authors.initials: C
authors.lastname: Taya
authors.affiliation: Division of Life Science and Engineering, School of Science and Engineering, Tokyo Denki University, Saitama 350-0394, Japan.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Muramatsu
authors.affiliation: Laboratory of Genome and Biosignals, Tokyo University of Pharmacy and Life Sciences, Tokyo 192-0392, Japan.
authors.forename: Kiyoko
authors.initials: K
authors.lastname: Fukami
authors.affiliation: Department of Evolution, Ecology, and Organismal Biology, Ohio State University, Ohio 43210, USA.
authors.forename: Agustí
authors.initials: A
authors.lastname: Muñoz-Garcia
authors.affiliation: Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37232-6304, USA.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Brash
authors.affiliation: Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences, Kanagawa 230-0045, Japan.
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Ikeda
authors.affiliation: Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences, Kanagawa 230-0045, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Arita
authors.affiliation: Department of Dermatology, Nagoya University Graduate School of Medicine, Aichi 466-8550, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Akiyama
authors.affiliation: Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.|AMED-CREST, Japan Agency for Medical Research and Development, Tokyo 100-0004, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Murakami
mesh_terms: D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase / Q000172:deficiency / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation; D002518:Ceramides / Q000096:biosynthesis*; D004817:Epidermis / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology; D008049:Lipase / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D010641:Phenotype; D012867:Skin / Q000378:metabolism* / Q000648:ultrastructure; D000217:Acyltransferases; D010740:Phospholipases
chemical_list: D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase; D002518:Ceramides; D008049:Lipase; C492986:Abhd5 protein, mouse; C549684:PNPLA1 protein, human; D000217:Acyltransferases; D010740:Phospholipases; C000613695:PNPLA1 protein, mouse