ω-O-Acylceramides but not ω-hydroxy ceramides are required for healthy lamellar phase architecture of skin barrier lipids.

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  • Additional Information
    • Source:
      Publisher: Elsevier Country of Publication: United States NLM ID: 0376606 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1539-7262 (Electronic) Linking ISSN: 00222275 NLM ISO Abbreviation: J Lipid Res Subsets: MEDLINE
    • Publication Information:
      Publication: 2021- : [New York] : Elsevier
      Original Publication: Memphis, Lipid Research, inc.
    • Subject Terms:
      Ceramides*/chemistry ; Skin*; Acyltransferases ; Animals ; Epidermis ; Ichthyosis ; Linoleic Acid ; Lipase ; Mice
    • Abstract:
      Epidermal omega-O-acylceramides (ω-O-acylCers) are essential components of a competent skin barrier. These unusual sphingolipids with ultralong N-acyl chains contain linoleic acid esterified to the terminal hydroxyl of the N-acyl, the formation of which requires the transacylase activity of patatin-like phospholipase domain containing 1 (PNPLA1). In ichthyosis with dysfunctional PNPLA1, ω-O-acylCer levels are significantly decreased, and ω-hydroxylated Cers (ω-OHCers) accumulate. Here, we explore the role of the linoleate moiety in ω-O-acylCers in the assembly of the skin lipid barrier. Ultrastructural studies of skin samples from neonatal Pnpla1 +/+ and Pnpla1 -/- mice showed that the linoleate moiety in ω-O-acylCers is essential for lamellar pairing in lamellar bodies, as well as for stratum corneum lipid assembly into the long periodicity lamellar phase. To further study the molecular details of ω-O-acylCer deficiency on skin barrier lipid assembly, we built in vitro lipid models composed of major stratum corneum lipid subclasses containing either ω-O-acylCer (healthy skin model), ω-OHCer (Pnpla1 -/- model), or combination of the two. X-ray diffraction, infrared spectroscopy, and permeability studies indicated that ω-OHCers could not substitute for ω-O-acylCers, although in favorable conditions, they form a medium lamellar phase with a 10.8 nm-repeat distance and permeability barrier properties similar to long periodicity lamellar phase. In the absence of ω-O-acylCers, skin lipids were prone to separation into two phases with diminished barrier properties. The models combining ω-OHCers with ω-O-acylCers indicated that accumulation of ω-OHCers does not prevent ω-O-acylCer-driven lamellar stacking. These data suggest that ω-O-acylCer supplementation may be a viable therapeutic option in patients with PNPLA1 deficiency.
      Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article.
      (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
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    • Contributed Indexing:
      Keywords: PNPLA1 deficiency; Skin; acylceramides; barrier function; ceramides; linoleic acid; lipids; model membranes; sphingolipids; stratum corneum
    • Accession Number:
      0 (Ceramides)
      9KJL21T0QJ (Linoleic Acid)
      EC 2.3.- (Acyltransferases)
      EC 3.1.1.3 (Lipase)
      EC 3.1.1.3 (PNPLA1 protein, mouse)
    • Publication Date:
      Date Created: 20220514 Date Completed: 20220628 Latest Revision: 20220724
    • Publication Date:
      20221213
    • Accession Number:
      PMC9192818
    • Accession Number:
      10.1016/j.jlr.2022.100226
    • Accession Number:
      35568253