title: Skin Barrier Development Depends on CGI-58 Protein Expression during Late-Stage Keratinocyte Differentiation.
abstract: Adipose triglyceride lipase (ATGL) and its coactivator comparative gene identification-58 (CGI-58) are limiting in cellular triglyceride catabolism. Although ATGL deficiency is compatible with normal skin development, mice globally lacking CGI-58 die postnatally and exhibit a severe epidermal permeability barrier defect, which may originate from epidermal and/or peripheral changes in lipid and energy metabolism. Here, we show that epidermis-specific disruption of CGI-58 is sufficient to provoke a defect in the formation of a functional corneocyte lipid envelope linked to impaired ω-O-acylceramide synthesis. As a result, epidermis-specific CGI-58-deficient mice show severe skin dysfunction, arguing for a tissue autonomous cause of disease development. Defective skin permeability barrier formation in global CGI-58-deficient mice could be reversed via transgenic restoration of CGI-58 expression in differentiated but not basal keratinocytes suggesting that CGI-58 is essential for lipid metabolism in suprabasal epidermal layers. The compatibility of ATGL deficiency with normal epidermal function indicated that CGI-58 may stimulate an epidermal triglyceride lipase beyond ATGL required for the adequate provision of fatty acids as a substrate for ω-O-acylceramide synthesis. Pharmacological inhibition of ATGL enzyme activity similarly reduced triglyceride-hydrolytic activities in wild-type and CGI-58 overexpressing epidermis implicating that CGI-58 participates in ω-O-acylceramide biogenesis independent of its role as a coactivator of epidermal triglyceride catabolism.
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Graz, Austria.
authors.forename: Susanne
authors.initials: S
authors.lastname: Grond
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Graz, Austria.
authors.forename: Franz P W
authors.initials: FPW
authors.lastname: Radner
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Graz, Austria.
authors.forename: Thomas O
authors.initials: TO
authors.lastname: Eichmann
authors.affiliation: Center for Medical Research/Institute of Cell Biology, Histology and Embryology, Medical University of Graz, Graz, Austria.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Kolb
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Graz, Austria.
authors.forename: Gernot F
authors.initials: GF
authors.lastname: Grabner
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Graz, Austria; BioTechMed-Graz, Microscopy Facility, University of Graz, Graz, Austria.
authors.forename: Heimo
authors.initials: H
authors.lastname: Wolinski
authors.affiliation: Department of Dermatology, Venereology and Allergology, University of Innsbruck, Innsbruck, Austria.
authors.forename: Robert
authors.initials: R
authors.lastname: Gruber
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Graz, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Hofer
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Graz, Austria.
authors.forename: Christoph
authors.initials: C
authors.lastname: Heier
authors.affiliation: Institute of Pathology, Medical University of Graz, Graz, Austria; Institute of Laboratory Animal Science, University of Veterinary Medicine Vienna, Vienna, Austria.
authors.forename: Silvia
authors.initials: S
authors.lastname: Schauer
authors.affiliation: Institute of Pathology, Medical University of Graz, Graz, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rülicke
authors.affiliation: BioTechMed-Graz, Microscopy Facility, University of Graz, Graz, Austria; Institute of Pathology, Medical University of Graz, Graz, Austria; Institute of Laboratory Animal Science, University of Veterinary Medicine Vienna, Vienna, Austria.
authors.forename: Gerald
authors.initials: G
authors.lastname: Hoefler
authors.affiliation: Department of Dermatology, Venereology and Allergology, University of Innsbruck, Innsbruck, Austria.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schmuth
authors.affiliation: Department of Dermatology, University of California San Francisco, San Francisco, California, USA.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Elias
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Graz, Austria.
authors.forename: Achim
authors.initials: A
authors.lastname: Lass
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Graz, Austria.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Zechner
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Graz, Austria. Electronic address: guenter.haemmerle@uni-graz.at.
authors.forename: Guenter
authors.initials: G
authors.lastname: Haemmerle
mesh_terms: D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase / Q000502:physiology*; D000818:Animals; D002454:Cell Differentiation; D002518:Ceramides / Q000096:biosynthesis; D015603:Keratinocytes / Q000166:cytology*; D008049:Lipase / Q000502:physiology; D051379:Mice; D012867:Skin / Q000196:embryology / Q000378:metabolism*; D014280:Triglycerides / Q000378:metabolism
chemical_list: D002518:Ceramides; D014280:Triglycerides; D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase; C492986:Abhd5 protein, mouse; D008049:Lipase