Skin Barrier Development Depends on CGI-58 Protein Expression during Late-Stage Keratinocyte Differentiation

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• 作者：Susanne Grond¹ ; ⁸ ; Franz P.W. Radner¹ ; ⁸ ; Thomas O. Eichmann¹ ; Dagmar Kolb² ; Gernot F. Grabner¹ ; Heimo Wolinski¹ ; ³ ; Robert Gruber⁴ ; Peter Hofer¹ ; Christoph Heier¹ ; Silvia Schauer⁵ ; ⁶ ; Thomas Rü ; licke⁵ ; Gerald Hoefler³ ; ⁵ ; ⁶ ; Matthias Schmuth⁴ ; Peter M. Elias⁷ ; Achim Lass¹ ; Rudolf Zechner¹ ; Guenter Haemmerle¹ ; ^{guenter.haemmerle@uni-graz.at}
• 关键词：ATGL ; adipose triglyceride lipase ; CE ; cornified envelope ; CGI-58 ; comparative gene identification-58 ; CLE ; corneocyte lipid envelope ; En ; embryonic day n ; FA ; fatty acid ; FLG ; filaggrin ; IVL ; involucrin ; Kn ; keratin n ; NLSDI ; neutral lipid storage disease with ichthyosis ; ω-O-AcylCer ; ω-O-acylceramide ; ω-OH-Cers ; ω-hydroxy-ceramides ; SC ; stratum corneum ; TEM ; transmission electron microscopy ; TEWL ; transepidermal water loss ; TG ; triglyceride ; WT ; wild type
• 刊名：Journal of Investigative Dermatology
• 出版年：2017
• 出版时间：February 2017
• 年：2017
• 卷：137
• 期：2
• 页码：403-413
• 全文大小：3731 K
• 卷排序：137

文摘

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.