PNPLA1 Deficiency in Mice and Humans Leads to a Defect in the Synthesis of Omega-O-Acylceramides

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• 作者：Susanne Grond¹ ; Thomas O. Eichmann¹ ; Sandrine Dubrac² ; Dagmar Kolb³ ; ⁴ ; ⁵ ; Matthias Schmuth² ; Judith Fischer⁶ ; Debra Crumrine⁷ ; Peter M. Elias⁷ ; Guenter Haemmerle¹ ; Rudolf Zechner¹ ; Achim Lass¹ ; Franz P.W. Radner¹ ; ^{franz.radner@uni-graz.at}
• 关键词：ABHD5 ; α/β hydrolase domain containing 5 ; ω-O-AcylCers ; ω-O-acylceramides ; ARCI ; autosomal recessive congenital ichthyosis ; CLE ; corneocyte-bound lipid envelope ; FA ; fatty acid ; ω-OH-(Glc)Cers ; ω-hydroxy-(glucosyl)ceramides ; PNPLA1 ; patatin-like phospholipase domain-containing 1 ; qRT-PCR ; quantitative real-time reverse transcriptase-PCR
• 刊名：Journal of Investigative Dermatology
• 出版年：2017
• 出版时间：February 2017
• 年：2017
• 卷：137
• 期：2
• 页码：394-402
• 全文大小：1954 K
• 卷排序：137

文摘

Mutations in PNPLA1 have been identified as causative for autosomal recessive congenital ichthyosis in humans and dogs. So far, the underlying molecular mechanisms are unknown. In this study, we generated and characterized PNPLA1-deficient mice and found that PNPLA1 is crucial for epidermal sphingolipid synthesis. The absence of functional PNPLA1 in mice impaired the formation of omega-O-acylceramides and led to an accumulation of nonesterified omega-hydroxy-ceramides. As a consequence, PNPLA1-deficient mice lacked a functional corneocyte-bound lipid envelope leading to a severe skin barrier defect and premature death of newborn animals. Functional analyses of differentiated keratinocytes from a patient with mutated PNPLA1 demonstrated an identical defect in omega-O-acylceramide synthesis in human cells, indicating that PNPLA1 function is conserved among mammals and indispensable for normal skin physiology. Notably, topical application of epidermal lipids from wild-type onto Pnpla1-mutant mice promoted rebuilding of the corneocyte-bound lipid envelope, indicating that supplementation of ichthyotic skin with omega-O-acylceramides might be a therapeutic approach for the treatment of skin symptoms in individuals affected by omega-O-acylceramide deficiency.