Mice with targeted disruption of the fatty acid transport protein 4 (Fatp 4, Slc27a4) gene show features of lethal restrictive dermopathy

doi:10.1083/jcb.200207080

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Published 23 June 2003. doi:10.1083/jcb.200207080

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© The Rockefeller University Press, 0021-9525/2003/6/1105 $5.00
The Journal of Cell Biology, Volume 161, Number 6, 1105-1115

Article

Mice with targeted disruption of the fatty acid transport protein 4 (Fatp 4, Slc27a4) gene show features of lethal restrictive dermopathy

Thomas Herrmann¹, Frank van der Hoeven², Hermann-Josef Gröne³, Adrian Francis Stewart⁵, Lutz Langbein⁴, Iris Kaiser¹, Gerhard Liebisch⁶, Isabella Gosch¹, Florian Buchkremer¹, Wolfgang Drobnik⁶, Gerd Schmitz⁶ and Wolfgang Stremmel¹

¹ Department of Internal Medicine IV, University of Heidelberg, 69115 Heidelberg, Germany
² Transgenic Core Facility, German Cancer Research Center, 69120 Heidelberg, Germany
³ Department of Cellular and Molecular Pathology, German Cancer Research Center, 69120 Heidelberg, Germany
⁴ Department of Cell Biology, German Cancer Research Center, 69120 Heidelberg, Germany
⁵ Biotec, Technical University of Dresden, 01307 Dresden, Germany
⁶ Institute of Clinical Chemistry, University of Regensburg, 93042 Regensburg, Germany

Address correspondence to Wolfgang Stremmel, Dept. of Internal Medicine IV, University of Heidelberg, Bergheimer Str. 58, 69115 Heidelberg, Germany. Tel.: 49-62-21-56-87-00. Fax: 49-62-21-56-41-16. E-mail: wolfgang_stremmel{at}med.uni-heidelberg.de

The fatty acid transport protein family is a group of evolutionarilyconserved proteins that are involved in the cellular uptakeand metabolism of long and very long chain fatty acids. However,little is known about their respective physiological roles.To analyze the functional significance of fatty acid transportprotein 4 (Fatp4, Slc27a4), we generated mice with a targeteddisruption of the Fatp4 gene. Fatp4-null mice displayed featuresof a neonatally lethal restrictive dermopathy. Their skin wascharacterized by hyperproliferative hyperkeratosis with a disturbedepidermal barrier, a flat dermal–epidermal junction, areduced number of pilo-sebaceous structures, and a compact dermis.The rigid skin consistency resulted in an altered body shapewith facial dysmorphia, generalized joint flexion contractures,and impaired movement including suckling and breathing deficiencies.Lipid analysis demonstrated a disturbed fatty acid compositionof epidermal ceramides, in particular a decrease in the C26:0and C26:0-OH fatty acid substitutes. These findings reveal apreviously unknown, essential function of Fatp4 in the formationof the epidermal barrier.

Key Words: ceramides; epidermis; Fatp4; fatty acid metabolism; fatty acid transport

^* Abbreviations used in this paper: CER, ceramide; ESI-MS/MS,electrospray ionization tandem mass spectrometry; Fatp, fattyacid transport protein; FC, cholesterol; PC, phosphatidylcholine;PE, phosphatidylethanolamine; PS, phosphatidylserine; SPM, sphingomyelin;TEWL, transepidermal water loss; X-gal, 5-bromo-4-chloro-3-indolyl-ß-D-galactopyranoside.

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