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J. Biol. Chem., Vol. 282, Issue 5, 3083-3094, February 2, 2007

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Integrity and Barrier Function of the Epidermis Critically Depend on Glucosylceramide Synthesis^*

Richard Jennemann¹², Roger Sandhoff¹, Lutz Langbein, Sylvia Kaden, Ulrike Rothermel, Hichem Gallala^¶, Konrad Sandhoff^¶, Herbert Wiegandt, and Hermann-Josef Gröne³

From the Department of Cellular und Molecular Pathology and Department of Cell Biology, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany and ^¶LIMES, Membrane Biology and Lipid Biochemistry Unit, c/o Kekulé Institute for Organic Chemistry and Biochemistry, University of Bonn, Gerhard-Domagk-Strasse 1, 53121 Bonn, Germany

Ceramides are vital components of the water barrier in mammalian skin. Epidermis-specific, a major ceramide portion contains -hydroxy very long chain fatty acids (C30–C36). These -hydroxy ceramides (Cers) are found in the extracellular lamellae of the stratum corneum either as linoleic acyl esters or protein bound. Glucosylceramide is the major glycosphingolipid of the epidermis. Synthesized from ceramide and UDP-glucose, it is thought to be itself an intracellular precursor and carrier for extracellular -hydroxy ceramides. To investigate whether GlcCer is an obligatory intermediate in ceramide metabolism to maintain epidermal barrier function, a mouse with an epidermis-specific glucosylceramide synthase (Ugcg) deficiency has been generated. Four days after birth animals devoid of GlcCer synthesis in keratinocytes showed a pronounced desquamation of the stratum corneum and extreme transepidermal water loss leading to death. The stratum corneum appeared as a thick unstructured mass. Lamellar bodies of the stratum granulosum did not display the usual ordered inner structure and were often irregularly arranged. Although the total amount of epidermal protein-bound ceramides remained unchanged, epidermal-free -hydroxy ceramides increased 4-fold and -hydroxy sphingomyelins, almost not detectable in wild type epidermis, emerged in quantities comparable with lost GlcCer. We conclude that the transient formation of GlcCer is vital for a regular arrangement of lipids and proteins in lamellar bodies and for the maintenance of the epidermal barrier.

Received for publication, November 3, 2006 , and in revised form, December 4, 2006.

^* This work was supported by Deutsche Forschungsgemeinschaft Grants SFB 405, B10, and Graduiertenkolleg 886 (to H.-J. G.) SFB 645 (to K. S.), and TZ-FSP I./3 (to L. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These authors contributed equally to this work.

² To whom correspondence may be addressed. Tel.: 49-6221-424356; Fax: 49-6221-424352; E-mail: r.jennemann{at}dkfz.de. ³ To whom correspondence may be addressed. Tel.: 49-6221-424350; Fax: 49-6221-424352; E-mail: h.-j.groene{at}dkfz.de.

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