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J. Biol. Chem., Vol. 282, Issue 18, 13211-13219, May 4, 2007

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Fatty Acid 2-Hydroxylase, Encoded by FA2H, Accounts for Differentiation-associated Increase in 2-OH Ceramides during Keratinocyte Differentiation^*

Yoshikazu Uchida¹, Hiroko Hama, Nathan L. Alderson, Sounthala Douangpanya, Yu Wang, Debra A. Crumrine, Peter M. Elias, and Walter M. Holleran^¶

From the Department of Dermatology, School of Medicine, University of California, San Francisco, and Veterans Affairs Medical Center, San Francisco, and the ^¶Department of Pharmaceutical Chemistry, School of Pharmacy, University of California, San Francisco, California 94121, and the Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina 29425

Ceramides in mammalian stratum corneum comprise a heterogeneous mixture of molecular species that subserve the epidermal permeability barrier, an essential function for survival in a terrestrial environment. In addition to a variation of sphingol species, hydroxylation of the amide-linked fatty acids contributes to the diversity of epidermal ceramides. Fatty acid 2-hydroxylase, encoded by the gene FA2H, the mammalian homologue of FAH1 in yeast, catalyzes the synthesis of 2-hydroxy fatty acid-containing sphingolipids. We assessed here whether FA2H accounts for 2-hydroxyceramide/2-hydroxyglucosylceramide synthesis in epidermis. Reverse transcription-PCR and Western immunoblots demonstrated that FA2H is expressed in cultured human keratinocytes and human epidermis, with FA2H expression and fatty acid 2-hydroxylase activity increased with differentiation. FA2H-siRNA suppressed 2-hydroxylase activity and decreased 2-hydroxyceramide/2-hydroxyglucosylceramide levels, demonstrating that FA2H accounts for synthesis of these sphingolipids in keratinocytes. Whereas FA2H expression and 2-hydroxy free fatty acid production increased early in keratinocyte differentiation, production of 2-hydroxyceramides/2-hydroxyglucosylceramides with longer chain amide-linked fatty acids (C24) increased later. Keratinocytes transduced with FA2H-siRNA contained abnormal epidermal lamellar bodies and did not form the normal extracellular lamellar membranes required for the epidermal permeability barrier. These results reveal that 1) differentiation-dependent up-regulation of ceramide synthesis and fatty acid elongation is accompanied by up-regulation of FA2H; 2) 2-hydroxylation of fatty acid by FA2H occurs prior to generation of ceramides/glucosylceramides; and 3) 2-hydroxyceramides/2-hydroxyglucosylceramides are required for epidermal lamellar membrane formation. Thus, late differentiation-linked increases in FA2H expression are essential for epidermal permeability barrier homeostasis.

Received for publication, December 18, 2006 , and in revised form, March 2, 2007.

^* This work was supported by National Institutes of Health Grants AR19098, AR39448, AR050629, and RR17677 and by the Medical Research Service of the Department of Veterans Affairs. 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 To whom correspondence should be addressed: Dermatology Service and Research Unit (190), Veterans Affairs Medical Center, 4150 Clement St., San Francisco, CA 94121. Tel.: 415-750-2091; Fax: 415-751-3927; E-mail: uchiday{at}derm.ucsf.edu.

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