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Reference: Uchida Y, et al. (2007) Fatty acid 2-hydroxylase, encoded by FA2H, accounts for differentiation-associated increase in 2-OH ceramides during keratinocyte differentiation. J Biol Chem 282(18):13211-9

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Abstract

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 at the alpha(2)- and omega-positions of the amide-linked fatty acids contribute 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-hydroxyglucosyl-ceramide synthesis in epidermis. RT-PCR and Western immunoblots demonstrated FA2H is expressed in cultured human keratinocytes and human epidermis. FA2H expression, and fatty acid 2-hydroxylase activity, increased with differentiation. FA2H-siRNA significantly suppressed 2-hydroxylase activity and decreased 2-hydroxyceramide/2-hydroxyglucosyl-ceramide levels, demonstrating that FA2H accounts for synthesis of these sphingolipids in keratinocytes. Whereas FA2H expression and 2-hydroxy free fatty acid production began to increase early in keratinocyte differentiation, production of 2-hydroxyceramides/2-hydroxyglucosylceramides with longer chain amide-linked fatty acids (>C24) increased later in differentiation. Keratinocytes transduced with FA2H-siRNA contained the abnormal epidermal lamellar bodies and did not form the normal extracellular lamellar membranes required for epidermal permeability barrier formation. These results reveal that 1) differentiation-dependent upregulation of ceramide synthesis and fatty acid elongation is accompanied by upregulation of FA2H, leading to the formation of unique 2-hydroxyceramides/2-hydroxyglucosyl-ceramides; 2) 2-hydroxylation of fatty acid by FA2H occurs prior to generation of ceramides/glucosylceramides; and 3) 2-hydroxyceramides/2-hydrooxyglucosylceramides are required for epidermal lamellar membrane formation. Thus, late-differentiation-linked increases in FA2H expression are essential for epidermal permeability barrier homeostasis.

Reference Type
Journal Article
Authors
Uchida Y, Hama H, Alderson NL, Douangpanya S, Wang Y, Crumrine DA, Elias PM, Holleran WM
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