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Originally published In Press as doi:10.1194/jlr.M700400-JLR200 on September 27, 2007

Papers In Press, published online ahead of print January 1, 2008
J. Lipid Res., doi:10.1194/jlr.M700400-JLR200
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Journal of Lipid Research, Vol. 49, 153-161, January 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

FA2H is responsible for the formation of 2-hydroxy galactolipids in peripheral nervous system myelinboxs

Eduardo N. Maldonado1,*, Nathan L. Alderson1,*, Paula V. Monje{dagger}, Patrick M. Wood{dagger} and Hiroko Hama2,*

* Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC
{dagger} Department of Neurological Surgery, Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL

boxs The online version of this article (available at http://www.jlr.org) contains supplementary data in the form of one figure.

Published, JLR Papers in Press, September 27, 2007.

1 E. N. Maldonado and N. L. Alderson contributed equally to this work.

2 To whom correspondence should be addressed. e-mail: hama{at}musc.edu

Myelin in the mammalian nervous system has a high concentration of galactolipids [galactosylceramide (GalCer) and sulfatide] with 2-hydroxy fatty acids. We recently reported that fatty acid 2-hydroxylase (FA2H), encoded by the FA2H gene, is the major fatty acid 2-hydroxylase in the mouse brain. In this report, we show that FA2H also plays a major role in the formation of 2-hydroxy galactolipids in the peripheral nervous system. FA2H mRNA and FA2H activity in the neonatal rat sciatic nerve increased rapidly during developmental myelination. The contents of 2-hydroxy fatty acids were ~5% of total galactolipid fatty acids at 4 days of age and increased to 60% in GalCer and to 35% in sulfatides at 60 days of age. The chain length of galactolipid fatty acids also increased significantly during myelination. FA2H expression in cultured rat Schwann cells was highly increased in response to dibutyryl cyclic AMP, which stimulates Schwann cell differentiation and upregulates myelin genes, such as UDP-galactose:ceramide galactosyltransferase and protein zero. These observations indicate that FA2H is a myelination-associated gene. FA2H-directed RNA interference (RNAi) by short-hairpin RNA expression resulted in a reduction of cellular 2-hydroxy fatty acids and 2-hydroxy GalCer in D6P2T Schwannoma cells, providing direct evidence that FA2H-dependent fatty acid 2-hydroxylation is required for the formation of 2-hydroxy galactolipids in peripheral nerve myelin. Interestingly, FA2H-directed RNAi enhanced the migration of D6P2T cells, suggesting that, in addition to their structural role in myelin, 2-hydroxy lipids may greatly influence the migratory properties of Schwann cells.

Supplementary key words fatty acid 2-hydroxylase • fatty acid {alpha}-hydroxylase • hydroxy fatty acids • galactosylceramide • sulfatide

Abbreviations: CGT, UDP-galactose:ceramide galactosyltransferase; CNS, central nervous system; GalCer, galactosylceramide; GlcCer, glucosylceramide; PNS, peripheral nervous system; P0, Protein Zero; Px, postnatal day x; RNAi, RNA interference; shRNA, short-hairpin RNA; siRNA, small interfering RNA


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