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Journal of Lipid Research, Vol. 47, 2772-2780, December 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

FA2H-dependent fatty acid 2-hydroxylation in postnatal mouse brain

Nathan L. Alderson^*, Eduardo N. Maldonado^*, Michael J. Kern, Narayan R. Bhat and Hiroko Hama^1,*

^* Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425
Department of Cell Biology and Anatomy, Medical University of South Carolina, Charleston, SC 29425
Department of Neuroscience, Medical University of South Carolina, Charleston, SC 29425

Published, JLR Papers in Press, September 23, 2006.

¹ To whom correspondence should be addressed. e-mail: hama{at}musc.edu

2-Hydroxy fatty acids are relatively minor species of membrane lipids found almost exclusively as N-acyl chains of sphingolipids. In mammals, 2-hydroxy sphingolipids are uniquely abundant in myelin galactosylceramide and sulfatide. Despite the well-documented abundance of 2-hydroxy galactolipids in the nervous system, the enzymatic process of the 2-hydroxylation is not fully understood. To fill this gap, we have identified a human fatty acid 2-hydroxylase gene (FA2H) that is highly expressed in brain. In this report, we test the hypothesis that FA2H is the major fatty acid 2-hydroxylase in mouse brain and that free 2-hydroxy fatty acids are formed as precursors of myelin 2-hydroxy galactolipids. The fatty acid compositions of galactolipids in neonatal mouse brain gradually changed during the course of myelination. The relative ratio of 2-hydroxy versus nonhydroxy galactolipids was very low at 2 days of age (8% of total galactolipids) and increased 6- to 8-fold by 30 days of age. During this period, free 2-hydroxy fatty acid levels in mouse brain increased 5- to 9-fold, and their composition was reflected in the fatty acids in galactolipids, consistent with a precursor-product relationship. The changes in free 2-hydroxy fatty acid levels coincided with fatty acid 2-hydroxylase activity and with the upregulation of FA2H expression. Furthermore, mouse brain fatty acid 2-hydroxylase activity was inhibited by anti-FA2H antibodies. Together, these data provide evidence that FA2H is the major fatty acid 2-hydroxylase in brain and that 2-hydroxylation of free fatty acids is the first step in the synthesis of 2-hydroxy galactolipids.

Supplementary key words fatty acid 2-hydroxylase • fatty acid -hydroxylase • hydroxy fatty acids • myelin • galactolipids • galactosylceramide • sulfatide

Abbreviations: CGT, UDP-galactose:ceramide galactosyltransferase; ER, endoplasmic reticulum; FA2H, fatty acid 2-hydroxylase protein or gene; GalCer, galactosylceramide; OPC, oligodendrocyte progenitor cell; PLP, proteolipid protein

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