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Originally published In Press as doi:10.1194/jlr.M600362-JLR200 on September 23, 2006

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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{dagger}, Narayan R. Bhat§ and Hiroko Hama1,*

* Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425
{dagger} 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 {alpha}-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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