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Papers In Press, published online ahead of print September 23, 2006
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Biochemistry and Molecular Biology, Medical Univeristy of South Carolina, Charleston, SC 29425
Corresponding Author: 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 tested 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 non-hydroxy galactolipids was very low at 2 days of age (approximately 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 on 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 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 for the synthesis of 2-hydroxy galactolipids.
Revised on September 13, 2006
Accepted on September 23, 2006
FA2H-dependent fatty acid 2-hydroxylation in postnatal mouse brain
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