Abstract
Myelin in the mammalian nervous system has a high concentration of galactolipids (galactosylceramide and sulfatide) with 2-hydroxy fatty acids. We recently reported that fatty acid 2-hydroxylase, 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 fatty acid 2-hydroxylase activity in the neonatal rat sciatic nerve rapidly increased during developmental myelination. The contents of 2-hydroxy fatty acids were approximately 5% of total galactolipid fatty acids at 4 days-of-age, and increased to 60% in galactosylceramide and to 35% in sulfatides at 60 days-of-age. The chain length of galactolipid fatty acids also significantly increased during myelination.
FA2H
expression in cultured rat Schwann cells was highly elevated in response to dibutyryl cyclic AMP, which stimulates Schwann cell differentiation and upregulates myelin genes, such as CGT and protein zero. These observations indicate that
FA2H
is a myelination-associated gene. FA2H-directed RNA interference by short-hairpin RNA expression resulted in a reduction of cellular 2-hydroxy fatty acids and 2-hydroxy galactosylceramide 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 RNA interference enhanced 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.
