FA2H is responsible for the formation of 2-hydroxy galactolipids in peripheral nervous system myelin
FA2H is responsible for the formation of 2-hydroxy galactolipids in peripheral nervous system myelin
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DOI：
10.1194/jlr.m700400-jlr200
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发表时间：
2008-01-01
影响因子：
6.5
通讯作者：
Hama, Hiroko
中科院分区：
文献类型：
--
作者：
Maldonado, Eduardo N.;Alderson, Nathan L.;Hama, Hiroko
哺乳动物神经系统中的髓鞘含有高浓度的半乳糖脂[半乳糖神经酰胺（GalCer）和硫苷脂]和2-羟基脂肪酸。我们最近报道了脂肪酸2-羟化酶（FA 2 H），由FA 2 H基因编码，是小鼠脑中主要的脂肪酸2-羟化酶。在这份报告中，我们表明，FA 2 H也发挥了重要作用，在周围神经系统中的2-羟基半乳糖脂的形成。新生大鼠坐骨神经中FA 2 H mRNA和FA 2 H活性在髓鞘形成过程中迅速增加。2-羟基脂肪酸的含量在4日龄时约占总半乳糖脂脂肪酸的5%，在60日龄时增加到60%，在60日龄时增加到35%。半乳糖脂脂肪酸的链长也在髓鞘形成过程中显著增加。FA 2 H在培养的大鼠雪旺细胞中的表达高度增加，响应于二丁酰环AMP，其刺激雪旺细胞分化和上调髓鞘基因，如UDP-半乳糖：神经酰胺半乳糖基转移酶和蛋白零。这些观察结果表明FA 2 H是髓鞘形成相关基因。通过短发夹RNA表达的FA 2 H定向RNA干扰（RNAi）导致D 6P 2 T神经鞘瘤细胞中细胞2-羟基脂肪酸和2-羟基GalCer的减少，提供了FA 2 H依赖性脂肪酸2-羟基化是外周神经髓鞘中2-羟基半乳糖脂形成所需的直接证据。
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 similar to 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.