Mfsd2a is a transporter for the essential omega-3 fatty acid docosahexaenoic acid
Mfsd2a is a transporter for the essential omega-3 fatty acid docosahexaenoic acid
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DOI：
10.1038/nature13241
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发表时间：
2014-05-22
期刊：
影响因子：
64.8
通讯作者：
Silver, David L.
中科院分区：
文献类型：
--
作者：
Nguyen, Long N.;Ma, Dongliang;Silver, David L.
二十二碳六烯酸（DHA）是一种ω-3脂肪酸，对正常的大脑生长和认知功能至关重要（1-4）。与其在大脑中的重要性相一致，DHA在脑磷脂中高度富集（5-7）。尽管脑磷脂中含有丰富的脂肪酸，但DHA不能在脑中从头合成，必须通过血脑屏障输入，但脑中DHA摄取的机制仍然是个谜。在这里，我们确定了一个主要的促进剂超家族成员Mfsd 2a（以前是孤儿转运蛋白）作为DHA摄取到大脑中的主要转运蛋白。发现Mfsd 2a仅在微血管的血脑屏障内皮中表达。脂质组学分析表明，Mfsd 2a缺陷（Mfsd 2a敲除）小鼠显示脑中DHA水平显著降低，伴有海马和小脑中神经元细胞损失，以及认知缺陷和严重焦虑和小头畸形。出乎意料的是，基于细胞的研究表明，Mfsd 2a以钠依赖性方式以溶血磷脂酰胆碱（LPC）的形式转运DHA，而不是未酯化的脂肪酸。值得注意的是，Mfsd 2a转运携带长链脂肪酸如LPC油酸酯和LPC棕榈酸酯的常见血浆LPC，但不转运具有少于14个碳酰基链的LPC。此外，我们确定LPC的磷-两性离子头基是至关重要的运输。重要的是，Mfsd 2a基因敲除小鼠从血浆到大脑的标记LPC DHA和其他LPC的摄取显著减少，表明Mfsd 2a是大脑摄取DHA所必需的。我们的研究结果揭示了一个意想不到的重要生理作用，血浆来源的LPCs在大脑的生长和功能。
Docosahexaenoic acid (DHA) is an omega-3 fatty acid that is essential for normal brain growth and cognitive function(1-4). Consistent with its importance in the brain, DHA is highly enriched in brain phospholipids(5-7). Despite being an abundant fatty acid in brain phospholipids, DHA cannot be de novo synthesized in brain and must be imported across the blood-brain barrier, but mechanisms for DHA uptake in brain have remained enigmatic. Here we identify a member of the major facilitator superfamily-Mfsd2a (previously an orphan transporter)-as the major transporter for DHA uptake into brain. Mfsd2a is found to be expressed exclusively in endothelium of the blood-brain barrier of micro-vessels. Lipidomic analysis indicates that Mfsd2a-deficient (Mfsd2a-knockout) mice show markedly reduced levels of DHA in brain accompanied by neuronal cell loss in hippocampus and cerebellum, as well as cognitive deficits and severe anxiety, and microcephaly. Unexpectedly, cell-based studies indicate that Mfsd2a transports DHA in the form of lysophosphatidylcholine (LPC), but not unesterified fatty acid, in a sodium-dependent manner. Notably, Mfsd2a transports common plasma LPCs carrying long-chain fatty acids such LPC oleate and LPC palmitate, but not LPCs with less than a 14-carbon acyl chain. Moreover, we determine that the phosphor-zwitterionic headgroup of LPC is critical for transport. Importantly, Mfsd2a-knockout mice have markedly reduced uptake of labelled LPC DHA, and other LPCs, from plasma into brain, demonstrating that Mfsd2a is required for brain uptake of DHA. Our findings reveal an unexpected essential physiological role of plasma-derived LPCs in brain growth and function.