Nature2014-06-17 5:00 PM

Mfsd2a在血-脑屏障中所起作用 Mfsd2a is a transporter for the essential omega-3 fatty acid docosahexaenoic acid

论文摘要 


血-脑屏障在为脑功能维持必要环境中起至关重要的作用,但对于以脑为方向的治疗药物却是一个不方便的障碍。本期Nature上发表的两篇论文报告了Mfsd2a (主要促进因子超级家族的一个成员,以前被认为是一个“孤儿运输因子”)在血-脑屏障功能的两个方面中的参与情况。David Silver及同事识别出Mfsd2a是奥米伽脂肪酸“二十二碳六烯酸”(DHA)向脑中吸收的主要运输因子。Mfsd2a只在血-脑屏障的内皮中表达,Mfsd2a被剔除的小鼠脑中DHA水平降低、神经元数量减少、脑大小和功能降低。Chenghua Gu及同事发现Mfsd2起血-脑屏障发育和功能的一个调控因子的作用:该屏障在缺失Mfsd2a的小鼠中会变得有泄漏,这可能是跨细胞的小泡运输量增加所造成的一个结果。


Abstract 


Docosahexaenoic acid (DHA) is an omega-3 fatty acid that is essential for normal brain growth and cognitive function. Consistent with its importance in the brain, DHA is highly enriched in brain phospholipids. 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.

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