Docosahexaenoic acid (DHA) is an omega-3 fatty acid that is essential for normal brain growth and cognitive function1,2,3,4. Consistent with its importance in the brain, DHA is highly enriched in brain phospholipids5,6,7. 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.
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This work was supported in part by grants from the Singapore Ministry of Health’s National Medical Research Council CBRG/0012/2012 (to D.L.S.), the Singapore National Research Foundation Competitive Research Program grants 2008-01 (to E.L.G.) and 2007-04 (to M.R.W.), National University of Singapore’s Life Sciences Institute (to M.R.W.), and Singapore National Medical Research Council Translational and Clinical Research Program NMRC/TCR/003-GMS/2008 (to X.Z.). We would like to thank B. Tan (Duke-NUS) for technical assistance with lipid extractions, and S. Ying (Duke-NUS) for assistance with behavioural phenotyping.
Extended data figures
Mass spectrometry analysis of free fatty acid uptake in HEK239 cells. Mfsd2a expressing HEK293 cells were incubated with 100µM of indicated fatty acid/BSA complex overnight. Lipids extraction and phospholipid analysis by MS were performed as described in Methods section. Amount of each lipid species was normalized to internal standard and expressed as mol percent in total phospholipid analysed.