Mfsd2a is a transporter for the essential omega-3 fatty acid docosahexaenoic acid

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.

Docosahexaenoic acid is a beneficial replacement treatment for spinocerebellar ataxia 38

“…The endogenous synthesis of DHA within the brain is low compared with its uptake from dietary and/or liver sources 15, 16. DHA is a well‐known dietary supplement, well tolerated at high dosage and with the ability to cross the blood–brain barrier by passive and active transport 17, 18, 19…”

AceDoPC, a structured phospholipid to target the brain with docosahexaenoic acid

“…Furthermore, the use of a re-constituted blood-brain barrier allowed to confirm that DHA provided in LysoPC was more efficient to cross this barrier than non-esterified DHA (Bernoud et al, 1999). Interestingly, a very recent work has demonstrated that the blood-brain barrier expresses a specific protein that specifically binds LysoPC-DHA (Nguyen et al, 2014), which may explain the preferential uptake of DHA when esterified in LysoPC. However, a likely important issue for the further metabolism of DHA is its position in LysoPC, if this lipid is processed within the brain after its uptake.…”

N-3 PUFAs and neuroinflammatory processes in cognitive disorders

“…Non esterified DHA freely entries the brain (Bazinet and Laye, 2014;Song et al, 2010). Recently, an orphan receptor, the major facilitator superfamily domaincontaining protein 2a (Mfsd2a) has been described as important to transport DHA through the BBB (Nguyen et al, 2014). Once in the brain, DHA exerts anti-inflammatory/proresolutive activities through several action modes briefly described below.…”

“…DHA entry in the brain is still a matter of debate. Non esterified DHA freely enters the brain (Bazinet and Laye, 2014;Song et al, 2010) and recently, an orphan receptor, the major facilitator superfamily domaincontaining protein 2a (Mfsd2a) has been described as important to transport DHA through the BBB (Nguyen et al, 2014). In retinal cells, adiponectin receptor 1 is key for DHA uptake and retention (Rice et al, 2015).…”