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.
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MFSD2A was identified as a blood-brain barrier transporter for LPC esterified DHA supplying the brain with the essential circulating omega-3 fatty acid.
“Previously an orphan MFS transporter, MFSD2A, was identified as a BBB transporter for LPC esterified DHA supplying the brain with the essential circulating omega-3 fatty acid (430).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [430]
Murine Mfsd2a is expressed in the brain exclusively in endothelium of the blood-brain barrier.
“As in humans, murine Mfsd2a is expressed in the brain exclusively in endothelium of the BBB (62, 430).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [430]
Mfsd2a-deficient mice exhibit impaired brain uptake of lysophosphatidylcholine-long fatty acyl chains and develop blood-brain barrier breakdown, accompanied by neuronal loss in hippocampus and cerebellum causing microcephaly and behavioral deficits.
“Mfsd2a -deficient mice exhibit impaired brain uptake of lysophosphatidylcholine-long fatty acyl chains and develop BBB breakdown, which is accompanied by neuronal loss in hippocampus and cerebellum causing microcephaly and behavioral deficits (62, 63, 430, 684).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [430]
Mfsd2a mediates DHA transport across the blood brain barrier.
“Recently, an essential role for Mfsd2a, a member of the major facilitator superfamily, was shown to mediate DHA transport across the blood brain barrier (Nguyen et al., 2014; Wong et al., 2016).”
From Docosanoids and elovanoids from omega-3 fatty acids are pro-homeostatic modulators of inflammatory responses, cell damage and neuroprotection (2018) · cites this paper as Nguyen et al., 2014
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- Authors
- Nguyen, L. N., Ma, D., Shui, G., Wong, P., Cazenave-Gassiot, A., Zhang, X., Wenk, M. R., Goh, E. L. K., & Silver, D. L.
- Affiliations
- National University of Singapore (SG)
- Corresponding author
- Silver, David L.
- ORCID
- Venue
- Nature
- Published
- 2014-05-14
- Volume
- 509
- Issue
- 7501
- Pages
- 503-506
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2092474731
- Cited by
- 1,048
- References
- 20
- Citations by year
- 2026: 102 · 2025: 88 · 2024: 96 · 2023: 89 · 2022: 115 · 2021: 88 · 2020: 108 · 2019: 74 · 2018: 74 · 2017: 74 · 2016: 53 · 2015: 60 · 2014: 25
- FWCI
- 36.48
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Nursing › Nutrition and Dietetics › Fatty Acid Research and Health
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- MFSD2A, docosahexaenoic acid, omega-3 fatty acids, blood-brain barrier, fatty acid uptake, major facilitator superfamily, lysophosphatidylcholine, neuronal loss, cognitive impairment, blood-brain barrier development
- MeSH terms
- Animals, Anxiety, Biological Transport, Blood-Brain Barrier, Brain, Cognition Disorders, Docosahexaenoic Acids, Endothelium, Vascular, Female, Lysophosphatidylcholines, Male, Microcephaly, Neurons, Organ Size, Sodium, Mice, Knockout, Membrane Transport Proteins, Symporters, Mice, Microvessels
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