Mfsd2a is a transporter for the essential omega-3 fatty acid docosahexaenoic acid.
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.
Signature Research Program in Cardiovascular and Metabolic Disorders, Duke-NUS Graduate Medical School Singapore, 8 College Road, 169857 Singapore.
Long N
LN
Nguyen
Signature Research Program in Neuroscience and Behavioral Disorders, Duke-NUS Graduate Medical School Singapore, 8 College Road, 169857 Singapore.
Dongliang
D
Ma
Department of Biochemistry, National University of Singapore, 8 Medical Drive, Block MD7, 117597 Singapore.
Guanghou
G
Shui
Signature Research Program in Neuroscience and Behavioral Disorders, Duke-NUS Graduate Medical School Singapore, 8 College Road, 169857 Singapore.
Peiyan
P
Wong
Department of Biochemistry, National University of Singapore, 8 Medical Drive, Block MD7, 117597 Singapore.
Amaury
A
Cazenave-Gassiot
Signature Research Program in Neuroscience and Behavioral Disorders, Duke-NUS Graduate Medical School Singapore, 8 College Road, 169857 Singapore.
Xiaodong
X
Zhang
Department of Biochemistry, National University of Singapore, 8 Medical Drive, Block MD7, 117597 Singapore.
Markus R
MR
Wenk
Signature Research Program in Neuroscience and Behavioral Disorders, Duke-NUS Graduate Medical School Singapore, 8 College Road, 169857 Singapore.
Eyleen L K
EL
Goh
Signature Research Program in Cardiovascular and Metabolic Disorders, Duke-NUS Graduate Medical School Singapore, 8 College Road, 169857 Singapore.
David L
DL
Silver
D000818:Animals; D001007:Anxiety / Q000503:physiopathology; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D003072:Cognition Disorders / Q000473:pathology / Q000503:physiopathology; D004281:Docosahexaenoic Acids / Q000172:deficiency / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism; D005260:Female; D008244:Lysophosphatidylcholines / Q000737:chemistry / Q000378:metabolism; D008297:Male; D026901:Membrane Transport Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008831:Microcephaly / Q000378:metabolism / Q000473:pathology; D055806:Microvessels / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009929:Organ Size; D012964:Sodium / Q000378:metabolism; D027981:Symporters
D008244:Lysophosphatidylcholines; D026901:Membrane Transport Proteins; C534136:Mfsd2a protein, mouse; D027981:Symporters; D004281:Docosahexaenoic Acids; D012964:Sodium