Brain docosahexaenoic acid uptake and metabolism

Abstract

Docosahexaenoic acid (DHA) is the most abundant n-3 polyunsaturated fatty acid in the brain where it serves to regulate several important processes and, in addition, serves as a precursor to bioactive mediators. Given that the capacity of the brain to synthesize DHA locally is appreciably low, the uptake of DHA from circulating lipid pools is essential to maintaining homeostatic levels. Although, several plasma pools have been proposed to supply the brain with DHA, recent evidence suggests non-esterified-DHA and lysophosphatidylcholine-DHA are the primary sources. The uptake of DHA into the brain appears to be regulated by a number of complementary pathways associated with the activation and metabolism of DHA, and may provide mechanisms for enrichment of DHA within the brain. Following entry into the brain, DHA is esterified into and recycled amongst membrane phospholipids contributing the distribution of DHA in brain phospholipids. During neurotransmission and following brain injury, DHA is released from membrane phospholipids and converted to bioactive mediators which regulate signaling pathways important to synaptogenesis, cell survival, and neuroinflammation, and may be relevant to treating neurological diseases. In the present review, we provide a comprehensive overview of brain DHA metabolism, encompassing many of the pathways and key enzymatic regulators governing brain DHA uptake and metabolism. In addition, we focus on the release of non-esterified DHA and subsequent production of bioactive mediators and the evidence of their proposed activity within the brain. We also provide a brief review of the evidence from post-mortem brain analyses investigating DHA levels in the context of neurological disease and mood disorder, highlighting the current disparities within the field.

Docosahexaenoic acid (22:6n‐3) Ameliorated the Onset and Severity of Experimental Autoimmune Encephalomyelitis in Mice

“…Specific membrane‐associated fatty acid transporters are involved in the transport of fatty acids into tissues, such as fatty acid translocase/CD36, plasma membrane fatty acid binding proteins, and fatty acid transport proteins (Glatz et al, ). Phospholipase A2 hydrolyzes PtdCho‐DHA to form lysophosphatidylcholine (lysoPtdCho)‐DHA, which is transported in circulation either bound to albumin or associated within the PL membrane of lipoproteins (Lacombe et al, ). Major facilitator superfamily domain‐containing protein 2a (Mfsd2a) is a lysoPtdCho transporter present in the endothelium of the BBB microvessels that has an affinity for lysoPtdCho‐bound fatty acids with a high capacity to transport lysoPtdCho‐DHA followed by lysoPtdCho‐18:0 and lysoPtdCho‐16:0 (Nguyen et al, ).…”

“…or associated within the PL membrane of lipoproteins (Lacombe et al, 2018). Major facilitator superfamily domain-containing protein 2a (Mfsd2a) is a lysoPtdCho transporter present in the endothelium of the BBB microvessels that has an affinity for lysoPtdCho-bound fatty acids with a high capacity to transport lysoPtdCho-DHA followed by lysoPtdCho-18:0 and lysoPtdCho-16:0 (Nguyen et al, 2014).…”

Altered SPMs and age‐associated decrease in brain DHA inAPOE4female mice

“…Aging is associated with brain atrophy and a loss of total tissue and fatty acid concentration per unit volume. As recently highlighted by Lacombe et al (29), it is important to consider brain fatty acid content as a percentage of total fatty acids and relative to the weight of total lipids when interpreting the meaning of altered status. Here, we observed a lower percentage and concentration of cortex DHA in older female APOE4 mice compared with their APOE3 or male counterparts.…”

“…Here, we observed a lower percentage and concentration of cortex DHA in older female APOE4 mice compared with their APOE3 or male counterparts. Previous studies in rodents have demonstrated the impact of aging on brain DHA (29) and identified DHA transporters across the blood-brain barrier using transgenic animal models [for review (30)]. Vandal et al (31) described the impact of APOE4 genotype on DHA uptake.…”

Sports-related concussions and subconcussive impacts in athletes: incidence, diagnosis, and the emerging role of EPA and DHA

“…(Cao et al 2009). Due to the brains poor capacity to convert DHA on its own, almost all DHA must first pass through the blood brain barrier (BBB) (Lacombe et al 2018). The BBB is highly selective and contains specialized tight junctions for increased protection (Lo Van et al 2016).Transport of DHA is mediated by the Major Facilitator Superfamily Domain containing 2a (Mfsd2a) which is found to be expressed exclusively in the endothelium of the BBB (Nguyen et al 2014).…”