Dietary lysophosphatidylcholine-EPA enriches both EPA and DHA in the brain: potential treatment for depression

Abstract

The two major long-chain omega 3 FAs in animal tissues are EPA and DHA. Both of these FAs are known to have beneficial effects as anti-inflammatory agents and protect against various metabolic and neurologic diseases. Although the DHA concentration is higher than EPA in most tissues, the brain and retina are unique in having very high levels of DHA but virtually no EPA (1). The major dietary sources of EPA and DHA are fish, fish oil, and krill oil, all of which usually contain more EPA than DHA (2). However, the EPA levels in the brain are not increased significantly following the feeding of fish oil, krill oil, or even ethyl ester of EPA, although other tissues are enriched in both EPA and DHA (3-6). Interestingly, several clinical and preclinical studies showed that dietary EPA is superior to dietary DHA in the prevention and treatment of depression (7-9). It is therefore puzzling how EPA protects against depression without being incorporated appreciably into the brain. To explain this paradox, it has been proposed that the beneficial effects of EPA may result from the suppression of peripheral inflammation or from its hepatic conversion to DHA, rather than from a direct effect on the brain (10). However, the conversion of EPA to DHA cannot explain why dietary DHA does not have similar effects. The lack of enrichment of brain EPA by the dietary EPA has been explained by proposing that EPA is rapidly oxidized by the brain, in contrast to DHA (11,12). This mechanism is supported by kinetic studies with labeled FAs showing the generation of more water-soluble degradation products from EPA, compared with DHA in the brain (10,11). An alternative explanation that has not been explored is that the omega 3 FAs taken up into the brain do not Abstract EPA and DHA protect against multiple metabolic and neurologic disorders. Although DHA appears more effective for neuroinflammatory conditions, EPA is more beneficial for depression. However, the brain contains negligible amounts of EPA, and dietary supplements fail to increase it appreciably. We tested the hypothesis that this failure is due to absorption of EPA as triacylglycerol, whereas the transporter at the blood-brain barrier requires EPA as lysophosphatidylcholine (LPC). We compared tissue uptake in normal mice gavaged with equal amounts (3.3 mol/day) of either LPC-EPA or free EPA (surrogate for current supplements) for 15 days and also measured target gene expression. Compared with the no-EPA control, LPC-EPA increased brain EPA >100-fold (from 0.03 to 4 mol/g); free EPA had little effect. Furthermore, LPC-EPA, but not free EPA, increased brain DHA 2-fold. Free EPA increased EPA in adipose tissue, and both supplements increased EPA and DHA in the liver and heart. Only LPC-EPA increased EPA and DHA in the retina, and expression of brain-derived neurotrophic factor, cyclic AMP response element binding protein, and 5-hydroxy tryptamine (serotonin) receptor 1A in the brain. These novel results show that brain EPA can be increased through diet. Because LPC-EPA increase...

Plasma BDNF is a more reliable biomarker than erythrocyte omega-3 index for the omega-3 fatty acid enrichment of brain

“…Whereas previous studies reported that brain EPA levels cannot be increased through diet 34,35 , we have demonstrated that feeding LPC-EPA to normal mice not only increases brain EPA levels by several fold, but also increases brain DHA by about 100% in normal mice 36 . We determined whether the increase in plasma BDNF can be used as a biomarker for the increase in brain EPA and DHA after feeding free and LPC-EPA.…”

“…Animals and dietary treatments. Most of the analyses were carried out on samples obtained from our studies published previously 24,25,36,37 . All animal protocols were approved by the UIC institutional animal care committee, and all methods were carried out in accordance with the relevant guidelines and regulations.…”

Efficient Enrichment of Retinal DHA with Dietary Lysophosphatidylcholine-DHA: Potential Application for Retinopathies

“…Therefore, we suggest that the failure of previous studies to show an increase in brain or retinal EPA was due to the inability of the supplements to generate LPC-EPA in vivo. We have previously shown that similar enrichment of brain EPA and retinal EPA occurred after feeding pure LPC-EPA [ 50 ]. Increasing retinal EPA in addition to DHA may be more beneficial than increasing only its DHA content, because EPA is the preferred substrate for the synthesis of VLCFA [ 51 , 52 ], which have unique functional significance in retina [ 53 ].…”

FADS genetic and metabolomic analyses identify the ∆5 desaturase (FADS1) step as a critical control point in the formation of biologically important lipids

“…Consequently, most LC-PUFAs are thought to move from circulation across the blood brain barrier. Recent studies reveal that much of the acquisition of LC-PUFAs by the brain is mediated by a transporter, Mfsd2a, which moves n-3 and n-6 LC-PUFAs as lyso-GPCs from circulation across the blood brain barrier [49][50][51][52][53] . The current study shows that FADS variants are strongly associated with levels of n-6 and n-3 LC-PUFA-containing lyso-GPCs, including 1-arachidonoyl-2-lyso-GPC, 1-lyso-2-arachidonoyl-GPC, 1-docosapentaenoyl-2-lyso-GPC, and 1-eicosapentaenoyl-2-lyso-GPC, which are substrates for the Mfsd2a transporter.…”