Docosahexaenoic acid (DHA) is uniquely concentrated in the brain, and is essential for its function, but must be mostly acquired from diet. Most of the current supplements of DHA, including fish oil and krill oil, do not significantly increase brain DHA, because they are hydrolyzed to free DHA and are absorbed as triacylglycerol, whereas the transporter at blood brain barrier is specific for phospholipid form of DHA. Here we show that oral administration of DHA to normal adult mice as lysophosphatidylcholine (LPC) (40 mg DHA/kg) for 30 days increased DHA content of the brain by >2-fold. In contrast, the same amount of free DHA did not increase brain DHA, but increased the DHA in adipose tissue and heart. Moreover, LPC-DHA treatment markedly improved the spatial learning and memory, as measured by Morris water maze test, whereas free DHA had no effect. The brain derived neurotrophic factor increased in all brain regions with LPC-DHA, but not with free DHA. These studies show that dietary LPC-DHA efficiently increases brain DHA content and improves brain function in adult mammals, thus providing a novel nutraceutical approach for the prevention and treatment of neurological diseases associated with DHA deficiency, such as Alzheimer's disease. Docosahexaenoic acid (DHA), an essential omega 3 fatty acid, is uniquely concentrated in the brain, nervous tissues and retina, and is essential for the normal neurological development and function. The deficiency of DHA is associated with several neurological disorders, including Alzheimer's, Parkinson's, schizophrenia, and depression [1][2][3][4][5] . Unlike liver, the brain cannot efficiently convert dietary alpha linolenic acid (18:3, n-3) to DHA 6,7 , and is almost completely dependent upon the uptake of preformed DHA from the plasma. However, dietary supplementation with the currently available preparations of DHA such as fish or krill oil 8 , algal DHA 9 , DHA-enriched egg phospholipids 10 ethyl esters 11 and sardines 12 does not appreciably increase brain DHA levels in adult mammals, although peripheral tissues are enriched with DHA under the same conditions. One possible explanation for this is that DHA from the above supplements is hydrolyzed to free DHA by the pancreatic enzymes and absorbed as triacylglycerol (TAG) in chylomicrons (Fig. 1), whereas the brain uniquely takes up DHA in the form of lysophosphatidylcholine (LPC) [13][14][15] . The recent demonstration of a transporter at the blood brain barrier (Mfsd2a), which specifically transports LPC-DHA, but not free DHA 16, further supports this mechanism. It is therefore necessary to increase the levels of LPC-DHA in plasma for an efficient enrichment of brain DHA. We propose that if dietary DHA is provided in the sn-1 position of phosphatidylcholine (PC) or in the form of LPC in the diet, it should escape the hydrolysis by pancreatic PLA 2 , and will be absorbed as PC-DHA (Fig. 1). The PC-DHA is more likely to be taken up by the brain after conversion to LPC-DHA in plasma or liver by the phospholipases, compare...

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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...

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ScopeCurrently available omega‐3 fatty acid supplements do not enrich the docosahexaenoic acid (DHA) of the adult brain because they are absorbed as triacylglycerol, whereas the transporter at the blood brain barrier requires lysophosphatidylcholine (LPC)‐DHA. The hypothesis that treatment of krill oil (KO), which contains DHA/eicosapentaenoic acid (EPA) at the SN2 position of phosphatidylcholine, with SN1‐specific lipase will generate LPC‐DHA/EPA and which can be absorbed intact and transported into the brain, is tested.MethodsKO and fish oil (FO) are treated with Mucor meihei lipase, incorporated into AIN 93G diet, and fed to 2‐month‐old mice for 30 days. Fatty acid composition is analyzed by gas chromatography/mass spectroscopy. Brain derived neurotrophic factor (BDNF) is measured by ELISA.ResultsLipase‐treated (LT) KO increases brain DHA and EPA, respectively, 5‐and 70‐fold better than untreated (UT) KO. FO, whether lipase‐treated or not, has no effect on brain DHA/EPA. LTKO is also more efficient in enriching liver DHA/EPA, but less efficient than UTKO and FO in enriching adipose tissue and heart. Brain BDNF is significantly increased by LTKO, but only marginally by other preparations.ConclusionsPretreatment of dietary KO with lipase enables it to efficiently increase brain DHA/EPA because of the generation of LPC‐DHA/EPA.

Compared with APOE3, APOE4 is associated with greater age-related cognitive decline and higher risk of neurodegenerative disorders. Therefore, development of supplements that target APOE genotype-modulated processes could provide a great benefit for the aging population. Evidence suggests a link between APOE genotype and docosahexaenoic acid (DHA); however, clinical studies with current DHA supplements have produced negative results in dementia. The lack of beneficial effects with current DHA supplements may be related to limited bioavailability, as the optimal form of DHA for brain uptake is lysophosphatidylcholine (LPC)-DHA. We previously developed a method to enrich the LPC-DHA content of krill oil through lipase treatment (LT-krill oil), which resulted in fivefold higher enrichment in brain DHA levels in wild-type mice compared with untreated krill oil. Here, we evaluated the effect of a control diet, diet containing krill oil, or a diet containing LT-krill oil in APOE3- and APOE4-targeted replacement mice (APOE-TR mice; treated from 4 to 12 months of age). We found that DHA levels in the plasma and hippocampus are lower in APOE4-TR mice and that LT-krill oil increased DHA levels in the plasma and hippocampus of both APOE3- and APOE4-TR mice. In APOE4-TR mice, LT-krill oil treatment resulted in higher levels of the synaptic vesicle protein SV2A and improved performance on the novel object recognition test. In conclusion, our data demonstrate that LPC-DHA/EPA-enriched krill oil can increase brain DHA and improve memory-relevant behavior in mice that express APOE4. Therefore, long-term use of LT-krill oil supplements may on some level protect against age-related neurodegeneration.

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The effects of feeding rats with groundnut oil (GNO), rice bran oil (RBO), and sesame oil (SESO) on serum lipids, liver lipids, and inflammatory markers were evaluated in rats. Male Wistar rats were fed with AIN-93 diet supplemented with 10 wt% of GNO, RBO, and SESO in the form of native (N) and minor constituent-removed (MCR) oils. Rats given RBO and SESO showed significant reduction in serum and liver lipids, 8-hydroxy-2-deoxyguanosine, cytokines in liver, and eicosanoids in leukocytes as compared with the rats given GNO and MCR oils. The rats fed with native oils of RBO and SESO showed an upregulation of sterol regulatory element-binding protein (SREBP)-2 and peroxisome proliferator-activated receptor gamma (PPARγ) and downregulation of nuclear factor-kappa B (NF-κB) p65. These effects of native oil were significantly compromised when rats were given MCR oils. In conclusion, the minor constituents significantly support the hypolipidemic and anti-inflammatory properties of RBO and SESO.