Male rat pups (21 days old) were placed on a diet deficient in n-3 polyunsaturated fatty acids (PUFAs) or on an n-3 PUFA adequate diet containing a-linolenic acid (a-LNA; 18 : 3n-3). After 15 weeks on a diet, [4, H]docosahexaenoic acid (DHA; 22 : 6n-3) was injected into the right lateral cerebral ventricle, and the rats were killed at fixed times over a period of 60 days. Compared with the adequate diet, 15 weeks of n-3 PUFA deprivation reduced plasma DHA by 89% and brain DHA by 37%; these DHA concentrations did not change thereafter. In the n-3 PUFA adequate rats, DHA loss half-lives, calculated by plotting log 10 (DHA radioactivity) against time after tracer injection, equaled 33 days in total brain phospholipid, 23 days in phosphatidylcholine, 32 days in phosphatidylethanolamine, 24 days in phosphatidylinositol and 58 days in phosphatidylserine; all had a decay slope significantly greater than 0 (p < 0.05). In the n-3 PUFA deprived rats, these half-lives were prolonged twofold or greater, and calculated rates of DHA loss from brain, J out , were reduced. Mechanisms must exist in the adult rat brain to minimize DHA metabolic loss, and to do so even more effectively in the face of reduced n-3 PUFA availability for only 15 weeks.

Adult male unanesthetized rats, reared on a diet enriched in both a-linolenic acid (a-LNA) and docosahexaenoic acid (DHA), were infused intravenously for 5 min with [1-14 C]a-LNA. Timed arterial samples were collected until the animals were killed at 5 min and the brain was removed after microwaving. Plasma and brain lipid concentrations and radioactivities were measured. Within plasma lipids, > 99% of radioactivity was in the form of unchanged [1-14 C]a-LNA.Eighty-six per cent of brain radioactivity at 5 min was present as b-oxidation products, whereas the remainder was mainly in 'stable' phospholipid or triglyceride as a-LNA or DHA.Equations derived from kinetic modeling demonstrated that unesterified unlabeled a-LNA rapidly enters brain from plasma, but that its incorporation into brain phospholipid and triglyceride, as in the form of synthesized DHA, is £ 0.2% of the amount that enters the brain. Thus, in rats fed a diet containing large amounts of both a-LNA and DHA, the a-LNA that enters brain from plasma largely undergoes b-oxidation, and is not an appreciable source of DHA within brain phospholipids.

Docosahexaenoic acid (DHA; 22:6n-3) is a critical constituent of the brain, but its metabolism has not been measured in the human brain in vivo. In monkeys, using positron emission tomography (PET), we first showed that intravenously injected [1-11 C]DHA mostly entered nonbrain organs, with ?0.5% entering the brain. Then, using PET and intravenous [1-11 C]DHA in 14 healthy adult humans, we quantitatively imaged regional rates of incorporation (K*) of DHA. We also imaged regional cerebral blood flow (rCBF) using PET and intravenous [15 O]water. Values of K* for DHA were higher in gray than white matter regions and correlated significantly with values of rCBF in 12 of 14 subjects despite evidence that rCBF does not directly influence K*. For the entire human brain, the net DHA incorporation rate J in , the product of K*, and the unesterified plasma DHA concentration equaled 3.8 6 1.7 mg/day. This net rate is equivalent to the net rate of DHA consumption by brain and, considering the reported amount of DHA in brain, indicates that the half-life of DHA in the human brain approximates 2.5 years. Thus, PET with [1-11 C]DHA can be used to quantify regional and global human brain DHA metabolism in relation to health and

We quantified incorporation rates of plasmaderived a-linolenic acid (a-LNA, 18:3n-3) into "stable" liver lipids and the conversion rate of a-LNA to docosahexaenoic acid (DHA, 22:6n-3) in male rats fed, after weaning, an n-3 PUFA-adequate diet (4.6% a-LNA, no DHA) or an n-3 PUFAdeficient diet (0.2% a-LNA, no DHA) for 15 weeks. Unanesthetized rats were infused intravenously with [1-14 C]a-LNA, and arterial plasma was sampled until the liver was microwaved at 5 min. Unlabeled a-LNA and DHA concentrations in arterial plasma and liver were reduced .90% by deprivation, whereas unlabeled arachidonic acid (20:4n-6) and docosapentaenoic acid (22:5n-6) concentrations were increased. Deprivation did not change a-LNA incorporation coefficients into stable liver lipids but increased synthesis-incorporation coefficients of DHA from a-LNA by 6.6-, 8.4-, and 2.3-fold in triacylglycerol, phospholipid, and cholesteryl ester, repectively. Assuming that synthesized-incorporated DHA even tually would be secreted within lipoproteins, calculated liver DHA secretion rates equaled 2.19 and 0.82 mmol/day in the n-3 PUFA-adequate and -deprived rats, respectively. These rates exceed the published rates of brain DHA consumption by 6-and 10-fold, respectively, and should be sufficient to maintain normal and reduced brain DHA concentrations, respectively, in the two dietary conditions.-

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Rates of conversion of a-linolenic acid (a-LNA, 18:3n-3) to docosahexaenoic acid (DHA, by the mammalian brain and the brain's ability to upregulate these rates during dietary deprivation of n-3 polyunsaturated fatty acids (PUFAs) are unknown. To answer these questions, we measured conversion coefficients and rates in post-weaning rats fed an n-3 PUFA deficient (0.2% a-LNA of total fatty acids, no DHA) or adequate (4.6% a-LNA, no DHA) diet for 15 weeks. Unanesthetized rats in each group were infused intravenously with [1-14 C]a-LNA, and their arterial plasma and microwaved brains collected at 5 minutes were analyzed. The deficient compared with adequate diet reduced brain DHA by 37% and increased brain arachidonic (20:4n-6) and docosapentaenoic (22:5n-6) acids. Only 1% of plasma [1][2][3][4][5][6][7][8][9][10][11][12][13][14]

Fifteen weeks of dietary n-3 PUFA deprivation increases coefficients of conversion of circulating alinolenic acid (a-LNA; 18:3n-3) to docosahexaenoic acid (DHA; 22:6n-3) in rat liver but not brain. To determine whether these increases reflect organ differences in enzymatic activities, we examined brain and liver expression of converting enzymes and of two of their transcription factors, peroxisome proliferator-activated receptor a (PPARa) and sterol-regulatory element binding protein-1 (SREBP-1), in rats fed an n-3 PUFA "adequate" (4.6% a-LNA of total fatty acid, no DHA) or "deficient" (0.2% a-LNA, no DHA) diet for 15 weeks after weaning. In rats fed the deficient compared with the adequate diet, mRNA and activity levels of #5 and #6 desaturases and elongases 2 and 5 were upregulated in liver but not brain, but liver PPARa and SREBP-1 mRNA levels were unchanged. In rats fed the adequate diet, enzyme activities generally were higher in liver than brain. Thus, differences in conversion enzyme expression explain why the liver has a greater capacity to synthesize DHA from circulating a-LNA than does the brain in animals on an adequate n-3 PUFA diet and why liver synthesis capacity is increased by dietary deprivation. These data suggest that liver n-3 PUFA metabolism determines DHA availability to the brain when DHA is absent from the diet.-Igarashi, M., K. Ma, L. Chang, J. M. Bell, and S. I. Rapoport. Dietary n-3 PUFA deprivation for 15 weeks upregulates elongase and desaturase expression in rat liver but not brain.

Alzheimer disease (AD) is a progressive neurodegenerative disorder characterized by brain deposition of senile (neuritic) plaques containing β-amyloid, neurofibrillary tangles, synaptic loss, neuroinflammation, and overexpression of arachidonic acid (AA, 20:4n-6) metabolizing enzymes. Lipid concentration changes have been reported in different brain regions, but often partially and/or as a percent of the total concentration. In this study, we measured absolute concentrations (per gram wet weight) of a wide range of lipids in postmortem prefrontal cortex (Brodmann area 9) from 10 AD patients and 9 controls. Mean total brain lipid, phospholipid, cholesterol and triglyceride concentrations did not differ significantly between AD and controls. There was a significant 73% decrease in plasmalogen choline, but no difference in other measured phospholipids. Fatty acid concentrations in total phospholipid did not differ from control. However, docosahexaenoic acid (DHA, 22:6n-3) was reduced in ethanolamine glycerophospholipid and choline glycerophospholipid, but increased in phosphatidylinositol. AA was reduced in choline glycerophospholipid, but increased in phosphatidylinositol, while docosatetraenoic acid (22:4n-6), an AA elongation product, was reduced in total brain lipid, cholesteryl ester and triglyceride. These lipid changes may contribute to membrane instability and synaptic loss in AD, and reflect neuroinflammation and excitotoxicity.