Lipid Nutrition and the Brain

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BRAIN DOCOSAHEXAENOIC ACID SYNTHESIS FROM ALPHA-LINOLENIC ACID IS UNAFFECTED BY DIETARY N-3 PUFA DEPRIVATION. Rates of conversion of alpha-linolenic acid (alpha-LNA, 18:3n-3) to docosahexaenoic acid (DHA, 22:6n-3) by the mammalian brain and the brain's ability to modulate these rates during dietary deprivation of n-3 polyunsaturated fatty acids (PUFAs) are poorly understood. To address these issues, we measured conversion coefficients and rates in post-weaning rats fed an n-3 PUFA deficient (0.2% alpha-LNA of total fatty acids, no DHA) or adequate (4.6% alpha-LNA, no DHA) diet for 15 weeks. Unanesthetized rats in each group were infused intravenously with 1-14Calpha-LNA, and arterial plasma samples as well as their microwaved brains collected at 5 minutes, were analyzed. Rats fed the deficient compared with adequate diet had a 37% reduced brain DHA and increased brain arachidonic (20:4n-6) and docosapentaenoic (22:5n-6) acid concentrations. Only 1% of plasma 1-14Calpha-LNA that entered brain was converted to DHA in rats on the adequate diet, and conversion coefficients of alpha-LNA to DHA were unchanged by the deficient diet. In summary, the brain's ability to synthesize DHA from alpha-LNA is very low and is not altered by n-3 PUFA deprivation. Because the liver's reported ability is much higher (see below), and can be upregulated by the deficient diet, DHA converted by the liver from circulating alpha-LNA is likely the source of the brain's DHA when DHA is not in the diet (1). UPREGULATED LIVER CONVERSION OF ALPHA-LINOLENIC ACID TO DOCOSAHEXAENOIC ACID IN RATS ON A 15 WEEK N-3 PUFA-DEFICIENT DIET. We quantified incorporation rates of plasma-derived alpha-LNA into "stable" liver lipids and the conversion rate of alpha-LNA to DHA in male rats fed, after weaning, an n-3 PUFA-adequate diet (4.6% alpha-LNA, no DHA) or an n-3 PUFA-deficient diet (0.2% alpha-LNA, no DHA) for 15 weeks. Unanesthetized rats were infused intravenously with 1-14Calpha-LNA, and arterial plasma was sampled until the liver was microwaved at 5 min. Unlabeled alpha-LNA and DHA concentrations in arterial plasma and liver were reduced >90% by deprivation, whereas unlabeled arachidonic acid (AA, 20:4n-6) and docosapentaenoic acid (DPA, 22:5n-6) concentrations were increased. Deprivation did not change alpha-LNA incorporation coefficients into stable liver lipids, but increased synthesis-incorporation coefficients of DHA from alpha-LNA by 2-8 fold. Assuming that newly synthesized DHA eventually would be secreted as circulating lipoproteins, calculated liver DHA secretion rates exceeded published rates of brain DHA consumption by 6-10-fold. Thus liver synthesis and secretion of DHA is sufficient to maintain a normal brain DHA concentration when sufficient alpha-LNA but no DHA is in the diet (2). LOW DIETARY N-3 PUFA UPREGULATES ELONGASE AND DESATURASE EXPRESSION IN RAT LIVER BUT NOT BRAIN. As noted above, fifteen weeks of dietary n-3 polyunsaturated fatty acid (PUFA) deprivation increased kinetic coefficients of conversion of circulating alpha-LNA to DHA in rat liver but not brain. These increases reflect differences in organ activities of enzymes that desaturate and elongate alpha-LNA to DHA. We examined brain and liver expression of these converting enzymes in rats fed the n-3 PUFA "adequate" or "deficient" diet (see above). In rats fed the "adequate" diet, enzyme activities generally were higher in liver than brain. In rats fed the "deficient" compared with "adequate" diet, mRNA and activity levels of delta-5 and delta-6 desaturases and of elongases 2 and 5 were upregulated in liver but not brain. Thus, differences in conversion enzyme expression explain why the liver has a greater capacity to synthesize DHA from circulating alpha-LNA than does the brain, and why the liver but not the brain can upregulate this capacity during n-3 PUFA dietary deprivation. Liver conversion of alpha-LNA to DHA determines brain n-3 PUFA content and metabolism when DHA is absent from the diet (3). DIETARY N-3 PUFA DEPRIVATION ALTERS EXPRESSION OF ENZYMES OF THE ARACHIDONIC AND DOCOSAHEXAENOIC ACID CASCADES IN RAT BRAIN. Enzymes of brain arachidonic acid (AA) metabolism have been implicated in bipolar disorder and Alzheimer disease, and dietary n-3 PUFA deprivation has been implicated as well. We found that 15 weeks of dietary n-3 PUFA deprivation in rats (see above) significantly decreased the activity, protein and mRNA expression of DHA-regulatory calcium-independent iPLA2 in frontal cortex, while increasing expression of calcium-dependent AA-selective cytosolic phospholipase (cPLA2) and secretory sPLA2. Cyclooxygenase (COX)-1 expression was decreased, whereas COX-2 expression was increased. Downregulated iPLA2 and COX-1 may account for our finding that n-3 PUFA deprivation prolongs DHA half-life in rat brain. Increased cPLA2, sPLA2 and COX-2 expression caused by deprivation is opposite in direction to what happens after chronic administration of anti-manic agents to rats. This suggests that dietary n-3 PUFA deprivation could increase susceptibility to bipolar disorder and neuroinflammation (4). N-3 POLYUNSATURATED FATTY ACID DEPRIVATION IN RATS DECREASES FRONTAL CORTEX BDNF VIA A P38 MAPK-DEPENDENT MECHANISM. Decreased brain-derived neurotrophic factor (BDNF) has been implicated in bipolar disorder and other brain diseases. We showed that the dietary n-3 PUFA deprivation discussed above reduced rat brain levels of brain derived neurotrophic factor (BDNF), cAMP response element binding protein (CREB), and p38 mitogen-activated protein kinase (MAPK) activity. Adding DHA to rat primary cortical astrocytes in vitro induced BDNF protein and this was blocked by a p38 MAPK inhibitor. The results show that brain DHA composition, influenced by diet, can regulate expression of an important kinase, transcription factor and neurotrophic factor. These actions may be related to reported positive effects of DHA supplementation on brain function, and negative effects of n-3 PUFA deprivation, in human subjects (5).