DIETARY N-6 PUFA CHANGES AND BRAIN DIETARY N-6 PUFA DEPRIVATION DOWNREGULATES ARACHIDONATE- BUT UPREGULATES DOCOSAHEXAENOATE-METABOLIZING ENZYMES IN RAT BRAIN. There is substantial evidence that modern diets contain much more n-6 polyunsaturated fatty acids (PUFAs) than diets at the beginning of the 19th century, and that this change has contributed to increased prevalence of a number of diseases, including depression and bipolar disorder. One of these n-6 PUFAs, arachidonic acid (AA, 20:4n-6), is thought to contribute to disease progression associated with neuroinflammation in Alzheimer disease and other brain disorders. To understand the effect of dietary n-6 PUFA content on brain metabolism and integrity, we measured expression of AA and DHA (22:6n-3) metabolizing enzymes and other factors in male rats fed an n-6 PUFA adequate or deficient diet for 15 weeks post-weaning. The deficient compared with adequate diet increased mRNA, protein and activity of the DHA-metabolizing calcium independent phospholipase A2, iPLA2 VIA, and 15-lipoxygenase (LOX), but decreased expression of AA metabolizing cytosolic cPLA2 IVA and cyclooxygenase (COX)-2. The protein level of the iPLA2 transcription factor SREBP-1 was elevated, while protein levels were decreased for AP-2alpha and NF-kappaB p65, cPLA2 and COX-2 transcription factors, respectively. These changes would be expected to dampen brain n-6 PUFA metabolism, while increasing n-3 PUFA metabolism, and to be clinically neuroprotective (4). DIETARY N-6 PUFA DEPRIVATION INCREASES DOCOSAHEXAENOIC ACID METABOLISM IN RAT BRAIN. We hypothesized that the molecular brain changes produced by dietary n-6 PUFA deprivation, particularly upregulation of DHA metabolizing iPLA2 VIA, would be accompanied by increased DHA kinetics. 1-14CDHA was infused intravenously, arterial blood was sampled, and the brain was microwaved and analyzed in unanesthetized rats that had been fed n-6 PUFA adequate and deficient diet for 15 weeks. Incorporation rates of unesterified DHA from plasma, which represent DHA metabolic loss from brain, were increased 45% in brain phospholipids, as was DHA turnover. Increased DHA metabolism following dietary n-6 PUFA deprivation may increase brain concentrations of antiinflammatory DHA metabolites, and with a reduced brain n-6 PUFA content, reduce neuroinflammation and be neuroprotective. (1) LOWERING DIETARY LINOLEIC ACID REDUCES BIOACTIVE OXIDIZED LINOLEIC ACID METABOLITES IN HUMANS. The dietary content of n-6 PUFAs, particularly the linoleic acid (LA, 18:2n-6) precursor of arachidonic acid (AA, 20:4n-6), is highly abundant in modern human diets. LA is a precursor of bioactive oxidized LA metabolites (OXLAMs): 9- and 13 hydroxy-octadecadienoic acid (9- and 13-HODE) and 9- and 13-oxo-octadecadienoic acid (9- and 13-oxoODE), which have been linked to chronic pain, Alzheimer disease and non-alcoholic steatohepatitis. In a collaboration with the NIAAA, we measured circulating LA and OXLAMs before and after a 12-week LA lowering dietary intervention in chronic headache patients. Lowering dietary LA significantly reduced plasma OXLAMs. Thus, lowering dietary LA reduces the accumulation of oxidized LA derivatives that have been implicated in a variety of pathological conditions (5). To further study effects of LA in the diet in animal models, we developed a new analytical method using novel ultra high definition quadrupole time-of-flight (Q-TOF) mass spectrometry for quantitation and identification of target OXLAMs in plasma (6). DIETARY N-3 PUFA CHANGES AND BRAIN FIFTEEN WEEKS OF DIETARY N-3 POLYUNSATURATED FATTY ACID DEPRIVATION INCREASE TURNOVER OF N-6 DOCOSAPENTAENOIC ACID IN RAT-BRAIN PHOSPHOLIPIDS. Docosapentaenoic acid (DPAn-6, 22:5n-6) is an n-6 polyunsaturated fatty acid (PUFA) whose brain concentration can be increased in rodents by dietary n-3 PUFA deficiency, which may contribute to their behavioral dysfunction. We used our in vivo intravenous infusion method to see if brain DPAn-6 turnover and metabolism also were altered with n-3 PUFA deprivation. We studied male rats that had been fed for 15 weeks post-weaning an n-3 PUFA adequate diet containing 4.6% alpha-linolenic acid (alpha-LNA, 18:3n-3) or a deficient diet (0.2% alpha-LNA), each lacking docosahexaenoic acid (22:6n-3) and arachidonic acid (AA, 20:4n-6). 1-(14)CDPAn-6 was infused intravenously for 5 min in unanesthetized rats, after which the brain underwent high-energy microwaving, and was analyzed. The n-3 PUFA deficient compared with adequate diet increased DPAn-6 and decreased DHA concentrations in plasma and brain, while minimally changing brain AA concentration. Incorporation rates of unesterified DPAn-6 from plasma into individual brain phospholipids were increased 5.2-7.7 fold, while turnover rates were increased 2.1-4.7 fold. Increased brain metabolism and concentrations of DPAn-6 and its metabolites, together with a reduced brain DHA concentration, likely contribute to behavioral and functional abnormalities with dietary n-3 PUFA deprivation in rodents. (2) REGULATION OF RAT BRAIN POLYUNSATURATED FATTY ACID (PUFA) METABOLISM DURING GRADED DIETARY N-3 PUFA DEPRIVATION. Most rodent studies of dietary PUFA deprivation compare a PUFA-adequate diet with a diet with extreme and likely not clinically relevant PUFA concentration reductions. Knowing threshold changes in brain lipids and lipid enzymes during dietary deprivation can elucidate regulation processes of brain lipid metabolism, and identify whether brain changes with inadequate diets routinely studied are clinically relevant. To determine thresholds with n-3 PUFA deprivation, rats were fed for 15 weeks DHA-free diets having graded reductions of its precursor α-linolenic acid (alpha-LNA, 18:3n-3). Compared with control diet (4.6% alpha-LNA), plasma DHA fell significantly at 1.7% dietary alpha-LNA. Brain DHA remained unchanged down to 0.8% alpha-LNA, when plasma and brain docosapentaenoic acid (DPAn-6) were increased and DHA-selective iPLA2 and COX-1 activities were downregulated. Brain AA was unchanged by deprivation, but AA selective-cPLA2, sPLA2 and COX-2 activities were increased at or below 0.8% dietary α-LNA, likely in response to elevated brain DPAn-6. Homeostatic mechanisms appear to maintain a control brain DHA concentration down to 0.8% dietary alpha-LNA, despite reduced plasma DHA, when DPAn-6 replaces DHA. At extreme deprivation, decreased brain iPLA2 and COX-1 activities likely reduce brain DHA loss. A review of the literature indicates that extreme deprivation does not appear to occur in the human conditions (3).

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Keleshian, Vasken L; Kellom, Matthew; Kim, Hyung-Wook et al. (2014) Neuropathological responses to chronic NMDA in rats are worsened by dietary n-3 PUFA deprivation but are not ameliorated by fish oil supplementation. PLoS One 9:e95318
Bondi, Corina O; Taha, Ameer Y; Tock, Jody L et al. (2014) Adolescent behavior and dopamine availability are uniquely sensitive to dietary omega-3 fatty acid deficiency. Biol Psychiatry 75:38-46
Rapoport, Stanley I (2013) Translational studies on regulation of brain docosahexaenoic acid (DHA) metabolism in vivo. Prostaglandins Leukot Essent Fatty Acids 88:79-85
Yuan, Zhi-Xin; Rapoport, Stanley I; Soldin, Steven J et al. (2013) Identification and profiling of targeted oxidized linoleic acid metabolites in rat plasma by quadrupole time-of-flight mass spectrometry. Biomed Chromatogr 27:422-32
Igarashi, Miki; Chang, Lisa; Ma, Kaizong et al. (2013) Kinetics of eicosapentaenoic acid in brain, heart and liver of conscious rats fed a high n-3 PUFA containing diet. Prostaglandins Leukot Essent Fatty Acids 89:403-12
Igarashi, Miki; Kim, Hyung-Wook; Gao, Fei et al. (2012) Fifteen weeks of dietary n-3 polyunsaturated fatty acid deprivation increase turnover of n-6 docosapentaenoic acid in rat-brain phospholipids. Biochim Biophys Acta 1821:1235-43
Igarashi, Miki; Kim, Hyung-Wook; Chang, Lisa et al. (2012) Dietary n-6 polyunsaturated fatty acid deprivation increases docosahexaenoic acid metabolism in rat brain. J Neurochem 120:985-97
Ramsden, Christopher E; Ringel, Amit; Feldstein, Ariel E et al. (2012) Lowering dietary linoleic acid reduces bioactive oxidized linoleic acid metabolites in humans. Prostaglandins Leukot Essent Fatty Acids 87:135-41
Kim, Hyung-Wook; Rao, Jagadeesh S; Rapoport, Stanley I et al. (2011) Regulation of rat brain polyunsaturated fatty acid (PUFA) metabolism during graded dietary n-3 PUFA deprivation. Prostaglandins Leukot Essent Fatty Acids 85:361-8
Kim, Hyung-Wook; Rao, Jagadeesh S; Rapoport, Stanley I et al. (2011) Dietary n-6 PUFA deprivation downregulates arachidonate but upregulates docosahexaenoate metabolizing enzymes in rat brain. Biochim Biophys Acta 1811:111-7

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