DIETARY OMEGA-6 FATTY ACID LOWERING INCREASES THE BIOAVAILABILITY OF PLASMA OMEGA-3 FATTY ACIDS IN HUMAN PLASMA LIPID POOLS. Dietary linoleic acid (LA, 18:2n-6) lowering in rats reduces n-6 polyunsaturated fatty acid (PUFA) plasma concentrations and increases n-3 PUFA (eicosapentaenoic (EPA) and docosahexaenoic acid (DHA)) concentrations. OBJECTIVE: To evaluate the extent to which 12 weeks of dietary n-6 PUFA lowering, with or without increased dietary n-3 PUFAs, alters unesterified and esterified plasma n-6 and n-3 PUFA concentrations in subjects with chronic headache. DESIGN: Secondary analysis of a randomized trial. Subjects with chronic headache were randomized for 12 weeks to (1) average n-3, low n-6 (L6) diet;or (2) high n-3, low n-6 LA (H3-L6) diet. Esterified and unesterified plasma fatty acids were quantified at baseline (0 weeks) and after 12 weeks on a diet. RESULTS: Compared to baseline, the L6 diet reduced esterified plasma LA and increased esterified n-3 PUFA concentrations (nmol/ml), but did not significantly change plasma arachidonic acid (AA, 20:4n-6) concentration. In addition, unesterified EPA concentration was increased significantly among unesterified fatty acids. The H3-L6 diet decreased esterified LA and AA concentrations, and produced more marked increases in esterified and unesterified n-3 PUFA concentrations. CONCLUSION: Dietary n-6 PUFA lowering for 12 weeks significantly reduces LA and increases n-3 PUFA concentrations in plasma, without altering plasma AA concentration. A concurrent increase in dietary n-3 PUFAs for 12 weeks further increases n-3 PUFA plasma concentrations and reduces AA. (1) SYSTEMS FRAMEWORK FOR TRPV1 MODULATION BY LIPID-AUTACOIDS BASED ON TRANSCRIPTOMICS. PRECURSOR FATTY ACIDS AND FUNCTIONAL ACTIVATION. The TRPV1 (transient receptor potential cation) channel is involved in detecting temperature and pain. Important gaps remain in our understanding of TRPV1 modulation by endogenously produced lipid-autacoids known as endovanilloids. In the present study, two families of candidate endovanilloids were observed to produce different effects on TRPV1 activation. While N-acylethanolamines acted as TRPV1 agonists, monohydroxy fatty acids demonstrated no TRPV1 activity under basal conditions, but positively modulated TRPV1 activation by N-acylethanolamines, low pH, and the exogenous TRPV1 ligand capsaicin. Both the lipid-autacoid transcriptomes and biosynthetic precursor fatty acid compositions of glabrous skin, dorsal root/trigeminal ganglia, and spinal cord displayed strong tissue-specific signatures. Dietary intervention markedly altered the composition of fatty acid endovanilloid biosynthetic precursor pools. These data demonstrate the tissue-specific participation of lipid-related gene networks, modification of precursor pools by diet and form an integrative framework for TRPV1 activation through the concerted actions of lipid-autacoids with agonist and positive modulatory functions. This work has been submitted for publication. QUANTIFYING HEPATIC SECRETION OF DOCOSAHEXAENOIC ACID (DHA) IN HUMANS. DHA is a polyunsaturated a fatty acid enriched in brain tissue that has important structural and signaling implications for addictive disorders and neurological function. Rodent data and human trials suggest that dietary omega-6 linoleic acid interferes with liver synthesis-secretion of omega-3 DHA. Therefore high omega-6 linoleic acid diets may contribute to deficits in omega-3 DHA, leading to suboptimal neurological function. A reduction in dietary omega-6 linoleic acid may increase liver synthesis-secretion and tissue accumulation of omega-3 DHA from its dietary precursor omega-3 alpha-linolenic acid (LNA). To test this, we plan to use the BPMS established infusion method and model to quantify liver synthesis-secretion rates of long-chain omega-3 polyunsaturated fatty acids, (omega-3 EPA and DHA) from circulating unesterified omega-3 LNA in humans consuming an average US diet for 12 weeks. We are initiating an IRB approved protocol that requires a 22-hour hospital admission to the NIAAA inpatient unit, including an 8-hour infusion of d5-LNA with serial blood draws and LC/GC analysis. The primary outcome will be the liver synthesis-secretion rate of d5-DHA from infused d5-LNA. PUFAS IN BIPOLAR DISORDER. Several publication indicate a distortion of plasma concentrations of n-3 and n-6 polyunsaturated fatty acids (PUFAs) and their metabolites in bipolar disorder, possibly related to general neuroinflammatory risk. We have initiated a collaboration with Dr. Erika Saunders at Penn State School of Medicine at Hershey to measure plasma concentrations of esterified and unesterified PUFAs and other fatty acids in patients with bipolar disorder and in controls in relation to diet and drug history. We have received and analyzed blinded plasma samples from Dr. Saunders, and have sent her the blinded concentration measurements. In addition, with Dr. Saunders and Dr. Christopher Ramsden at the NIAAA, we are initiating a clinical trial to test whether a high n-3 low n-6 diet will be beneficial in patients with bipolar disorder.

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Saunders, Erika Fh; Reider, Aubrey; Singh, Gagan et al. (2015) Low unesterified:esterified eicosapentaenoic acid (EPA) plasma concentration ratio is associated with bipolar disorder episodes, and omega-3 plasma concentrations are altered by treatment. Bipolar Disord 17:729-42
Ramsden, Christopher E; Faurot, Keturah R; Zamora, Daisy et al. (2015) Targeted alterations in dietary n-3 and n-6 fatty acids improve life functioning and reduce psychological distress among patients with chronic headache: a secondary analysis of a randomized trial. Pain 156:587-96
Liu, Joanne J; Green, Pnina; John Mann, J et al. (2015) Pathways of polyunsaturated fatty acid utilization: implications for brain function in neuropsychiatric health and disease. Brain Res 1597:220-46
Taha, Ameer Y; Cheon, Yewon; Faurot, Keturah F et al. (2014) Dietary omega-6 fatty acid lowering increases bioavailability of omega-3 polyunsaturated fatty acids in human plasma lipid pools. Prostaglandins Leukot Essent Fatty Acids 90:151-7
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
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