Omega-3 PUFA derived anti-inflammatory lipid mediator resolvin E1

Inflammation is a defensive response to injury and infection, but excessive or inappropriate inflammation contributes to a range of acute and chronic human diseases. Clinical assessment of dietary supplementation of omega-3 polyunsaturated fatty acids (PUFA) including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) indicate their beneficial impact on human diseases in which inflammation is suspected as a key component of the pathogenesis. Although the mechanism of EPA and DHA action is still not fully defined in molecular terms, recent studies have revealed that, during the course of acute inflammation, omega-3 PUFA-derived mediators including resolvins and protectins with potent anti-inflammatory and pro-resolving properties are produced. In this review, we provide an overview of the formation and actions of EPA-derived anti-inflammatory lipid mediator resolvin E1.     

n-3脂肪酸代谢产物抗炎作用的研究进展

炎症反应是机体正常组织对感染和损伤的应答,然而过度的炎症反应往往会引起急性和慢性疾病的发生.最近研究发现,由n-3多不饱和脂肪酸二十碳五烯酸和二十二碳六烯酸代谢产生的resolvins和protectins两类化合物,具有很强的抗炎和炎症修复活性.综述了resolvins和protectin D1的来源、抗炎作用和抗炎机制,为进一步开展n-3多不饱和脂肪酸及其代谢产物的抗炎作用研究、为炎症的防治提供新的思路.     

Maternal dietary omega-3 fatty acid intake increases resolvin and protectin levels in the rat placenta

Placental inflammation is associated with several pregnancy disorders. Inflammation is limited by anti-inflammatory and proresolving mechanisms, the latter partly mediated by resolvins and protectins derived from omega-3 polyunsaturated fatty acids (n-3PUFA). We examined effects of dietary n-3PUFAs on levels of resolvins, protectins, and lipoxygenase (ALOX) enzymes in the rat placenta. Rats consumed standard (Std) or high n-3PUFA (Hn3) diets from day 1 of pregnancy; tissues were collected on day 17 or 22 (term = day 23). Maternal Hn3 diet increased resolvin and protectin precursors, 18R/S-HEPE (P < 0.001), and 17R/S-HDHA (P < 0.01) at both days. Resolvins (17R-RvD1 and RvD1) increased at day 22 (P < 0.001) after Hn3 consumption, coincident with higher Alox15b and Alox5 mRNA expression, while RvD2 increased at both days (P < 0.05). Protectins, PD1, and 10S,17S-DiHDHA increased over late gestation (P < 0.001), coincident with higher Alox15 mRNA expression (P < 0.001) and further increased with Hn3 diet (P < 0.05). Maternal systemic and placental proinflammatory mediators were not suppressed by Hn3 diet; systemic IL1β, placental Il1β, and Il6 mRNA expression increased marginally with Hn3 at day 22 (P < 0.001), while Ptgs1 (Cox1) expression increased both days (P < 0.05). Our data indicate that maternal n-3PUFA supplementation enhances expression of enzymes in the n-3PUFA metabolic pathway and increases placental levels of resolvins and protectins.     

Rainbow trout (Oncorhynchus mykiss) brain cells biosynthesize novel docosahexaenoic acid-derived resolvins and protectins-Mediator lipidomic analysis

Docosahexaenoic acid (DHA; C22:6 n-3) is an abundant fatty acid in fish phospholipids. In the present study, we employed liquid chromatography-ultraviolet spectrometry-tandem mass spectrometry and dissociated rainbow trout (Oncorhynchus mykiss) brain cells to determine whether fish utilize endogenous DHA to produce the recently uncovered novel lipid mediators termed the resolvins and protectins, generated by mammalian cells [Serhan CN, Hong S, Gronert K, et al. Resolvins: a family of bioactive products of omega-3 fatty acid transformation circuits initiated by aspirin treatment that counter proinflammation signals. J Exp Med 2002; 196:1025-37; Hong S, Gronert K, Devchand P, Moussignac R-L, Serhan, CN. Novel docosatrienes and 17S-resolvins generated from docosahexaenoic acid in murine brain, human blood, and glial cells. J Biol Chem 2003;278:14677-87]. Trout brain cells biosynthesize a range of recently identified di- and tri-hydroxy-containing bioactive products from endogenous sources of DHA when challenged in vitro. We identified neuroprotectin D1, resolvin D5, resolvin D1 and resolvin D2 from trout brain cells. Each compound was identified on the basis of its characteristic physical chemical properties that included MS, MS-MS, UV spectra and chromatographic behavior. The monohydroxy products from DHA, signatures of DHA conversion by lipoxygenases, were also identified. These included both 14S-hydroxy-docosahexaenoic acid and 17S-hydroxy-docosahexaenoic acid. The biosynthesis of these novel bioactive lipid mediators, namely resolvins and protectins, by fish cells provides the first evidence for the conservation of these structures from fish to humans as chemical signals in diverse biological systems.     

Grouping Newly Isolated Docosahexaenoic Acid-Producing Thraustochytrids Based on Their Polyunsaturated Fatty Acid Profiles and Comparative Analysis of 18S rRNA Genes

Seven strains of marine microbes producing a significant amount of docosahexaenoic acid (DHA; C22:6, n-3) were screened from seawater collected in coastal areas of Japan and Fiji. They accumulate their respective intermediate fatty acids in addition to DHA. There are 5 kinds of polyunsaturated fatty acid (PUFA) profiles which can be described as (1) DHA/docosapentaenoic acid (DPA; C22:5, n-6), (2) DHA/DPA/eicosapentaenoic acid (EPA; C20:5, n-3), (3) DHA/EPA, (4) DHA/DPA/EPA/arachidonic acid (AA; C20:4, n-6), and (5) DHA/DPA/EPA/AA/docosatetraenoic acid (C22:4, n-6). These isolates are proved to be new thraustochytrids by their specific insertion sequences in the 18S rRNA genes. The phylogenetic tree constructed by molecular analysis of 18S rRNA genes from the isolates and typical thraustochytrids shows that strains with the same PUFA profile form each monophyletic cluster. These results suggest that the C20-22 PUFA profile may be applicable as an effective characteristic for grouping thraustochytrids.     

Old and new generation lipid mediators in acute inflammation and resolution

Originally regarded as just membrane constituents and energy storing molecules, lipids are now recognised as potent signalling molecules that regulate a multitude of cellular responses via receptor-mediated pathways, including cell growth and death, and inflammation/infection. Derived from polyunsaturated fatty acids (PUFAs), such as arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), each lipid displays unique properties, thus making their role in inflammation distinct from that of other lipids derived from the same PUFA. The diversity of their actions arises because such metabolites are synthesised via discrete enzymatic pathways and because they elicit their response via different receptors. This review will collate the bioactive lipid research to date and summarise the findings in terms of the major pathways involved in their biosynthesis and their role in inflammation and its resolution. It will include lipids derived from AA (prostanoids, leukotrienes, 5-oxo-6,8,11,14-eicosatetraenoic acid, lipoxins and epoxyeicosatrienoic acids), EPA (E-series resolvins), and DHA (D-series resolvins, protectins and maresins).     

Docosahexaenoic acid synthesis from alpha-linolenic acid is inhibited by diets high in polyunsaturated fatty acids

The conversion of the plant-derived omega-3 (n-3) α-linolenic acid (ALA, 18:3n-3) to the long-chain eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3) can be increased by ALA sufficient diets compared to ALA deficient diets. Diets containing ALA above an optimal level result in no further increase in DHA levels in animals and humans. The present study evaluates means of maximizing plasma DHA accumulation by systematically varying both linoleic acid (LA, 18:2n-6) and ALA dietary level. Weanling rats were fed one of 54 diets for three weeks. The diets varied in the percentage of energy (en%) of LA (0.07–17.1 en%) and ALA (0.02–12.1 en%) by manipulating both the fat content and the balance of vegetable oils. The peak of plasma phospholipid DHA (>8% total fatty acids) was attained as a result of feeding a narrow dietary range of 1–3 en% ALA and 1–2 en% LA but was suppressed to basal levels (～2% total fatty acids) at dietary intakes of total polyunsaturated fatty acids (PUFA) above 3 en%. We conclude it is possible to enhance the DHA status of rats fed diets containing ALA as the only source of n-3 fatty acids but only when the level of dietary PUFA is low (<3 en%).     

Cloning and functional characterisation of a fatty acyl elongase from southern bluefin tuna (Thunnus maccoyii)

The synthesis of long chain polyunsaturated fatty acids (LCPUFA), such as eicosapentaenoic acid (EPA; 20:5n-3) and docosahexaenoic acid (DHA; 22:6n-3), involves fatty acyl desaturase and elongase enzymes. The marine fish species southern bluefin tuna (SBT) can accumulate large quantities of omega-3 (n-3) LCPUFA in its flesh but their capacity to synthesize EPA and DHA is uncertain. A cDNA, sbtElovl5, encoding a putative fatty acyl elongase was amplified from SBT liver tissue. The cDNA included an open reading frame (ORF) encoding 294 amino acids. Sequence comparisons and phylogenetic analyses revealed a high level of sequence conservation between sbtElovl5 and fatty acyl elongase sequences from other fish species. Heterologous expression of the sbtElovl5 ORF in Saccharomyces cerevisiae confirmed that it encoded a fatty acyl elongase capable of elongating C_18/20 polyunsaturated fatty acid (PUFA) substrates, but not C₂₂ PUFA substrates. For the first time in an Elovl5, the substrate competition occurring in nature was investigated. Higher activity towards n-3 PUFA substrates than omega-6 (n-6) PUFA substrates was exhibited, regardless of substrate chain length. The sbtElovl5 preferentially elongated 18:4n-3 and 18:3n-6 rather than 20:5n-3 and 20:4n-6. The sbtElovl5 enzyme also elongated saturated and monounsaturated fatty acids.     

Differences in dietary and plasma fatty acids between wild and captive populations of a rare reptile, the tuatara (Sphenodon punctatus)

Tuatara (Sphenodon) are rare reptiles endemic to New Zealand. Wild tuatara on Stephens Island (study population) prey on insects as well as the eggs and chicks of a small nesting seabird, the fairy prion (Pachyptila turtur). Tuatara in captivity (zoos) are fed diets containing different insects and lacking seabirds. We compared the fatty acid composition of major dietary items and plasma of wild and captive tuatara. Fairy prions (eaten by tuatara in the wild) were rich in C20 and C22 polyunsaturated fatty acids (PUFA), especially the n-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). In contrast, items from the diet of captive tuatara contained no C20 and C22 PUFA and were higher in medium-chain and less unsaturated fatty acids. Plasma from wild tuatara was higher in n-3 PUFA [including alpha-linoleic acid (C18:3n-3), EPA and DHA], and generally lower in oleic acid (C18:1) and palmitic acid (C16:0), than plasma from captive tuatara in the various fractions (phospholipid, triacylglycerol, cholesterol ester and free fatty acids). Plasma from wild adult tuatara showed strong seasonal variation in fatty acid composition, reflecting seasonal consumption of fairy prions. Differences in the composition of diets and plasma between wild and captive tuatara may have consequences for growth and reproduction in captivity. Accepted: 3 August 1998     

Effects of essential fatty acid deficiency and supplementation with docosahexaenoic acid (DHA; 22:6n-3) on cellular fatty acid compositions and fatty acyl desaturation in a cell culture model

The desaturation of [1-(14)C] 18:3n-3 to docosahexaenoic acid (DHA; 22:6n-3) is enhanced in an essential fatty acid deficient cell line (EPC-EFAD) in comparison with the parent cell line (EPC) from carp. In the present study, the effects of DHA on lipid and fatty acid compositions, and the metabolism of [1-(14)C]18:3n-3 were investigated in EPC-EFAD cells in comparison with EPC cells. DHA supplementation had only relatively minor effects on lipid content and lipid class compositions in both EPC and EPC-EFAD cells, but significantly increased the amount of DHA, 22:5n-3, eicosapentaenoic acid (EPA; 20:5n-3), total n-3 polyunsaturated fatty acids (PUFA), total PUFA and saturated fatty acids in total lipid and total polar lipid in both cell lines. Retroconversion of supplemental DHA to EPA was significantly greater in EPC cells. Monounsaturated fatty acids, n-9 and n-6PUFA were all decreased in total lipid and total polar lipid in both cell lines by DHA supplementation. The incorporation of [1-(14)C]18:3n-3 was greater into EPC-EFAD compared to EPC cells but DHA had no effect on the incorporation of [1-(14)C]18:3n-3 in either cell line. In contrast, the conversion of [1-(14)C]18:3n-3 to tetraenes, pentaenes and total desaturation products was similar in the two cell lines and was significantly reduced by DHA supplementation in both cell lines. However, the production of DHA from [1-(14)C]18:3n-3 was significantly greater in EPC-EFAD cells compared to EPC cells and, whereas DHA supplementation had no effect on the production of DHA from [1-(14)C]18:3n-3 in EPC cells, DHA supplementation significantly reduced the production of DHA from [1-(14)C] 18:3n-3 in EPC-EFAD cells. Greater production of DHA in EPC-EFAD cells could be a direct result of significantly lower levels of end-product DHA in these cells' lipids compared to EPC cells. Consistent with this, the suppression of DHA production upon DHA supplementation was associated with increased cellular and membrane DHA concentrations in EPC-EFAD cells. However, an increase in cellular DHA content to similar levels failed to suppress DHA production in DHA-supplemented EPC cells. A possible explanation is that greatly increased levels of EPA, derived from retroconversion of the added DHA, acts to offset the suppression of the pathway by DHA by stimulating conversion of EPA to DHA in DHA-supplemented EPC cells.     

Effect of frozen storage on fatty acid composition and changes in lipid content of Scomberomorus commersoni and Carcharhinus dussumieri

Investigated were the changes in fatty acid composition, oxidation and enzymatic deterioration of lipids in frozen (−30°C) fish fillets from the Persian Gulf. The narrow barred Spanish mackerel ( Scomberomorus commersoni ) and white cheek shark ( Carcharhinus dussumieri ) were tested with storage times of 0, 1, 2, 3, 4, 5 and 6 months at −18°C. Statistical results showed that the major fatty acids among the saturated and monounsaturated fatty acids of each fish species were palmitic (C16:0) and oleic (C18:1n-9) acids, respectively. Both linoleic acid (C18:2n-6) and arachidonic acid (AA) (C20:4n-6) were predominant in total n-6 polyunsaturated fatty acids in both mackerel and shark. The EPA (eicosapentaenoic acid; C20:5 n-3) and DHA (docosahexaenoic acid; C22:6 n-3) acids were the major fatty acids among total n-3 acids in both fishes. During frozen storage, the PUFA (40.1 and 23.94%), n-3 (48 and 42.83%), ω 3/ ω 6 (41.36 and 50%), PUFA/SFA (56 and 42.23%) and EPA + DHA/C16 (55.55 and 46.66%) contents decreased in S. commersoni and C. dussumieri , respectively. Also peroxide, thiobarbituric acid (TBA) and free fatty acid (FFA) values significantly increased (P < 0.01) with the time of storage.     

Half-lives of docosahexaenoic acid in rat brain phospholipids are prolonged by 15 weeks of nutritional deprivation of n-3 polyunsaturated fatty acids

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 alpha-linolenic acid (alpha-LNA; 18 : 3n-3). After 15 weeks on a diet, [4,5-3H]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 log10 (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, Jout, 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.     

Short-term n-3 fatty acid supplementation but not aspirin increases plasma proresolving mediators of inflammation

Resolution of inflammation is an active process involving specialized proresolving mediators (SPM) formed from the n-3 fatty acids. This study examined the effect of n-3 fatty acid supplementation and aspirin on plasma SPMs in healthy humans. Healthy volunteers (n = 21) were supplemented with n-3 fatty acids (2.4g/day) for 7 days with random assignment to take aspirin (300 mg/day) or placebo from day 5 to day 7. Blood was collected at baseline (day 0), day 5, and day 7. Plasma 18R/S-HEPE, E-series resolvins, 17R/S-HDHA, D-series resolvins, 14R/S-HDHA, and MaR-1 were measured by LC/MS/MS. At baseline concentrations of E- and D- series resolvins and the upstream precursors 18R/S-HEPE, 17R/S-HDHA ranged from 0.1nM to 0.2nM. 14R/S-HDHA was 3-fold higher than the other SPMs at baseline but MaR-1 was below the limit of detection. Supplementation with n-3 fatty acids significantly increased RvE1, 18R/S-HEPE, 17R/S-HDHA, and 14R/S-HDHA but not other SPMs. The addition of aspirin after 5 days of n-3 fatty acids did not affect concentrations of any SPM. N-3 fatty acid supplementation for 5 days results in concentrations of SPMs that are biologically active in healthy humans. Aspirin administered after n-3 fatty acids did not offer any additional benefit in elevating the levels of SPMs.     

The role of marine omega-3 (n-3) fatty acids in inflammatory processes, atherosclerosis and plaque stability

Atherosclerosis has an important inflammatory component and acute cardiovascular events can be initiated by inflammatory processes occurring in advanced plaques. Fatty acids influence inflammation through a variety of mechanisms; many of these are mediated by, or associated with, the fatty acid composition of cell membranes. Human inflammatory cells are typically rich in the n-6 fatty acid arachidonic acid, but the contents of arachidonic acid and of the marine n-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) can be altered through oral administration of EPA and DHA. Eicosanoids produced from arachidonic acid have roles in inflammation. EPA also gives rise to eicosanoids and these are usually biologically weak. EPA and DHA give rise to resolvins which are anti-inflammatory and inflammation resolving. EPA and DHA also affect production of peptide mediators of inflammation (adhesion molecules, cytokines, etc.). Thus, the fatty acid composition of human inflammatory cells influences their function; the contents of arachidonic acid, EPA and DHA appear to be especially important. The anti-inflammatory effects of marine n-3 polyunsaturated fatty acids (PUFAs) may contribute to their protective actions towards atherosclerosis and plaque rupture.     

许氏平鲉发育早期的氨基酸与脂肪酸组成及变化

为了研究许氏平鲉(Sebastes schlegelii)雌鱼体内受精后仔鱼开口前和仔鱼开口后两个阶段氨基酸和脂肪酸的组成变化规律, 采用生化常规方法定量测定并分析了许氏平鲉发育早期的受精卵(FE)、胚胎期(ES)、初产仔鱼(PL₁)、前仔鱼期(PL₂)、后仔鱼期(PL₃)和稚鱼期(J)6个阶段的氨基酸和脂肪酸组成特点及含量变动。结果表明: 总氨基酸含量从FE至PL₁显著下降, 至PL₃显著上升, 至J又显著下降(P<0.05); 游离氨基酸含量以FE最低(12.77 mg/g), 从FE到PL₁显著上升(P<0.05), 并在PL₁含量达到最高值(92.19 mg/g), PL₁发育到J呈现先下降后上升再下降的变化趋势(P<0.05), 游离氨基酸与总氨基酸的比值范围在2.37%—19.66%。在各发育阶段干样中检出碳链长度在C₁₄-C₂₄的29种脂肪酸, 分别为9种饱和脂肪酸(SFA)、9种单不饱和脂肪酸(MUFA)和11种多不饱和脂肪酸为(PUFA), 受精卵中主要脂肪酸依次为C_22:6n-3(DHA)、C_18:ln-9c、C_16:0和C_20:5n-3(EPA)。胚胎期(FE-ES)的脂肪酸利用率顺序为SFA、MUFA、n-6PUFA、n-3PUFA, 主要以C_18:3n-3、C_18:0、C_16:1n-7及C_20:5n-3(EPA)作为胚胎期的能量来源, C_22:6n-3(DHA)的实际利用率最低(9.71%), 被优先保存下来, C_16:0的实际利用量最高(10.94mg/g); 仔鱼内源营养阶段(ES-PL₁)脂肪酸利用率顺序为MUFA、n-6PUFA、SFA、n-3PUFA, 主要以C_16:1n-7、C_18:0、C_20:4n-6(ARA)及C_18:1n-9c作为开口前仔鱼的主要能量来源, 其中仔鱼对DHA实际利用量最高(18.23 mg/g)。PL₁-PL₃阶段DHA相对于EPA和ARA被选择性利用; PL₃至J阶段ARA相对于EPA和DHA被选择性利用。研究表明: 许氏平鲉仔鱼开口前阶段总氨基酸含量与游离氨基酸含量的变化趋势截然相反, 胚胎期与仔鱼内源营养阶段脂肪酸利用率和利用量均有所不同, 仔鱼期DHA优先被利用, 过渡至稚鱼期ARA优先被利用。建议在仔鱼开口后添加富含DHA生物性饵料, 仔鱼过渡到稚鱼期在配合饵料中添加ARA营养物质, 防止苗种营养不足, 保证成活率。     

Polyunsaturated fatty acid profiles of whole body phospholipids and triacylglycerols in anadromous and landlocked Atlantic salmon (Salmo salar L.) fry

We compared the fatty acid compositions and gains of whole body triacylglycerols (TAG) and phospholipids (PL) in anadromous and landlocked Atlantic salmon (Salmo salar) fry, of the same age, fed the same commercial marine oil-rich diet over a 42-day feeding trial. The landlocked strain exhibited significantly (P<0.05) higher growth rate and feed efficiency, due principally to a higher fat retention, particularly of monounsaturated and saturated fatty acids (SFA). n-3 and n-6 long-chain polyunsaturated fatty acid (PUFA) gains and retentions were significantly higher (P<0.05) in the landlocked fry. Great similarities were found in the fatty acid profiles of whole body TAG of both strains. However, marked genotypic differences were observed in the PUFA profiles of whole body PL fractions. The total PUFA, n-3 PUFA and docosahexaenoic acid (DHA) level in PL was significantly higher (P<0.05) while the SFA level, and the PUFA C18/C20 and eicosapentaenoic acid/arachidonic acid ratios were significantly lower (P<0.05) in the anadromous fry than in landlocked fry. Our results indicate that the level of DHA in salmon PL is under strong genetic control and that the capacity for incorporation, and possibly for the conversion of dietary n-3 and n-6 PUFA, is higher in the landlocked strain.     

Docosahexaenoic acid synthesis from alpha-linolenic acid by rat brain 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 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% 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-(14)C]alpha-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-(14)C]alpha-LNA entering brain was converted to DHA with 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, and can be upregulated by the deficient diet, DHA converted by the liver from circulating alphaLNA is the source of the brain's DHA when DHA is not in the diet.