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Concept: Arachidonic acid

213

Long chain polyunsaturated fatty acids (LCPUFA) are bioactive components of membrane phospholipids and serve as substrates for signaling molecules. LCPUFA can be obtained directly from animal foods or synthesized endogenously from 18 carbon precursors via the FADS2 coded enzyme. Vegans rely almost exclusively on endogenous synthesis to generate LCPUFA and we hypothesized that an adaptive genetic polymorphism would confer advantage. The rs66698963 polymorphism, a 22-bp insertion-deletion within FADS2, is associated with basal FADS1 expression, and coordinated induction of FADS1 and FADS2 in vitro. Here, we determined rs66698963 genotype frequencies from 234 individuals of a primarily vegetarian Indian population and 311 individuals from the US. A much higher I/I genotype frequency was found in Indians (68%) than in the US (18%). Analysis using 1000 Genomes Project data confirmed our observation, revealing a global I/I genotype of 70% in South Asians, 53% in Africans, 29% in East Asians, and 17% in Europeans. Tests based on population divergence, site frequency spectrum, and long-range haplotype consistently point to positive selection encompassing rs66698963 in South Asian, African, and some East Asian populations. Basal plasma phospholipid arachidonic acid (ARA) status was 8% greater in I/I compared with D/D individuals. The biochemical pathway product-precursor difference, ARA minus linoleic acid, was 31% and 13% greater for I/I and I/D compared with D/D, respectively. This study is consistent with previous in vitro data suggesting that the insertion allele enhances n-6 LCPUFA synthesis and may confer an adaptive advantage in South Asians because of the traditional plant-based diet practice.

Concepts: Genetics, Allele, Fatty acid, Fatty acids, Essential fatty acid, Omega-6 fatty acid, Linoleic acid, Arachidonic acid

169

BACKGROUND: The objective of this study was to evaluate the mediating role of maternal early pregnancy plasma levels of long chain polyunsaturated fatty acids (LCPUFAs) in the association of interpregnancy interval (IPI) with birth weight and smallness for gestational age (SGA) at birth. METHODS: We analysed a subsample of the Amsterdam Born Children and their Development (ABCD) cohort, comprising 1,659 parous pregnant women recruited between January 2003 and March 2004. We used linear and logistic regression to evaluate the associations between fatty acid status, interpregnancy interval and pregnancy outcome. RESULTS: Low plasma phospholipids concentrations of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and dihomo-gamma-linolenic acid (DGLA), and high concentrations of arachidonic acid (AA) during early pregnancy were associated with reduced birth weight and/or an increased risk of SGA. Short IPIs (< 6 months, with 18--23 months as a reference) were associated with a mean decrease of 207.6 g (SE: +/- 73.1) in birth weight (p = 0.005) and a twofold increased risk of SGA (OR: 2.05; CI: 0.93--4.51; p = 0.074). Adjustment for maternal fatty acid concentrations did not affect these results to any meaningful extent. CONCLUSIONS: Despite the observed association of maternal early pregnancy LCPUFA status with birth weight and SGA, our study provides no evidence for the existence of an important role of maternal EPA, DHA, DGLA or AA in the association of short interpregnancy intervals with birth weight and SGA.

Concepts: Fatty acid, Fatty acids, Essential fatty acid, Eicosapentaenoic acid, Omega-6 fatty acid, Linoleic acid, Arachidonic acid, Polyunsaturated fatty acid

167

BACKGROUND & AIMS: The endocannabinoid and eicosanoid lipid signaling pathways have important roles in inflammatory syndromes. Monoacylglycerol lipase (MAGL) links these pathways, hydrolyzing the endocannabinoid 2-arachidonoylglycerol to generate the arachidonic acid precursor pool for prostaglandin production. We investigated whether blocking MAGL protects against inflammation and damage from hepatic ischemia/reperfusion (I/R) and other insults. METHODS: We analyzed the effects of hepatic I/R in mice given the selective MAGL inhibitor JZL184, in Mgll-/-mice, FAAH-/- mice, and in Cnr1(-/-)and Cnr2(-/-)mice, which have disruptions in the cannabinoid receptors 1 and 2 (CB(½)). Liver tissues were collected and analyzed, along with cultured hepatocytes and Kupffer cells. We measured endocannabinoids, eicosanoids, and markers of inflammation, oxidative stress, and cell death using molecular biology, biochemistry, and mass spectrometry analyses. RESULTS: Wild-type mice given JZL184 and Mgll-/- mice were protected from hepatic I/R injury by a mechanism that involved increased endocannabinoid signaling via CB(2) and reduced production of eicosanoids in the liver. JZL184 suppressed the inflammation and oxidative stress that mediate hepatic I/R injury. Hepatocytes were the major source of hepatic MAGL activity and endocannabinoid and eicosanoid production. JZL184 also protected from induction of liver injury by D-(+)-galactosamine and lipopolysaccharides or CCl(4). CONCLUSIONS: MAGL promotes hepatic injury via endocannabinoid and eicosanoid signaling; blockade of this pathway protects mice from liver injury. MAGL inhibitors might be developed to treat for conditions that expose the liver to oxidative stress and inflammatory damage.

Concepts: Inflammation, Liver, Lipid, Eicosanoid, Prostaglandin, Leukotriene, Arachidonic acid, Monoacylglycerol lipase

148

Within the secreted phospholipase A2 (sPLA2) family, group X sPLA2 (sPLA2-X) has the highest capacity to hydrolyze cellular membranes and has long been thought to promote inflammation by releasing arachidonic acid (AA), a precursor of pro-inflammatory eicosanoids. Unexpectedly, we found that transgenic mice globally overexpressing human sPLA2-X (PLA2G10-Tg) displayed striking immunosuppressive and lean phenotypes with lymphopenia and increased M2-like macrophages, accompanied by marked elevation of free ω-3 polyunsaturated fatty acids (PUFAs) and their metabolites. Studies using Pla2g10-deficient mice revealed that endogenous sPLA2-X, which is highly expressed in the colon epithelium and spermatozoa, mobilized ωPUFAs or their metabolites to protect against dextran sulfate-induced colitis and to promote fertilization, respectively. In colitis, sPLA2-X deficiency increased colorectal expression of Th17 cytokines, and ω3 PUFAs attenuated their production by lamina propria cells partly through the fatty acid receptor GPR120. In comparison, cytosolic phospholipase A2 (cPLA2α) protects from colitis by mobilizing ω-6 AA metabolites including prostaglandin E2. Thus, our results underscore a previously unrecognized role of sPLA2-X as an ω3 PUFA mobilizer in vivo, segregated mobilization of ω-3 and ω-6 PUFA metabolites by sPLA2-X and cPLA2α, respectively, in protection against colitis, and the novel role of a particular sPLA2-X-driven PUFA in fertilization.

Concepts: Nutrition, Fatty acid, Fatty acids, Essential fatty acid, Phospholipase A2, Omega-6 fatty acid, Prostaglandin, Arachidonic acid

138

The small intestine plays an essential role in the health and well-being of animals. Previous studies have shown that Lactobacillus has a protective effect on intestinal morphology, intestinal epithelium integrity and appropriate maturation of gut-associated tissues. Here, gene expression in jejunum tissue of weaned piglets was investigated by RNA-seq analysis after administration of sterile saline, Lactobacillus reuteri, or an antibiotic (chlortetracycline). In total, 401 and 293 genes were significantly regulated by chlortetracycline and L. reuteri, respectively, compared with control treatment. Notably, the HP, NOX1 and GPX2 genes were significantly up-regulated in the L. reuteri group compared with control, which is related to the antioxidant ability of this strain. In addition, the expression of genes related to arachidonic acid metabolism and linoleic acid metabolism enriched after treatment with L. reuteri. The fatty acid composition in the jejunum and colon was examined by GC-MS analysis and suggested that the MUFA C18:1n9c, and PUFAs C18:2n6c and C20:4n6 were increased in the L. reuteri group, verifying the GO enrichment and KEGG pathway analyses of the RNA-seq results. The results contribute to our understanding of the probiotic activity of this strain and its application in pig production.

Concepts: Gene expression, Bacteria, Fatty acid, Probiotic, Omega-6 fatty acid, Linoleic acid, Arachidonic acid, Essential fatty acid interactions

54

Demand for organic milk is partially driven by consumer perceptions that it is more nutritious. However, there is still considerable uncertainty over whether the use of organic production standards affects milk quality. Here we report results of meta-analyses based on 170 published studies comparing the nutrient content of organic and conventional bovine milk. There were no significant differences in total SFA and MUFA concentrations between organic and conventional milk. However, concentrations of total PUFA and n-3 PUFA were significantly higher in organic milk, by an estimated 7 (95 % CI ���1, 15) % and 56 (95 % CI 38, 74) %, respectively. Concentrations of ��-linolenic acid (ALA), very long-chain n-3 fatty acids (EPA+DPA+DHA) and conjugated linoleic acid were also significantly higher in organic milk, by an 69 (95 % CI 53, 84) %, 57 (95 % CI 27, 87) % and 41 (95 % CI 14, 68) %, respectively. As there were no significant differences in total n-6 PUFA and linoleic acid (LA) concentrations, the n-6:n-3 and LA:ALA ratios were lower in organic milk, by an estimated 71 (95 % CI ���122, ���20) % and 93 (95 % CI ���116, ���70) %. It is concluded that organic bovine milk has a more desirable fatty acid composition than conventional milk. Meta-analyses also showed that organic milk has significantly higher ��-tocopherol and Fe, but lower I and Se concentrations. Redundancy analysis of data from a large cross-European milk quality survey indicates that the higher grazing/conserved forage intakes in organic systems were the main reason for milk composition differences.

Concepts: Nutrition, Fatty acid, Fatty acids, Omega-3 fatty acid, Oleic acid, Omega-6 fatty acid, Linoleic acid, Arachidonic acid

51

Eicosapentaenoic acid (EPA, C20:5n-3), docosahexaenoic acid (DHA, C22:6n-3) and arachidonic acid (AA, C20:4n-6) are long-chain polyunsaturated fatty acids (LCPUFAs) with relevant roles in the organism. EPA and DHA are synthesized from the precursor alpha-linolenic acid (ALA, C18:3n-3), whereas AA is produced from linoleic acid (LA, C18:2n-6) through the action of Δ5 and Δ6-desaturases. High-fat diet (HFD) decreases the activity of both desaturases and LCPUFA accretion in liver and other tissues. Hydroxytyrosol (HT), a natural antioxidant, has an important cytoprotective effects in different cells and tissues.

Concepts: Nutrition, Fatty acid, Fatty acids, Essential fatty acid, Eicosapentaenoic acid, Omega-6 fatty acid, Linoleic acid, Arachidonic acid

44

FADS genes encode fatty acid desaturases that are important for the conversion of short chain polyunsaturated fatty acids (PUFAs) to long chain fatty acids. Prior studies indicate that the FADS genes have been subjected to strong positive selection in Africa, South Asia, Greenland, and Europe. By comparing FADS sequencing data from present-day and Bronze Age (5-3k years ago) Europeans, we identify possible targets of selection in the European population, which suggest that selection has targeted different alleles in the FADS genes in Europe than it has in South Asia or Greenland. The alleles showing the strongest changes in allele frequency since the Bronze Age show associations with expression changes and multiple lipid-related phenotypes. Furthermore, the selected alleles are associated with a decrease in linoleic acid and an increase in arachidonic and eicosapentaenoic acids among Europeans; this is an opposite effect of that observed for selected alleles in Inuit from Greenland. We show that multiple SNPs in the region affect expression levels and PUFA synthesis. Additionally, we find evidence for a gene-environment interaction influencing low-density lipoprotein (LDL) levels between alleles affecting PUFA synthesis and PUFA dietary intake: carriers of the derived allele display lower LDL cholesterol levels with a higher intake of PUFAs. We hypothesize that the selective patterns observed in Europeans were driven by a change in dietary composition of fatty acids following the transition to agriculture, resulting in a lower intake of arachidonic acid and eicosapentaenoic acid, but a higher intake of linoleic acid and α-linolenic acid.

Concepts: Cholesterol, Nutrition, Fatty acid, Fatty acids, Essential fatty acid, Omega-6 fatty acid, Linoleic acid, Arachidonic acid

39

The metabolic effects of omega-6 polyunsaturated fatty acids (PUFAs) remain contentious, and little evidence is available regarding their potential role in primary prevention of type 2 diabetes. We aimed to assess the associations of linoleic acid and arachidonic acid biomarkers with incident type 2 diabetes.

Concepts: Nutrition, Fatty acid, Fatty acids, Essential fatty acid, Omega-6 fatty acid, Linoleic acid, Arachidonic acid, Essential fatty acid interactions

28

A myxobacterial strain, designated SYR-2(T), was obtained from a mud sample from an estuarine marsh alongside the Yoshino River, Shikoku, Japan. It had rod-shaped vegetative cells and formed bacteriolytic enlarging colonies or so-called ‘swarms’ in the agar media. Fruiting-body-like globular to polyhedral cell aggregates and myxospore-like spherical to ellipsoidal cells within them were observed. Those features coincided with the general characteristics of myxobacteria. The strain was mesophilic and strictly aerobic. Growth of SYR-2(T) was observed at 18-40 °C (optimum, 30-35 °C), pH 5.5-8.3 (optimum, pH 7.0-7.5) and with 0.0-2.5 % (w/v) NaCl (optimum, 0.2-1.0 %). Both Mg(2+) and Ca(2+) were essential cations for the growth. The predominant fatty acids were iso-C15 : 0 (43.8 %), iso-C17 : 0 (22.4 %) and iso-C16 : 0 (9.6 %). A C20 : 4 fatty acid [arachidonic acid (4.3 %)], iso-C19 : 0 (1.5 %) and anteiso-acids [ai-C15 : 0 (0.5 %), ai-C17 : 0 (0.3 %)] were also detected. The G+C content of the DNA was 69.7 mol%. The strain contained menaquinone-7 (MK-7) as the major respiratory quinone. Phylogenetic analyses based on 16S rRNA gene sequences showed that strain SYR-2(T) belonged to the suborder Nannocystineae, order Myxococcales in the class Deltaproteobacteria, and the strain was most closely related to two type strains of marine myxobacteria, Enhygromyxa salina SHK-1(T) and Plesiocystis pacifica SIR-1(T), with 96.5 % and 96.0 % similarities, respectively. These characteristics determined in this polyphasic study suggested that strain SYR-2(T) represents a novel species in a new genus of myxobacteria. The name Pseudenhygromyxa salsuginis gen. nov., sp. nov. is proposed to accommodate this isolate, and the type strain of Pseudenhygromyxa salsuginis is SYR-2(T) ( = NBRC 104351(T) = DSM 21377(T)).

Concepts: Fatty acid, Ribosomal RNA, Essential fatty acid, 16S ribosomal RNA, Proteobacteria, Omega-6 fatty acid, Linoleic acid, Arachidonic acid