Is there a role for essential fatty acids in osteoporosis?

Inflammatory markers are inversely associated with bone density, geometry, and strength in postmenopausal women, and elderly subjects suggesting that osteoporosis is a low-grade systemic inflammatory condition. But glucocorticoids that are potent anti-inflammatory compounds instead of arresting/preventing osteoporosis induce osteoporosis. These results indicate that IL-6 and TNF-α, post-menopausal state, and steroids produce osteoporosis by an unidentified mechanism. Pro-inflammatory cytokines, estrogen, and steroids bring about their actions by influencing the metabolism of essential fatty acids (EFAs). I propose that EFAs and their metabolites act as second messengers of actions of corticosteroids, cytokines, and estrogen. This implies that EFAs are of benefit in the prevention and management of osteoporosis. This argument is supported by the observation that plasma phospholipid content of unsaturated fatty acids is decreased in those with osteoporosis. The reports that long-chain metabolites of EFAs including arachidonic acid, docosahexaenoic acid and eicosapentaenoic acid, and lipoxin A4 are of benefit in the prevention and management of osteoporosis lends further support to this proposal.

The Dysregulation of Essential Fatty Acid (EFA) Metabolism May Be a Factor in the Pathogenesis of Sepsis.

I propose that a deficiency of essential fatty acids (EFAs) and an alteration in their (EFAs) metabolism could be a major factor in the pathogenesis of sepsis and sepsis-related mortality. The failure of corticosteroids, anti-TNF-α, and anti-interleukin-6 monoclonal antibodies can be attributed to this altered EFA metabolism in sepsis. Vitamin C; folic acid; and vitamin B1, B6, and B12 serve as co-factors necessary for the activity of desaturase enzymes that are the rate-limiting steps in the metabolism of EFAs. The altered metabolism of EFAs results in an imbalance in the production and activities of pro- and anti-inflammatory eicosanoids and cytokines resulting in both hyperimmune and hypoimmune responses seen in sepsis. This implies that restoring the metabolism of EFAs to normal may form a newer therapeutic approach both in the prevention and management of sepsis and other critical illnesses.

Can essential fatty acids (EFAs) prevent and ameliorate post-COVID-19 long haul manifestations?

It is hypothesized that COVID-19, post-COVID and post-mRNA COVID-19 (and other related) vaccine manifestations including "long haul syndrome" are due to deficiency of essential fatty acids (EFAs) and dysregulation of their metabolism. This proposal is based on the observation that EFAs and their metabolites can modulate the swift immunostimulatory response of SARS-CoV-2 and similar enveloped viruses, suppress inappropriate cytokine release, possess cytoprotective action, modulate serotonin and bradykinin production and other neurotransmitters, inhibit NF-kB activation, regulate cGAS-STING pathway, modulate gut microbiota, inhibit platelet activation, regulate macrophage and leukocyte function, enhance wound healing and facilitate tissue regeneration and restore homeostasis. This implies that administration of EFAs could be of benefit in the prevention and management of COVID-19 and its associated complications.

Predicted essential fatty acid intakes for a group of dairy cows also apply at individual animal level.

The ruminant requirements for essential fatty acids (EFAs), particularly linoleic acid (LA) and alpha-linolenic acid (ALA), have not been fully determined, although evidence suggests that an adequate supply of polyunsaturated fatty acids (FAs) could improve immunity and reproduction in transition cows. In previous studies, we predicted EFA intake for a group of cows based on animal characteristics and milk EFA secretions. However, to support precision livestock feeding, we need to match the nutrient requirements and intakes of each cow as closely as possible. Our group-level predictions may not be accurate enough to estimate the EFA intake of an individual cow, due to inter-individual variations in EFA digestion and metabolism related to differences in feed intake, intake patterns, and the composition and functioning of the rumen microbiota. To address this issue, here we set out to establish specific equations that predict EFA intake for an individual cow based on the difference (i.e. the residuals) between observed EFA intake and the predicted EFA intake based on our group-level equations. We studied a database of individual dairy cows (26 experiments; 503 datapoints from three research teams) and we predicted the residuals from (1) dietary and animal-related factors (i.e. full predictions) and (2) animal-related factors only (i.e. field predictions), which are considered more field-amenable. The variance of predicted LA and log ALA intake was explained to 68% by observed LA intake and 66% by observed log ALA intake, respectively. The residuals of LA intake were predicted by dietary ALA content, total FA intake, BW, milk yield and fat content in full predictions, and by BW, feeding level, milk yield and fat content, and sum of milk C4:0 to C14:0 FA in field predictions. The log residuals of ALA intake were predicted by dietary NDF and total FA contents, NDF intake, BW, milk protein, LA and ALA contents, and fat yield in full predictions, and by BW, DM intake, milk LA and ALA contents, and fat yield in field predictions. The field predictions showed a moderate loss of accuracy compared to full predictions based on RMSE of prediction (from 38 to 54 g/d for LA and from 0.090 to 0.12 log (g/d) for ALA). This work is the first to predict the EFA intake of an individual cow based on previously established group-level predictions of EFA intake adjusted for dietary and animal-related factors.

Review: Effect of essential fatty acids and conjugated linoleic acid on the adaptive physiology of dairy cows during the transition period.

Cows fed total mixed rations (silage-based) may not receive as much essential fatty acids (EFAs) and conjugated linoleic acids (CLAs) as cows fed pasture-based rations (fresh grass) containing rich sources of polyunsaturated fatty acids. CLA-induced milk fat depression allows dairy cows to conserve more metabolisable energy, thereby shortening the state of negative energy balance and reducing excessive fat mobilisation at early lactation. EFAs, particularly α-linolenic acid, exert anti-inflammatory and antioxidative properties, thereby modulating immune functions. Thus, combined EFA and CLA supplementation seems to be an effective nutritional strategy to relieve energy metabolism and to improve immune response, which are often compromised during the transition from late pregnancy to lactation in high-yielding dairy cows. There has been extensive research on this idea over the last two decades, and despite promising results, several interfering factors have led to varying findings, making it difficult to conclude whether and under what conditions EFA and CLA supplementations are beneficial for dairy cows during the transition period. This article reviews the latest studies on the effects of EFA and CLA supplementation, alone or in combination, on dairy cow metabolism and health during various stages around parturition. Our review article summarises and provides novel insights into the mechanisms by which EFA and/or CLA influence markers of metabolism, energy homeostasis and partitioning, immunity, and inflammation revealed by a deep molecular phenotyping.

Evaluation of essential fatty acids in lactating sow diets on sow reproductive performance, colostrum and milk composition, and piglet survivability.

Mixed parity sows (n = 3,451; PIC, Hendersonville, TN; parities 2 through 9) and their litters were used to evaluate the effects of essential fatty acid (EFA) intake on sow reproductive performance, piglet growth and survivability, and colostrum and milk composition. Our hypothesis, like observed in earlier research, was that increasing linoleic acid (LA) and α-linolenic acid (ALA) would improve sow and litter performance. At approximately day 112 of gestation, sows were randomly assigned within parity groups to 1 of 4 corn-soybean meal-wheat-based lactation diets that contained 0.5 (Control) or 3% choice white grease (CWG), 3% soybean oil (SO), or a combination of 3% soybean oil and 2% choice white grease (Combination). Thus, sows were provided diets with low LA and ALA in diets with CWG or high LA and ALA in diets that included soybean oil. Sows received their assigned EFA treatments until weaning and were then fed a common gestation and lactation diet in the subsequent reproductive cycle. Average daily feed intake during the lactation period increased (P < 0.05) for sows fed the Combination and CWG diets compared with sows fed the Control or SO diet. However, daily LA and ALA intakes of sows fed the Combination and SO diets were still greater (P < 0.05) than those of sows fed 0.5 or 3% CWG. Overall, sows consuming high EFA from the Combination or SO diets produced litters with heavier (P < 0.05) piglet weaning weights and greater (P < 0.05) litter ADG when compared with litters from sows fed diets with CWG that provided low EFA. Despite advantages in growth performance, there was no impact of sow EFA intake on piglet survivability (P > 0.10). Additionally, lactation diet EFA composition did not influence sow colostrum or milk dry matter, crude protein, or crude fat content (P > 0.10). However, LA and ALA content in colostrum and milk increased (P < 0.05) in response to elevated dietary EFA from SO. There was no evidence for differences (P > 0.10) in subsequent sow reproductive or litter performance due to previous lactation EFA intake. In conclusion, increased LA and ALA intake provided by soybean oil during lactation increased overall litter growth and pig weaning weights, reduced sow ADFI, but did not affect piglet survivability or subsequent performance of sows.

Supplemental fat sources are an effective and widely accepted strategy to increase energy density of sow lactation diets that can also provide essential fatty acids such as linoleic acid (LA) and α-linolenic acid (ALA). Currently, the effects of supplemental LA and ALA provided shortly before farrowing on colostrum and milk composition are not fully understood. Additionally, the influence of elevated LA and ALA provided in sow lactation diets on litter growth and survivability responses has not been extensively evaluated. Therefore, this trial was conducted to evaluate the effects of fat sources providing low and high LA and ALA intake on sow performance, litter growth and survivability, colostrum and milk composition, and subsequent reproductive performance. Overall, sows consuming diets with high LA and ALA provided by soybean oil produced litters with heavier piglet weaning weights and greater litter average daily gain when compared with sows consuming diets with low LA and ALA content. Increasing LA and ALA by added soybean oil also increased their content in colostrum and milk. However, there was no influence of sow LA and ALA intake on litter survivability or subsequent reproductive performance of sows.

Lowered nutritional quality of prey decrease the growth and biomolecule content of rainbow trout fry.

Diet quality is crucial for the development of offspring. Here, we examined how the nutritional quality of prey affects somatic growth and the lipid, carbohydrate, protein, amino acid, and polyunsaturated fatty acid content of rainbow trout (Oncorhynchus mykiss) fry using a three-trophic-level experimental setup. Diets differed especially in their content of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are physiologically essential polyunsaturated fatty acids for a fish fry. Trout were fed with an artificial diet (fish feed, DHA-rich), marine zooplankton diet (krill/Mysis, DHA-rich), or freshwater zooplankton diet (Daphnia, Cladocera, DHA-deficient). The Daphnia were grown either on a poor, intermediate, or high-quality algal/microbial diet simulating potential changes in the nutritional prey quality (EPA-content). Trout fed with the fish feed or marine zooplankton entirely replaced their muscle tissue composition with compounds of dietary origin. In contrast, fish tissue renewal was only partial in fish fed any Daphnia diet. Furthermore, fish grew five times faster on marine zooplankton than on any of the Daphnia diets. This was mainly explained by the higher dietary contents of arachidonic acid (ARA), EPA, and DHA, but also by the higher content of some amino acids in the marine zooplankton than in the Daphnia diets. Moreover, fatty acid-specific carbon isotopes revealed that trout fry could not biosynthesize ARA, EPA, or DHA efficiently from their precursors. Our results suggest that changes in the zooplankton and macroinvertebrate communities' structure in freshwater habitats from DHA-rich to DHA-poor species may reduce the somatic growth of fish fry.

Liver proteome profiling in dairy cows during the transition from gestation to lactation: Effects of supplementation with essential fatty acids and conjugated linoleic acids as explored by PLS-DA.

This study aimed at investigating the synergistic effects of essential fatty acids (EFA) and conjugated linoleic acids (CLA) on the liver proteome profile of dairy cows during the transition to lactation. 16 Holstein cows were infused from 9 wk. antepartum to 9 wk. postpartum into the abomasum with either coconut oil (CTRL) or a mixture of EFA (linseed + safflower oil) and CLA (EFA + CLA). Label-free quantitative proteomics was performed in liver tissue biopsied at days -21, +1, +28, and + 63 relative to calving. Differentially abundant proteins (DAP) between treatment groups were identified at the intersection between a multivariate and a univariate analysis. In total, 1680 proteins were identified at each time point, of which between groups DAP were assigned to the metabolism of xenobiotics by cytochrome P450, drug metabolism - cytochrome P450, steroid hormone biosynthesis, glycolysis/gluconeogenesis, and glutathione metabolism. Cytochrome P450, as a central hub, enriched with specific CYP enzymes comprising: CYP51A1 (d - 21), CYP1A1 & CYP4F2 (d + 28), and CYP4V2 (d + 63). Collectively, supplementation of EFA + CLA in transition cows impacted hepatic lipid metabolism and enriched several common biological pathways at all time points that were mainly related to ω-oxidation of fatty acids through the Cytochrome p450 pathway. SIGNIFICANCE: In three aspects this manuscript is notable. First, this is among the first longitudinal proteomics studies in nutrition of dairy cows. The selected time points are critical periods around parturition with profound endocrine and metabolic adaptations. Second, our findings provided novel information on key drivers of biologically relevant pathways suggested according to previously reported performance, zootechnical, and metabolism data (already published elsewhere). Third, our results revealed the role of cytochrome P450 that is hardly investigated, and of ω-oxidation pathways in the metabolism of fatty acids with the involvement of specific enzymes.

Longitudinal liver proteome profiling in dairy cows during the transition from gestation to lactation: Investigating metabolic adaptations and their interactions with fatty acids supplementation via repeated measurements ANOVA-simultaneous component analysis.

Repeated measurements analysis of variance - simultaneous component analysis (ASCA) has been developed to handle complex longitudinal omics datasets and combine novel information with existing data. Herein, we aimed at applying ASCA to 64 liver proteomes collected at 4-time points (day -21, +1, +28, and + 63 relative to parturition) from 16 Holstein cows treated from 9 wk. antepartum to 9 wk. postpartum (PP) with coconut oil (CTRL) or a mixture of essential fatty acids (EFA) and conjugated linoleic acid (CLA) (EFA + CLA). The ASCA modeled 116, 43, and 97 differentially abundant proteins (DAP) during the transition to lactation, between CTRL and EFA + CLA, and their interaction, respectively. Time-dependent DAP were annotated to pathways related to the metabolism of carbohydrates, FA, and amino acid in the PP period. The DAP between FA and the interaction effect were annotated to the metabolism of xenobiotics by cytochrome P450, drug metabolism - cytochrome P450, retinol metabolism, and steroid hormone biosynthesis. Collectively, ASCA provided novel information on molecular markers of metabolic adaptations and their interactions with EFA + CLA supplementation. Bioinformatics analysis suggested that supplemental EFA + CLA amplified hepatic FA oxidation; cytochrome P450 was enriched to maintain metabolic homeostasis by oxidation/detoxification of endogenous compounds and xenobiotics. SIGNIFICANCE: This report is among the first ones applying repeated measurement analysis of variance-simultaneous component analysis (ASCA) to deal with longitudinal proteomics results. ASCA separately identified differentially abundant proteins (DAP) in 'transition time', 'between fatty acid treatments', and 'their interaction'. We first identified the molecular signature of hepatic metabolic adaptations during postpartum negative energy balance; the enriched pathways were well-known pathways related to mobilizing fatty acids (FA) and amino acids to support continuous energy production through fatty acid oxidation, TCA cycle, and gluconeogenesis. Some of the DAP were not previously reported in transition dairy cows. Secondly, we provide novel information on the mechanisms by which supplemented essential FA and conjugated linoleic acids interact with hepatic metabolism. In this regard, FA amplified hepatic detoxifying and oxidation capacity through ligand activation of nuclear receptors. Finally, we briefly compared the strengths and weaknesses of the ASCA model with PLS-DA and outlined why these methods are complementary.

Essential Fatty Acids and Their Metabolites in the Pathobiology of Inflammation and Its Resolution.

Arachidonic acid (AA) metabolism is critical in the initiation and resolution of inflammation. Prostaglandin E2 (PGE2) and leukotriene B4/D4/E4 (LTB4/LD4/LTE4), derived from AA, are involved in the initiation of inflammation and regulation of immune response, hematopoiesis, and M1 (pro-inflammatory) macrophage facilitation. Paradoxically, PGE2 suppresses interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) production and triggers the production of lipoxin A4 (LXA4) from AA to initiate inflammation resolution process and augment regeneration of tissues. LXA4 suppresses PGE2 and LTs' synthesis and action and facilitates M2 macrophage generation to resolve inflammation. AA inactivates enveloped viruses including SARS-CoV-2. Macrophages, NK cells, T cells, and other immunocytes release AA and other bioactive lipids to produce their anti-microbial actions. AA, PGE2, and LXA4 have cytoprotective actions, regulate nitric oxide generation, and are critical to maintain cell shape and control cell motility and phagocytosis, and inflammation, immunity, and anti-microbial actions. Hence, it is proposed that AA plays a crucial role in the pathobiology of ischemia/reperfusion injury, sepsis, COVID-19, and other critical illnesses, implying that its (AA) administration may be of significant benefit in the prevention and amelioration of these diseases.

The Partitioning of Newly Assimilated Linoleic and α-Linolenic Acids Between Synthesis of Longer-Chain Polyunsaturated Fatty Acids and Hydroxyoctadecaenoic Acids Is a Putative Branch Point in T-Cell Essential Fatty Acid Metabolism.

Longer-chain polyunsaturated fatty acids (LCPUFAs) ≥20 carbons long are required for leukocyte function. These can be obtained from the diet, but there is some evidence that leukocytes can convert essential fatty acids (EFAs) into LCPUFAs. We used stable isotope tracers to investigate LCPUFA biosynthesis and the effect of different EFA substrate ratios in human T lymphocytes. CD3+ T cells were incubated for up to 48 h with or without concanavalin A in media containing a 18:2n-6:18:3n-3 (EFA) ratio of either 5:1 or 8:1 and [13C]18:3n-3 plus [d5]18:2n-6. Mitogen stimulation increased the amounts of 16:1n-7, 18:1n-9, 18:2n-6, 20:3n-6, 20:4n-6, 18:3n-3, and 20:5n-3 in T cells. Expression of the activation marker CD69 preceded increased FADS2 and FADS1 mRNA expression and increased amounts of [d5]20:2n-6 and [13C]20:3n-3 at 48 h. In addition, 22-carbon n-6 or n-3 LCPUFA synthesis was not detected, consistent with the absence of ELOVL2 expression. An EFA ratio of 8:1 reduced 18:3n-3 conversion and enhanced 20:2n-6 synthesis compared to a 5:1 ratio. Here, [d5]9- and [d5]-13-hydroxyoctadecadienoic (HODE) and [13C]9- and [13C]13-hydroxyoctadecatrienoic acids (HOTrE) were the major labelled oxylipins in culture supernatants; labelled oxylipins ≥20 carbons were not detected. An EFA ratio of 8:1 suppressed 9- and 13-HOTrE synthesis, but there was no significant effect on 9- and 13-HODE synthesis. These findings suggest that partitioning of newly assimilated EFA between LCPUFA synthesis and hydroxyoctadecaenoic acid may be a metabolic branch point in T-cell EFA metabolism that has implications for understanding the effects of dietary fats on T lymphocyte function.

Correcting iron deficiency anemia with iron dextran alters the serum metabolomic profile of the infant Rhesus Monkey.

BACKGROUND: The effects of infantile iron deficiency anemia (IDA) extend beyond hematological indices and include short- and long-term adverse effects on multiple cells and tissues. IDA is associated with an abnormal serum metabolomic profile, characterized by altered hepatic metabolism, lowered NAD flux, increased nucleoside levels, and a reduction in circulating dopamine levels. OBJECTIVES: The objective of this study was to determine whether the serum metabolomic profile is normalized after rapid correction of IDA using iron dextran injections. METHODS: Blood was collected from iron-sufficient (IS; n = 10) and IDA (n = 12) rhesus infants at 6 months of age. IDA infants were then administered iron dextran and vitamin B via intramuscular injections at weekly intervals for 2 to 8 weeks. Their hematological and metabolomic statuses were evaluated following treatment and compared with baseline and a separate group of age-matched IS infants (n = 5). RESULTS: Serum metabolomic profiles assessed at baseline and after treatment via HPLC/MS using isobaric standards identified 654 quantifiable metabolites. At baseline, 53 metabolites differed between IS and IDA infants. Iron treatment restored traditional hematological indices, including hemoglobin and mean corpuscular volume, into the normal range, but the metabolite profile in the IDA group after iron treatment was markedly altered, with 323 metabolites differentially expressed when compared with an infant's own baseline profile. CONCLUSIONS: Rapid correction of IDA with iron dextran resulted in extensive metabolic changes across biochemical pathways indexing the liver function, bile acid release, essential fatty acid production, nucleoside release, and several neurologically important metabolites. The results highlight the importance of a cautious approach when developing a route and regimen of iron repletion to treat infantile IDA.

The need for precision nutrition, genetic variation and resolution in Covid-19 patients.

The health of the individual and the population in general is the result of interaction between genetics and various environmental factors, of which diet/nutrition is the most important. The focus of this paper is on the association of high n-6 PUFA or low n-3 PUFA due to genetic variation and/or dietary intake, with changes in specialized pro-resolving mediators (SPMs), cytokine storm, inflammation-resolution and Covid-19. Human beings evolved on a diet that was balanced in the n-6 and n-3 essential fatty acids with a ratio of n-6/n-3 of 1-2/1 whereas today this ratio is 16/1. Such a high ratio due to high amounts of n-6 fatty acids leads to a prothrombotic and proinflammatory state and is associated with obesity, diabetes, cardiovascular disease, and some forms of cancer. In addition to the high intake of n-6 fatty acids that increases inflammation there is genetic variation in the biosynthesis of n-6 linoleic acid (LA) to arachidonic acid (ARA) and of linolenic (ALA) to eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Present day humans have two common FADS haplotypes that differ dramatically in their ability to generate long-chain fatty acids. The more efficient, evolutionary derived haplotype increases the efficiency of synthesizing essential long-chain fatty acids from precursors and could have provided an advantage in environments with limited access to dietary long-chain fatty acids ARA, EPA and DHA. In the modern world this haplotype has been associated with lifestyle-related diseases, such as cardiovascular disease, obesity, diabetes, all of which are characterized by increased levels of inflammation. African Americans and Latino populations have increased susceptibility and higher death rates from SARS-CoV-2 than whites. These populations are characterized by increased numbers of persons (about 80%) that are fast metabolizers, leading to increased production of ARA, as well as poor intake of fruits and vegetables. The combinations of fast metabolism and high n-6 intake increases their inflammatory status and possibly susceptibility of SARS-CoV-2. In vitro and human studies indicate that the specialized pro-resolving mediators (SPM) produced from the n-3, EPA and DHA influence the resolution of inflammation, allowing the tissues to return to function and homeostasis. The SPMs each counter-regulate cytokine storms, as well as proinflammatory lipid mediators via NFκB and inflammasome down regulation and reduce the proinflammatory eicosanoids produced from ARA. The nutritional availability of dietary n-3 fatty acids from marine oils enriched with SPM intermediate precursors, along with increasing local biosynthesis of SPMs to functional concentrations may be an approach of value during SARS-CoV2 infections, as well as in prevention, and shortening their recovery from infections. It is evident that populations differ in their genetic variants and their frequencies and their interactions with the food they eat. Gene-nutrient interactions is a very important area of study that provides specific dietary advice for individuals and subgroups within a population in the form of Precision Nutrition. Nutritional science needs to focus on Precision Nutrition, genetic variants in the population and a food supply composed of Nutrients that have been part of our diet throughout evolution, which is the diet that our genes are programmed to respond.

"Cell Membrane Theory of Senescence" and the Role of Bioactive Lipids in Aging, and Aging Associated Diseases and Their Therapeutic Implications.

Lipids are an essential constituent of the cell membrane of which polyunsaturated fatty acids (PUFAs) are the most important component. Activation of phospholipase A2 (PLA2) induces the release of PUFAs from the cell membrane that form precursors to both pro- and ant-inflammatory bioactive lipids that participate in several cellular processes. PUFAs GLA (gamma-linolenic acid), DGLA (dihomo-GLA), AA (arachidonic acid), EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) are derived from dietary linoleic acid (LA) and alpha-linolenic acid (ALA) by the action of desaturases whose activity declines with age. Consequently, aged cells are deficient in GLA, DGLA, AA, AA, EPA and DHA and their metabolites. LA, ALA, AA, EPA and DHA can also be obtained direct from diet and their deficiency (fatty acids) may indicate malnutrition and deficiency of several minerals, trace elements and vitamins some of which are also much needed co-factors for the normal activity of desaturases. In many instances (patients) the plasma and tissue levels of GLA, DGLA, AA, EPA and DHA are low (as seen in patients with hypertension, type 2 diabetes mellitus) but they do not have deficiency of other nutrients. Hence, it is reasonable to consider that the deficiency of GLA, DGLA, AA, EPA and DHA noted in these conditions are due to the decreased activity of desaturases and elongases. PUFAs stimulate SIRT1 through protein kinase A-dependent activation of SIRT1-PGC1α complex and thus, increase rates of fatty acid oxidation and prevent lipid dysregulation associated with aging. SIRT1 activation prevents aging. Of all the SIRTs, SIRT6 is critical for intermediary metabolism and genomic stability. SIRT6-deficient mice show shortened lifespan, defects in DNA repair and have a high incidence of cancer due to oncogene activation. SIRT6 overexpression lowers LDL and triglyceride level, improves glucose tolerance, and increases lifespan of mice in addition to its anti-inflammatory effects at the transcriptional level. PUFAs and their anti-inflammatory metabolites influence the activity of SIRT6 and other SIRTs and thus, bring about their actions on metabolism, inflammation, and genome maintenance. GLA, DGLA, AA, EPA and DHA and prostaglandin E2 (PGE2), lipoxin A4 (LXA4) (pro- and anti-inflammatory metabolites of AA respectively) activate/suppress various SIRTs (SIRt1 SIRT2, SIRT3, SIRT4, SIRT5, SIRT6), PPAR-γ, PARP, p53, SREBP1, intracellular cAMP content, PKA activity and peroxisome proliferator-activated receptor γ coactivator 1-α (PGC1-α). This implies that changes in the metabolism of bioactive lipids as a result of altered activities of desaturases, COX-2 and 5-, 12-, 15-LOX (cyclo-oxygenase and lipoxygenases respectively) may have a critical role in determining cell age and development of several aging associated diseases and genomic stability and gene and oncogene activation. Thus, methods designed to maintain homeostasis of bioactive lipids (GLA, DGLA, AA, EPA, DHA, PGE2, LXA4) may arrest aging process and associated metabolic abnormalities.

Supplementation with alpha-linolenic acid and inflammation: a feasibility trial.

Consumption of omega-3 fatty acids, including the precursor α-linolenic acid (ALA) is often sub-optimal and not in line with international guidelines. Supplementation is debatable, but some individuals, e.g., pre-diabetic, low-grade inflammation, cardiometabolic yet otherwise healthy subjects, might benefit from supra-physiological omega-3 intake, particularly to lessen inflammation. We explored the feasibility of a large clinical trial by performing a pilot study to evaluate adherence, palatability, and self-reported side effects of ALA administration in a group of volunteers. We enrolled 12 individuals with borderline dyslipidemia or overweight, treated with dietary advice according to international guidelines and who had insufficient intakes of essential fatty acids. Subjects were followed for nutritional counselling and were matched with appropriate controls. Patients were administered 6 g/day of ALA, for two months. We report the absence of side effects. such as fishy aftertaste and gastrointestinal distress, in addition to a slight decrease of C-reactive protein concentrations (Identifier: ISRCTN13118704).

Effects of co-administration of rapamycin and evening primrose/hemp seed oil supplement on immunologic factors and cell membrane fatty acids in experimental autoimmune encephalomyelitis.

BACKGROUND: The immune response is influenced by the administration of omega-3 polyunsaturated fatty acids (PUFA). Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE) are affected by PUFA. The combination of evening primrose/hemp seed oil (EPO/HSO) has essential fatty acids (EFAs) for human optimal health due to the favorable ratio of omega-6/omega-3 and antioxidantal properties. The study was conducted to evaluate the effects of EPO/HSO on improving the membrane fatty acids composition of spleen and blood cells and immunologic factors in compared to rapamycin (RAPA) in the EAE model. METHODS AND MATERIALS: Chronic-EAE was induced by induction of MOG in C57BL/6J mice (female, age: 6-8 weeks, weight 18-21). Mice were assigned to 5 groups (6/group) to evaluate the therapeutic effects of EPO/HSO supplement in comparison with rapamycin: A group; EPO/HSO + RAPA, B group; RAPA, C group; EPO/HSO. Results were compared to two control groups (EAE and naive). The fatty acid profile of the spleen and blood cell membrane was evaluated. Real-time-polymerase chain reaction was used for the evaluate the genes expression levels of interleukin (IL) -4, IL-5, and IL-13 in lymphocytes. Also, IL-4 of serum was evaluated by enzyme-linked immunosorbent assay (ELISA). RESULTS: Our findings indicated that EPO/HSO therapy significantly increased the percentage of essential fatty acids in cell membrane of the spleen and blood. The relative expression of IL-4, IL-5, and IL-13 genes in lymphocytes and serum level of IL-4 was significantly increased in the HSO/EPO treated group versus other groups. CONCLUSION: These results point to potential therapeutic effects on the repair of the structure of cell membranes and suppression of inflammation by EPO/HSO in EAE.

Ambient temperature and algal prey type affect essential fatty acid incorporation and trophic upgrading in a herbivorous marine copepod.

The essential fatty acids (EFA) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are critical nutrients for all organisms, and the temperature sensitivity of their trophic transfer in marine systems is of concern because of rising ocean temperatures. Laboratory-reared copepodites of the marine calanoid Calanus finmarchicus were used to test the effects of temperature (at 6°C, 12°C and increasing temperature stress) and prey type (the dinoflagellate Heterocapsa triquetra and the diatom Thalassiosira weissflogii) on the extent and efficiency of dietary EPA and DHA incorporation from phytoplankton to copepods in a set of feeding experiments using 13C labelling. Temperature was a significant determinant of C. finmarchicus copepodites' EFA incorporation and gross growth efficiency, defined as the fraction of ingested EFA retained in copepod tissue. Ingestion and incorporation of both EFA were higher at warmer temperature, except in the case of DHA in copepods feeding on diatoms. DHA-associated growth efficiency was higher at the higher temperature for copepodites consuming the dinoflagellate, but temperature-related variation in algal EFA content was also a predictive factor. Moreover, our results strongly suggest that copepodites are capable of synthesizing EPA when consuming an EPA-depleted diet. Our study implies that the copepod link of marine food webs is resilient in terms of EFA transfer when confronted with alterations of ambient temperature and prey type availability. Measurements presented here are critical for estimating how EFA transfer dynamics respond to intra- and interannual environmental variability. This article is part of the theme issue 'The next horizons for lipids as 'trophic biomarkers': evidence and significance of consumer modification of dietary fatty acids'.

The role of essential fatty acids in cystic fibrosis and normalizing effect of fenretinide.

Cystic fibrosis (CF) is the most common autosomal-recessive disease in Caucasians caused by mutations in the CF transmembrane regulator (CFTR) gene. Patients are usually diagnosed in infancy and are burdened with extensive medical treatments throughout their lives. One of the first documented biochemical defects in CF, which predates the cloning of CFTR gene for almost three decades, is an imbalance in the levels of polyunsaturated fatty acids (PUFAs). The principal hallmarks of this imbalance are increased levels of arachidonic acid and decreased levels of docosahexaenoic acids (DHA) in CF. This pro-inflammatory profile of PUFAs is an important component of sterile inflammation in CF, which is known to be detrimental, rather than protective for the patients. Despite decades of intensive research, the mechanistic basis of this phenomenon remains unclear. In this review we summarized the current knowledge on the biochemistry of PUFAs, with a focus on the metabolism of AA and DHA in CF. Finally, a synthetic retinoid called fenretinide (N-(4-hydroxy-phenyl) retinamide) was shown to be able to correct the pro-inflammatory imbalance of PUFAs in CF. Therefore, its pharmacological actions and clinical potential are briefly discussed as well.

Bioactive Lipids in Age-Related Disorders.

Our own studies and those of others have shown that defects in essential fatty acid (EFA) metabolism occurs in age-related disorders such as obesity, type 2 diabetes mellitus, hypertension, atherosclerosis, coronary heart disease, immune dysfunction and cancer. It has been noted that in all these disorders there could occur a defect in the activities of desaturases, cyclo-oxygenase (COX), and lipoxygenase (LOX) enzymes leading to a decrease in the formation of their long-chain products gamma-linolenic acid (GLA), arachidonic acid, eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA). This leads to an increase in the production of pro-inflammatory prostaglandin E2 (PGE2), thromboxanes (TXs), and leukotrienes (LTs) and a decrease in anti-inflammatory lipoxin A4, resolvins, protectins and maresins. All these bioactive molecules are termed as bioactive lipids (BALs). This imbalance in the metabolites of EFAs leads to low-grade systemic inflammation and at times acute inflammatory events at specific local sites that trigger the development of various age-related disorders such as obesity, type 2 diabetes mellitus, hypertension, coronary heart disease, atherosclerosis, and immune dysfunction as seen in rheumatoid arthritis, lupus, nephritis and other localized inflammatory conditions. This evidence implies that methods designed to restore BALs to normal can prevent age-related disorders and enhance longevity and health.

Short-Term Effect of One-Anastomosis Gastric Bypass on Essential Fatty Acids in the Serum of Obese Patients.

One-anastomosis gastric bypass is a promising type of bariatric surgery, but it may lead to a deficiency in important nutrients, such as fatty acids. The short-term effects of one-anastomosis gastric bypass on serum fatty acids have not been studied thus far. Therefore, the aim of this study was to determine the effect of one-anastomosis gastric bypass on serum fatty acid composition two weeks after surgery. This study included 38 patients who underwent one-anastomosis gastric bypass as surgical treatment for morbid obesity. Serum fatty acid composition was analyzed before and two weeks after surgery using gas chromatography-mass spectrometry. We observed a decrease in essential polyunsaturated fatty acids (p < 0.001 for linolenic acid and p < 0.001 for linoleic acid) and odd-chain fatty acids (p = 0.004) in the serum of obese patients shortly after a one-anastomosis gastric bypass. Considering the benefits of the aforementioned fatty acids for human health, the implementation of a fatty-acid-rich diet or the use of supplementation may be recommended for patients immediately after one-anastomosis gastric bypass.