Polyunsaturated Fatty Acids Linoleic Acid Research Articles

Sex-specific responses in glucose-insulin homeostasis and lipoprotein-lipid components after high-dose supplementation with marine n-3 PUFAs in abdominal obesity: a randomized double-blind crossover study.

Clinical studies on effects of marine-derived omega-3 (n-3) polyunsaturated fatty acids (PUFAs), mainly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and the plant-derived omega-6 (n-6) PUFA linoleic acid (LA) on lipoprotein-lipid components and glucose-insulin homeostasis have shown conflicting results, which may partly be explained by differential responses in females and males. However, we have lacked data on sexual dimorphism in the response of cardiometabolic risk markers following increased consumption of n-3 or n-6 PUFAs. To explore sex-specific responses after n-3 (EPA + DHA) or n-6 (LA) PUFA supplementation on circulating lipoprotein subfractions, standard lipids, apolipoproteins, fatty acids in red blood cell membranes, and markers of glycemic control/insulin sensitivity among people with abdominal obesity. This was a randomized double-blind crossover study with two 7-week intervention periods separated by a 9-week washout phase. Females (n = 16) were supplemented with 3 g/d of EPA + DHA (fish oil) or 15 g/d of LA (safflower oil), while males (n = 23) received a dose of 4 g/d of EPA + DHA or 20 g/d of LA. In fasting blood samples, we measured lipoprotein particle subclasses, standard lipids, apolipoproteins, fatty acid profiles, and markers of glycemic control/insulin sensitivity. The between-sex difference in relative change scores was significant after n-3 for total high-density lipoproteins (females/males: -11%*/-3.3%, p = 0.036; *: significant within-sex change), high-density lipoprotein particle size (+2.1%*/-0.1%, p = 0.045), and arachidonic acid (-8.3%*/-12%*, p = 0.012), and after n-6 for total (+37%*/+2.1%, p = 0.041) and small very-low-density lipoproteins (+97%*/+14%, p = 0.021), and lipoprotein (a) (-16%*/+0.1%, p = 0.028). Circulating markers of glucose-insulin homeostasis differed significantly after n-3 for glucose (females/males: -2.1%/+3.9%*, p = 0.029), insulin (-31%*/+16%, p < 0.001), insulin C-peptide (-12%*/+13%*, p = 0.001), homeostasis model assessment of insulin resistance index 2 (-12%*/+14%*, p = 0.001) and insulin sensitivity index 2 (+14%*/-12%*, p = 0.001), and quantitative insulin sensitivity check index (+4.9%*/-3.4%*, p < 0.001). We found sex-specific responses after high-dose n-3 (but not n-6) supplementation in circulating markers of glycemic control/insulin sensitivity, which improved in females but worsened in males. This may partly be related to the sex differences we observed in several components of the lipoprotein-lipid profile following the n-3 intervention. https://clinicaltrials.gov/, identifier [NCT02647333].

Design of high-monounsaturated fatty acid soybean seed oil using GmPDCTs knockout via a CRISPR-Cas9 system.

Design of high-monounsaturated fatty acid soybean seed oil using GmPDCTs knockout via a CRISPR-Cas9 system.

Dietary Betaine Interacts with Very Long Chain n-3 Polyunsaturated Fatty Acids to Influence Fat Metabolism and Circulating Single Carbon Status in the Cat.

Simple SummaryThe domestic cat can metabolize and thrive on a range of intakes of different dietary polyunsaturated fatty acids (PUFA). However, changes in the intake of PUFA have relatively unknown effects on concentrations of other fatty acids and metabolites. Similarly, the effect of increasing dietary betaine (which is a single carbon donor) on circulating concentrations of metabolites and fatty acids is relatively unreported. As might be expected, increasing intake of specific dietary fatty acids resulted in an increased concentration of that fatty acid and moieties containing that fatty acid. Dietary betaine increased concentration of many compounds associated with single carbon metabolism (e.g., dimethyl glycine, sarcosine, methionine) and many PUFA such as the n-6 PUFA linoleic acid (LA) and arachidonic acid (ARA) and the n-3 fatty acids α-linolenic acid (αLA), and docosahexaenoic acid (DHA). Dietary betaine interacted with the addition of dietary fish oil to dampen diet-induced increase of ARA while potentiating the increase of circulating DHA occurring with increased DHA dietary intake. Dietary betaine and fish oil also combined to reduce the circulating concentration of the renal toxin 3-indoxyl sulfate, suggesting a positive effect on the gut microbiota. These data suggest a positive effect of a daily betaine intake which exceeds 60 mg per kg body weight. The data also support an added benefit of a combined EPA+DHA daily intake of greater than 26 mg/kg body weight as well as a daily intake of 75 mg/kg body weight of alpha linolenic acid.Six foods were used to evaluate the interaction of dietary betaine and n-3 PUFA in the cat. There was no ingredient added to the control food to specifically increase betaine or n-3 fatty acids. The experimental design was a 3 × 2 factorial (fatty acids were varied from the control food which had no added source of n-3 fatty acids, flax was included as a source of 18 carbon n-3, or menhaden fish oil as a source of EPA and DHA). Foods were then formulated using these three foods as a base with added betaine or without added betaine. Forty eight cats were used in this study. Equal numbers of cats were allotted by age and gender to each of the six dietary treatments. The cats were offered food amounts to maintain weight and consumed the food to which they were assigned for the length of the study (60 days). Metabolomics, selected circulating analytes and fatty acids were analyzed at the beginning and end of the feeding period. There was an increase in single carbon metabolites (betaine, dimethyl glycine, and methionine) with the consumption of dietary betaine. Betaine also increased the concentration of specific PUFA (ARA, αLA, DHA, and the sum of all circulating PUFA). The combination of dietary betaine and fish oil resulted in a reduction of circulating 3-indoxyl sulfate which suggests a renal benefit from their combined dietary presence.

Of fruits and fats: high-sugar diets restore fatty acid profiles in the white adipose tissue of captive dwarf lemurs.

Fat-storing hibernators rely on fatty acids from white adipose tissue (WAT) as an energy source to sustain hibernation. Whereas arctic and temperate hibernators preferentially recruit dietary polyunsaturated fatty acids (PUFAs), tropical hibernators can rely on monounsaturated fatty acids that produce fewer lipid peroxides during oxidation. Nevertheless, compositional data on WAT from tropical hibernators are scant and questions remain regarding fat recruitment and metabolism under different environmental conditions. We analyse fatty acid profiles from the WAT of captive dwarf lemurs (Cheirogaleus medius) subjected to high-sugar or high-fat diets during fattening and cold or warm conditions during hibernation. Dwarf lemurs fed high-sugar (compared to high-fat) diets displayed WAT profiles more comparable to wild lemurs that fatten on fruits and better depleted their fat reserves during hibernation. One PUFA, linoleic acid, remained elevated before hibernation, potentially lingering from the diets provisioned prior to fattening. That dwarf lemurs preferentially recruit the PUFA linoleic acid from diets that are naturally low in availability could explain the discrepancy between captive and wild lemurs' WAT. While demonstrating that minor dietary changes can produce major changes in seasonal fat deposition and depletion, our results highlight the complex role for PUFA metabolism in the ecology of tropical hibernators.

Probiotics Interact With Lipids Metabolism and Affect Gut Health.

Probiotics have attracted much attention due to their ability to modulate host intestinal microbe, participate in nutrient metabolism or immunomodulatory. Both inflammatory bowel disease (IBD) and bowel cancer are digestive system disease, which have become a global public health problem due to their unclear etiology, difficult to cure, and repeated attacks. Disturbed gut microbiota and abnormal lipid metabolism would increase the risk of intestinal inflammation. However, the link between lipid metabolism, probiotics, and IBD is unclear. In this review, we found that different lipids and their derivatives have different effects on IBD and gut microbes. ω-3 polyunsaturated fatty acids (PUFAs) docosahexaenoic acid, eicosapentaenoic acid, and their derivatives resolvin E1, resolvin D can inhibit oxidative stress and reactive oxygen species activate NFκB and MAPk pathway. While ω-6 PUFAs linoleic acid and arachidonic acid can be derived into leukotrienes and prostaglandins, which will aggravate IBD. Cholesterol can be converted into bile acids to promote lipid absorption and affect microbial survival and colonization. At the same time, it is affected by microbial bile salt hydrolase to regulate blood lipids. Low denstiy lipoprotein (LDL) is easily converted into oxidized LDL, thereby promoting inflammation, while high denstiy lipoprotein (HDL) has the opposite effect. Probiotics compete with intestinal microorganisms for nutrients or ecological sites and thus affect the structure of intestinal microbiota. Moreover, microbial short chain fatty acids, bile salt hydrolase, superoxide dismutase, glutathione, etc. can affect lipid metabolism and IBD. In conclusion, probiotics are directly or indirectly involved in lipids metabolism and their impact on IBD, which provides the possibility to explore the role of probiotics in improving gut health.

Edible flowers of Helichrysum italicum: Composition, nutritive value, and bioactivities

Helichrysum italicum (H. italicum) is a halophyte shrub with bright yellow flowers with a strong curry-like aroma. The essential oils of H. italicum have been used in the production of cosmetics and pharmaceuticals, due to their antiallergic and anti-inflammatory properties. In the agri-food sector, H. italicum flowers can be used for seasoning and flavoring food, and as natural food preservatives. Here, we report on the composition, bioactive compounds, and nutritive value of H. italicum flowers. Flowers were mainly composed of carbohydrates (>80 % dry weight), followed by minerals (6.31 ± 0.95 % dw), protein (5.44 ± 0.35 % dw), and lipids (3.59 % ± 0.53 % dw). High percentages of Fe, Zn, Ca, and K were found in the flower material, along with a high content in antioxidants, polyphenols, and carotenoids, as corroborated by the nuclear magnetic resonance (NMR) data. Flowers were mainly composed of saturated fatty acids (SFAs) (54.50 ± 0.95 % of total FA), followed by polyunsaturated fatty acids (PUFAs) (37.73 ± 1.25 % of total FA) and monounsaturated fatty acids (MUFAs) (7.77 ± 0.34 %), as detected by gas chromatography mass spectrometry (GC–MS). The omega-6 PUFA linoleic acid (22.55 ± 0.76 % of total FA) was the most abundant fatty acid found. Flower extracts showed antimicrobial activity against Saccharomyces cerevisiae and Komagataella phaffii, as well as against Gram-negative (Klebsiella pneumoniae) and Gram-positive (Staphylococcus aureus) bacteria. H. italicum flower material was nontoxic to human intestinal Caco-2 model cells at concentrations up to 1.0 % w/v.

Associations of circulating polyunsaturated fatty acids with coronary artery calcium score in hospitalized patients with suspected coronary artery disease

Abstract Background Inadequate intake of polyunsaturated fatty acids (PUFAs) is recognized as a modifiable risk factor for atherosclerotic cardiovascular disease (CVD) (1,2). The n-6 PUFA linoleic acid (LA) constitutes the predominant portion of total dietary PUFAs (3). However, whereas cardiometabolic effects of PUFAs belonging to the n-3 series have been studied for decades, less attention has been payed to potential health effects from n-6 PUFAs (4). Further, there has been concern regarding possible proinflammatory properties of several n-6 PUFA related metabolites. Purpose We explored correlations of serum total PUFAs, LA and the n-3 PUFA docosahexaenoic acid (DHA) with the inflammation marker GlycA. Further, we evaluated associations of total PUFAs, LA and DHA with the extension of atherosclerosis, as determined by the Agatston coronary artery calcium (CAC) score (5). Methods The study includes 250 patients who were hospitalized due to acute chest pain and referred to coronary CT angiography (CCTA) during in hospital stay. Exclusion criteria included diagnosis of acute myocardial infarction and/or revascularization within 24 hours after admittance. Serum levels of total PUFAs, LA, DHA and GlycA were analyzed by NMR technology in samples that had been frozen and stored at −80°C. After logarithmic transformation, relations of total PUFA, LA, and DHA with GlycA were evaluated by Pearson correlation analyses. The associations with CAC score were visualized in generalized additive regression plots and further evaluated in linear regression models including age, gender, body mass index, diabetes, hypertension and smoking status as independent covariables. Results Mean (SD) age was 57.6 (12.0) years, and 91 (36.4%) of the patients were women. Median (25th-75th percentiles) serum levels (in mmol/L) were for total PUFA 6.36 (5.76–7.06), LA 5.00 (4.51–5.55), DHA 0.36 (0.31–0.43) and GlycA 1.04 (0.94–1.13). Interestingly, GlycA was strongly, positively correlated with total PUFA (r=0.54). LA (r=0.53) and DHA (r=0.27), all P&amp;lt;0.001. In contrast, total PUFA and LA were inversely associated with CAC score both providing standardized betas of −0.17, P=0.03 after multivariable adjustments. No significant associations were found between CAC score and DHA or GlycA (P≥0.22). Further, the addition of GlycA to the multivariable model did not materially affect the relationship between CAC score and total PUFA or LA, which remained statistically significant (P=0.04). Conclusion In patients undergoing CCTA due to acute chest pain, serum levels of total PUFA and LA were strongly positively correlated with the pro-inflammatory marker GlycA. Still, total PUFA and LA were both inversely associated with the CAC score and the associations remained statistically significant after adjustments for CVD risk factors and GlycA levels. Future studies should further address the diverse effects of n-6 PUFAs on inflammatory pathways, atherogenesis and coronary calcification. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): Western Norway Regional Health Authority

Fatty Acids and Frailty: A Mendelian Randomization Study.

Background: Observational studies have suggested that fatty acids such as higher levels of n-3 polyunsaturated fatty acids (PUFAs) may prevent frailty. By using Mendelian randomization analysis, we examined the relationship between fatty acids and frailty. Methods: We used summary statistics data for single-nucleotide polymorphisms associated with plasma levels of saturated fatty acids (palmitic acid, stearic acid), mono-unsaturated fatty acids (MUFAs) (palmitoleic acid, oleic acid), n-6 PUFAs (linoleic acid, arachidonic acid), and n-3 PUFAs (alpha-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid, docosahexaenoic acid), and the corresponding data for frailty index (FI) in 356,432 individuals in the UK Biobank. Results: Although there were no robust associations on the MUFAs or the PUFAs, genetically predicted higher plasma stearic acid level (one of saturated fatty acids) was statistically significantly associated with higher FI (β = 0.178; 95% confidence interval = −0.050 to 0.307; p = 0.007). Such a relationship was also observed in a multivariate MR (β = 0.361; 95% confidence interval = 0.155 to 0.567; p = 0.001). Genetically predicted higher palmitic acid was also significantly associated with higher FI (β = 0.288; 95% confidence interval = 0.128 to 0.447; p < 0.001) in the multivariate MR analysis. Conclusions: The present MR study implies that saturated fatty acids, especially stearic acid, is a risk factor of frailty.

Beneficial Outcomes of Omega-6 and Omega-3 Polyunsaturated Fatty Acids on Human Health: An Update for 2021.

Oxidative stress and inflammation have been recognized as important contributors to the risk of chronic non-communicable diseases. Polyunsaturated fatty acids (PUFAs) may regulate the antioxidant signaling pathway and modulate inflammatory processes. They also influence hepatic lipid metabolism and physiological responses of other organs, including the heart. Longitudinal prospective cohort studies demonstrate that there is an association between moderate intake of the omega-6 PUFA linoleic acid and lower risk of cardiovascular diseases (CVDs), most likely as a result of lower blood cholesterol concentration. Current evidence suggests that increasing intake of arachidonic acid (up to 1500 mg/day) has no adverse effect on platelet aggregation and blood clotting, immune function and markers of inflammation, but may benefit muscle and cognitive performance. Many studies show that higher intakes of omega-3 PUFAs, especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are associated with a lower incidence of chronic diseases characterized by elevated inflammation, including CVDs. This is because of the multiple molecular and cellular actions of EPA and DHA. Intervention trials using EPA + DHA indicate benefit on CVD mortality and a significant inverse linear dose–response relationship has been found between EPA + DHA intake and CVD outcomes. In addition to their antioxidant and anti-inflammatory roles, omega-3 fatty acids are considered to regulate platelet homeostasis and lower risk of thrombosis, which together indicate their potential use in COVID-19 therapy.

Identification of PUFA interaction sites on the cardiac potassium channel KCNQ1.

Polyunsaturated fatty acids (PUFAs), but not saturated fatty acids, modulate ion channels such as the cardiac KCNQ1 channel, although the mechanism is not completely understood. Using both simulations and experiments, we find that PUFAs interact directly with the KCNQ1 channel via two different binding sites: one at the voltage sensor and one at the pore. These two amphiphilic binding pockets stabilize the negatively charged PUFA head group by electrostatic interactions with R218, R221, and K316, while the hydrophobic PUFA tail is selectively stabilized by cassettes of hydrophobic residues. The rigid saturated tail of stearic acid prevents close contacts with KCNQ1. By contrast, the mobile tail of PUFA linoleic acid can be accommodated in the crevice of the hydrophobic cassette, a defining feature of PUFA selectivity in KCNQ1. In addition, we identify Y268 as a critical PUFA anchor point underlying fatty acid selectivity. Combined, this study provides molecular models of direct interactions between PUFAs and KCNQ1 and identifies selectivity mechanisms. Long term, this understanding may open new avenues for drug development based on PUFA mechanisms.

Changes in lipoprotein particle subclasses, standard lipids, and apolipoproteins after supplementation with n-3 or n-6 PUFAs in abdominal obesity: A randomized double-blind crossover study

Summary Background & aims Marine-derived omega-3 (n-3) polyunsaturated fatty acids (PUFAs), mainly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), lower circulating levels of triacylglycerols (TAGs), and the plant-derived omega-6 (n-6) PUFA linoleic acid (LA) may reduce cholesterol levels. Clinical studies on effects of these dietary or supplemental PUFAs on other blood fat fractions are few and have shown conflicting results. This study aimed to determine effects of high-dose supplemental n-3 (EPA + DHA) and n-6 (LA) PUFAs from high-quality oils on circulating lipoprotein subfractions and standard lipids (primary outcomes), as well as apolipoproteins, fatty acids, and glycemic control (secondary outcomes), in females and males with abdominal obesity. Methods This was a randomized double-blind crossover study with two 7-wk intervention periods separated by a 9-wk washout phase. Females (n = 16) were supplemented with 3 g/d of EPA + DHA (TAG fish oil) or 15 g/d of LA (safflower oil), while males (n = 23) received a dose of 4 g/d of EPA + DHA or 20 g/d of LA. In fasting blood samples, we investigated lipoprotein particle subclasses by nuclear magnetic resonance spectroscopy, as well as standard lipids, apolipoproteins, fatty acid profiles, and glucose and insulin. Data were analyzed by linear mixed-effects modeling with ‘subjects’ as the random factor. Results The difference between interventions in relative change scores was among the lipoprotein subfractions significant for total very-low-density lipoproteins (VLDLs) (n-3 vs. n-6: −38%∗ vs. +16%, p Conclusions High-dose supplementation of high-quality oils with n-3 (EPA + DHA) or n-6 (LA) PUFAs was followed by reductions in primarily TAG- or cholesterol-related markers, respectively. The responses after both interventions point to changes in the lipoprotein–lipid–apolipoprotein profile that have been associated with reduced cardiometabolic risk, also among people with TAG or LDL-C levels within the normal range. Registration Registered under ClinicalTrials.gov Identifier: NCT02647333. Clinical trial registration Registered at https://clinicaltrials.gov/ct2/show/NCT02647333 .

Ewe's diet during gestation and lactation affects ready-to-eat meat from light lambs

Maternal grazing may benefit the fatty acid (FA) profile of lamb meat, although any improvement in terms of healthier polyunsaturated FAs (PUFA) may be impaired during subsequent culinary treatments. The objective was to assess the effects of a grass-based ewe diet on the FA profile of the ready-to-eat meat from grain-fed Segureña light lamb. The FA were determined in raw, grilled (G), Sous Vide (SV) cooked and cooked/hot-held (H) lamb leg patties resulting from two maternal rearing systems: grazing (Mediterranean trees, shrubs, herbs, stubble and fallow) or indoors (cereal grain and lucerne pellets). The grass-based ewe diet increased (P < 0.05) levels of n-3 PUFA and total linoleic conjugated acid (CLA), and decreased those of n-6 long chain PUFA and saturated FA (SFA) in the patties from all treatments. These changes in FA slightly increased (P < 0.05) the PUFA/SFA ratio and decreased (P < 0.05) the n-6/n-3 ratio in the raw (from 8.7 to 6.3), SV (from 8.8 to 6.2), G (from 9.0 to 6.3), SV + H (from 8.2 to 6.3) and G + H (from 9.3 to 6.4) patties, improving the atherogenic, thrombogenic and saturation indexes. The effects of the ewe's diet on lamb FA remained unaltered after successive culinary treatments, including aerobically mincing, cooking at an internal temperature of 72 °C and H at 65 °C for 4 h. Heating induced a partial degradation of meat PUFA but also favoured the loss of high saturated melted fat. Both facts balanced the PUFA/SFA ratio in cooked lamb despite the gradual formation of oxidised secondary lipids to the detriment of FA. Grilling or SV cooking did not affect the remaining levels of undegraded FA in the freshly cooked lamb, although SV improved the results obtained for the cooked/H lamb. Maternal diets based on grass result in a healthier ready-to-eat lamb.

Association of n-6 PUFAs with the risk of diabetic retinopathy in diabetic patients.

Diabetic retinopathy (DR), the most common microvascular complication of diabetes and leading cause of visual impairment in adults worldwide, is suggested to be linked to abnormal lipid metabolism. The present study aims to comprehensively investigate the relationship between n-6 polyunsaturated fatty acids (PUFAs) and DR. This was a propensity score matching based case–control study, including 69 pairs of DR patients and type 2 diabetic patients without DR with mean age of 56.7 ± 9.2 years. Five n-6 PUFAs were determined by UPLC-ESI-MS/MS system. Principle component regression (PCR) and multiple conditional logistic regression models were used to investigate the association of DR risk with n-6 PUFAs depending on independent training and testing sets, respectively. According to locally weighted regression model, we observed obvious negative correlation between levels of five n-6 PUFAs (linoleic acid, γ-linolenic acid, eicosadienoic acid, dihomo-γ-linolenic acid and arachidonicacid) and DR. Based on multiple PCR model, we also observed significant negative association between the five n-6 PUFAs and DR with adjusted OR (95% CI) as 0.62 (0.43,0.87). When being evaluated depending on the testing set, the association was still existed, and PCR model had excellent classification performance, in which area under the curve (AUC) was 0.88 (95% CI: 0.78, 0.99). In addition, the model also had valid calibration with a non-significant Hosmer–Lemeshow Chi-square of 9.44 (P = 0.307) in the testing set. n-6 PUFAs were inversely associated with the presence of DR, and the principle component could be potential indicator in distinguishing DR from other T2D patients.

Decreased Docosahexaenoic Acid Levels in Serum of HIV Carrier Patients.

The study aimed to measure serum fatty acids (FAs) composition in HIV carrier patients and compare it with non-HIV carrier patients. The FAs composition was measured by gas chromatography as follows: four saturated FAs myristic acid (14:0), palmitic acid (16:0), stearic acid (18:0), and docosanoic acid (22:0); four monounsaturated FAs 7-hexadecenoic acid (16:1 n-9), palmitoleic acid (16:1 n-7), oleic acid (18:1 n-9), and vaccenic acid (18:1 n-7); and three polyunsaturated FAs linoleic acid (18:2 n-6), dihomo-γ-linolenic acid (20:3 n-6), and docosahexaenoic acid (DHA, 22:6 n-3). We reported herein lower (P < .05) DHA concentration (by 40%) in the serum of HIV carrier patients than in non-HIV carrier patients. This FA has a pivotal role as a precursor of anti-inflammatory molecules with beneficial effects on metabolism, cardiovascular system, and immunological system. Even though most clinical studies reported beneficial effects of DHA supplementation in HIV carrier patients, this issue remains under debate. Further investigations then require to fully clarify the role of DHA in preventing or alleviating the comorbidities associated with HIV infection.

\u03c9-6 Polyunsaturated fatty acids (linoleic acid) activate both autophagy and antioxidation in a synergistic feedback loop via TOR-dependent and TOR-independent signaling pathways

ω-6 Polyunsaturated fatty acids (PUFAs) are essential fatty acids that participate in macroautophagy (hereafter referred to as autophagy) and the Kelch ECH-associating protein 1 (Keap1)—nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant system in organisms. However, the molecular mechanisms by which ω-6 PUFAs (linoleic acid) regulate autophagy and Keap1–Nrf2 antioxidant system are not completely understood. Therefore, the purposes of this study were to explore the molecular mechanisms by which ω-6 PUFAs (linoleic acid) regulate autophagy and antioxidant system and to investigate the potential relationship between autophagy and antioxidant system through transcriptomic analysis, quantitative real-time polymerase chain reaction (RT-qPCR), western blot analysis, coimmunoprecipitation (Co-IP) and electrophoretic mobility shift assays (EMSAs) in vivo and in vitro. The results of the present study indicated that ω-6 PUFAs in diets induced autophagy but decrease antioxidant ability in vivo. However, the results also provided evidence, for the first time, that ω-6 PUFAs (linoleic acid) induced autophagy and increased antioxidant ability through the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway and the AMPK-target of rapamycin (TOR) signaling pathway in hepatocytes in vitro. Interestingly, the findings revealed a ω-6 PUFA-induced synergistic feedback loop between autophagy and antioxidant system, which are connected with each other through the P62 and Keap1 complex. These results suggested that ω-6 PUFAs (linoleic acid) could be useful for activating a synergistic feedback loop between autophagy and antioxidant system and could greatly aid in the prevention and treatment of multiple pathologies.

The Ratio of Linoleic and Linolenic Acid in the Pre-hibernation Diet Influences NFκB Signaling in Garden Dormice During Torpor.

The fatty acid composition of a pre-hibernation diet can influence the depth and duration of metabolic suppression achieved by hibernators. More specifically, a diet high in n−6 polyunsaturated fatty acids (PUFAs) relative to n−3 PUFAs is essential to maximize torpor expression. However, few studies have investigated how diets with different n−6/n−3 PUFA ratios change stress-inducible cell signaling. Garden dormice (Eliomys quercinus) were fed one of three diets designed with different ratios of n−6 PUFA linoleic acid (LA) and n−3 PUFA linolenic acid (ALA). Then, NFκB signaling was assessed in the white adipose, brown adipose, and liver tissues of euthermic and hibernating dormice via multiplex and RT-qPCR analyses of relative protein and transcript levels, respectively. Dormice fed a high LA diet regulated NFκB signaling in a protective manner in all tissues. NFκB signaling was generally decreased in the high LA group, with significant decreases in the protein levels of NFκB mediators IKKα/β, IκBα, and downstream pro-apoptotic protein FADD. Liver and white adipose from torpid dormice fed a high LA diet increased sod2 expression relative to the other diets or relative to euthermic controls, indicating protection against ROS generated from potentially increased β-oxidation of n−6 PUFAs. The low LA diet increased biomarkers for apoptosis relative to other diets and relative to euthermia, suggesting low LA diets may be detrimental to hibernator health. Overall, this study suggests that changes in the ratio of n−6/ n−3 PUFAs in the diet influences apoptotic and antioxidant responses in white adipose, brown adipose, and liver of hibernating garden dormice.

Identification of PUFA Interaction Sites on a Cardiac Potassium Channel

Polyunsaturated fatty acids (PUFAs) have anti-arrhythmic effects in the heart, although the molecular mechanism is not fully understood. PUFAs have been shown to activate the cardiac KV7.1 channel by shifting voltage dependence of activation towards more negative voltages and increasing maximal conductance. In this study, we combine molecular dynamics simulations and electrophysiology experiments to resolve the atomistic basis for PUFA modulation of KV7.1. We find in molecular dynamics simulations that PUFAs interact with two sites on KV7.1: site 1 close to the voltage sensor in a pocket between S4 and S5 and site 2 close to the pore in a cavity between S6 and S1. The negatively-charged PUFA head group interacts with basic residues at both sites. The flexible tail of the PUFA linoleic acid allows it to form many and long-lasting interactions with hydrophobic residues in S4, S5, the pore helix, and S6. In contrast, the more rigid nature of saturated stearic acid limits its ability to form close contact with KV7.1. Mutation of several predicted binder residues from simulations were found experimentally to impair the ability of linoleic acid to activate KV7.1. Mutation of residues in site 1 primarily shifted the concentration-response for the effect on voltage dependence towards higher concentrations. Mutation of residues in site 2 primarily reduced the effect of linoleic acid on maximal conductance. Altogether, this study describes the atomistic basis of how PUFAs such as linoleic acid bind to two distinct sites in the KV7.1 channel to shift the voltage dependence of activation and increase the maximal conductance. Moreover, this study provides a mechanistic understanding of why saturated fatty acids such as stearic acid fail to activate KV7.1. The identified interactions open for development of more effective anti-arrhythmic drugs based on PUFAs.

Boundary Lipids of the Nicotinic Acetylcholine Receptor in Quasi-Native Membranes

The nicotinic acetylcholine receptor (nAChR) is a neurotransmitter receptor and pentameric ligand gated ion channel (pLGIC) critical for signaling across synapses, including the neuromuscular junction. In reconstituted membranes, the nAChR function depends heavily on cholesterol, leading to the hypothesis that nAChR will partition into cholesterol-enriched liquid-ordered domains ("rafts”). Native nAChR membranes are rich in lipids with saturated fatty acid (like palmitic acid) or polyunsaturated fatty acid (PUFA) acyl chains (like docosahexaenoic acid (DHA)). Using coarse-grained molecular dynamics simulations we characterized preferential lipid interactions and partitioning behavior of nAChR in binary membranes (cholesterol and lipids with two palmitic acid acyl chains) ternary membranes (cholesterol, a lipid with two palmitic acid acyl chains, and lipids with either two chains composed of the long-chain omega-3 PUFA DHA or of the omega-6 PUFA linoleic acid). We quantify occupation of non-annular and annular regions by cholesterol and saturated and polyunsaturated lipids. In the absence of PUFAs, cholesterol is enriched in the nAChR annulus in a concentration-dependent manner. Cholesterol is also distributed throughout the non-annular (embedded) sites, while palmatic acyl chains persistently occupy only one interface between the beta and alpha subunits. When lipids containing long-chain PUFA acyl chains are introduced, they displace cholesterol from two additional interfaces. Contrary to expectations, in domain-forming membranes containing PUFAs, the nAChR is observed to consistently partition into PUFA-rich, cholesterol-poor domains. Saturated lipids with either phosphatidylcholine and phosphatidylethanolamine head groups are significantly depleted in such systems, although the extent of depletion is reduced for phosphatidylethanolamine. While nAChR consistently partitions into the cholesterol poor domain, alpha-gamma and delta-beta faces interact more than other faces with the cholesterol-rich domains. We extend this approach to more complex membranes of interest, including more realistic synaptic membranes and the Xenopus oocyte membranes used for electrophysiology.

The Brain Oxylipin Profile Is Resistant to Modulation by Dietary n-6 and n-3 Polyunsaturated Fatty Acids in Male and Female Rats.

Oxylipins are bioactive lipids formed by the monooxygenation of polyunsaturated fatty acids (PUFA). Eicosanoids derived from arachidonic acid (ARA) are the most well-studied class of oxylipins that influence brain functions in normal health and in disease. However, comprehensive profiling of brain oxylipins from other PUFA with differing functions, and the examination of the effects of dietary PUFA and sex differences in oxylipins are warranted. Therefore, female and male Sprague-Dawley rats were provided standard rodent diets that provided additional levels of the individual n-3 PUFA α-linolenic acid (ALA), eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA), or the n-6 PUFA linoleic acid (LNA) alone or with ALA (LNA + ALA) compared to essential fatty acid-sufficient control diets. Oxylipins and PUFA were quantified in whole brains using HPLC-MS/MS and GC, respectively. Eighty-seven oxylipins were present at quantifiable levels: 51% and 17% of these were derived from ARA and DHA, respectively. At the mass level, ARA and DHA oxylipins comprised 81-90% and 6-12% of total oxylipins, while phospholipid ARA and DHA represented 25-35% and 49-62% of PUFA mass, respectively. Increasing dietary n-3 PUFA resulted in higher levels of oxylipins derived from their precursor PUFA; otherwise, the brain oxylipin profile was largely resistant to modulation by diet. Approximately 25% of oxylipins were higher in males, and this was largely unaffected by diet, further revealing a tight regulation of brain oxylipin levels. These fundamental data on brain oxylipin composition, diet effects, and sex differences will help guide future studies examining the functions of oxylipins in the brain.

Inadequate daily intakes of n-3 polyunsaturated fatty acids (PUFA) in the general French population of children (3-10 years) and adolescents (11-17 years): the INCA2 survey.

This paper deals with the dietary daily intakes of main polyunsaturated fatty acids (PUFA) in French children and adolescents. Dietary intakes of main PUFA were determined from a general French population of 1500 children (3-10 years) and adolescents (11-17 years) by using the most recent set of national robust data on food (National Survey INCA 2 performed in 2006 and 2007). Main results showed that mean daily intakes of total fat and n-6 PUFA linoleic acid (LA, 18:2n-6) were close to current recommended values for children and adolescent populations. However, 80% (children) to 90% (adolescents) of our French populations not only ingested low quantities of n-3 long-chain PUFA (docosahexaenoic (22:6n-3) and eicosapentaenoic (20:5n-3) acids) but also very low quantities of alpha-linolenic acid (ALA, 18:3n-3) at the origin of a non-balanced n-6/n-3 ratio. Inadequate consumption of EPA + DHA was also observed in subgroups of infants and adolescent who consumed more than two servings/week of fish. Such disequilibrium in PUFA dietary intakes in favor of n-6 PUFA could have adverse impact on cell membrane incorporation of long-chain n-3 PUFA and deleterious impacts on the health of children and adolescents. Promoting the consumption of both vegetable oils and margarines rich in ALA, and oily fish rich in long-chain n-3 PUFA might improve such PUFA disequilibrium.