Higher ratio of plasma omega-6/omega-3 fatty acids is associated with greater risk of all-cause, cancer, and cardiovascular mortality: A population-based cohort study in UK Biobank.

Background: Circulating omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) have been associated with various chronic diseases and mortality, but results are conflicting. Few studies examined the role of omega-6/omega-3 ratio in mortality. Methods: We investigated plasma omega-3 and omega-6 PUFAs and their ratio in relation to all-cause and cause-specific mortality in a large prospective cohort, the UK Biobank. Of 85,425 participants who had complete information on circulating PUFAs, 6461 died during follow-up, including 2794 from cancer and 1668 from cardiovascular disease (CVD). Associations were estimated by multivariable Cox proportional hazards regression with adjustment for relevant risk factors. Results: Risk for all three mortality outcomes increased as the ratio of omega-6/omega-3 PUFAs increased (all Ptrend <0.05). Comparing the highest to the lowest quintiles, individuals had 26% (95% CI, 15-38%) higher total mortality, 14% (95% CI, 0-31%) higher cancer mortality, and 31% (95% CI, 10-55%) higher CVD mortality. Moreover, omega-3 and omega-6 PUFAs in plasma were all inversely associated with all-cause, cancer, and CVD mortality, with omega-3 showing stronger effects. Conclusions: Using a population-based cohort in UK Biobank, our study revealed a strong association between the ratio of circulating omega-6/omega-3 PUFAs and the risk of all-cause, cancer, and CVD mortality. Funding: Research reported in this publication was supported by the National Institute of General Medical Sciences of the National Institute of Health under the award number R35GM143060 (KY). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Fatty acids play an essential role in health. Studies have shown that diets high in omega-3 fatty acids found in foods like fish, fish oil, flaxseed and walnuts may be beneficial. Yet some studies have raised concern that too many omega-6 fatty acids in Western diets rich in vegetable oils may be harmful. Some scientists have proposed that the balance of omega-3 and omega-6 in diets is vital to health. They hypothesize that a higher omega-6 to omega-3 fatty acids ratio is detrimental. But, proving that a higher ratio of omega-6 to omega-3 fatty acids is harmful has been difficult. Many studies have found conflicting results. Scientists have struggled to accurately measure fatty acid intake as tracking an individual's dietary intake is challenging and self-reported dietary intake may be incorrect. Additionally, scientists must follow individuals for many years to determine if a high ratio of omega-6 to omega-3 is linked with cancer, heart disease, or death. But, measuring circulating fatty acids in an individual's blood may offer an easier and more reliable approach to studying the health impacts of these vital nutrients. Zhang et al. show that people with higher ratios of omega-6 to omega-3 fatty acids in their blood are at greater risk of dying from cancer, heart disease, or any cause than those with lower ratios. The experiments measured omega-6 and omega-3 fatty acid levels in more than 85,000 participants in the UK Biobank who scientists followed for an average of about 13 years. Participants with the highest ratios of omega-6 to omega-3 fatty acids were 26% more likely to die of any cause, 14% more likely to die of cancer, and 31% more likely to die of heart disease than individuals with the lowest ratios. Individually, high levels of omega-6 fatty acids and high levels of omega-3 fatty acids were both associated with a lower risk of dying. But the protective effects of omega-3 were greater. For example, individuals with the highest levels of omega-6 fatty acids were 23% less likely to die of any cause. By comparison, those with the highest levels of omega-3s were 31% less likely to die. The stronger protection offered by high levels of omega-3s likely explains why having a high ratio of omega-6s to omega-3s was linked to harm. Both are protective. But the protection provided by omega-3s is more robust. The experiments support dietary interventions to raise omega-3 fatty acid levels and maintain a low omega-6 to omega-3 fatty acid ratio to prevent early deaths from cancer, heart disease or other causes. More research is needed to understand the impact of dietary fatty acid intake on other diseases and how genetics may influence the health impact of fatty acids.

RNA Sequencing Reveals the Inhibitory Effect of High Levels of Arachidonic Acid and Linoleic Acid on C2C12 Differentiation and Myogenic Biomarkers.

Over the past three decades, studies have shown that consuming polyunsaturated fatty acids (PUFAs) can enhance animal and human health and welfare through biological, biochemical, pathological, and pharmacological impacts. Furthermore, omega-6 plays key roles in the cardiopulmonary system, including promoting airway relaxation and inhibiting atherosclerosis and hypertension. However, findings from investigations of the effects of omega-6 fatty acids on molecular and cellular activity and discussions on their influence on biomarkers are still unclear. Therefore, the present study aimed to evaluate omega-6 fatty acids, the arachidonic acid (AA), and linoleic acid (LA) effects on C2C12 proliferation, myogenesis morphology, and relative myogenic biomarker expression through the Wnt pathway. C2C12 cells were cultured with and without 25, 50, 100, and 150 µM of LA and AA and then subjected to CCK8, Giemsa staining, RT qPCR, Western blotting, and RNA Sequencing. The CCK8 Assay results showed that 25, 50, 100, and 150 µM LA significantly decreased the viability after 72 h for 25, 50, 100, and 150 µM concentrations. Also, AA supplementation decreased cell viability after 24 h for 150 µM, 48 h for 150 µM, and 72 h for 50, 100, and 150 µM concentrations. Moreover, the LA and AA inhibitory effects noticed through Gimesa staining were morphological changes during myoblast differentiation. Both LA and AA showed inhibiting IGF1, Cola1, Col6a2, Col6a1, Itga10, Itga11, SFRP2, DAAM2, and NKD2 effects; however, the depressing effect was higher for AA compared to LA. The previous results were confirmed through Western blotting, which showed that 50 µM LA and AA significantly reduced DAAM2 and SFRP2 protein levels compared to the control. Regarding RNA sequencing results, LA and AA increased the number of differentially expressed (DE) Mt-rRNA and snoRNA; however, the numbers of lncRNA detected decreased compared to the control. Our findings demonstrate that high and moderate LA and AA concentrations reduce primary myoblast proliferation and differentiation. Also, they highlight novel biomarkers and regulatory factors to improve our understanding of how the nutrition of fatty acids can control and modulate the myogenesis and differentiation process through different biomarker families.

Bioactive metabolites of OMEGA-6 and OMEGA-3 fatty acids are associated with inflammatory cytokine concentrations in maternal and infant plasma at the time of delivery.

BACKGROUND & AIMS: Inflammation is necessary for a healthy pregnancy. However, unregulated or excessive inflammation during pregnancy is associated with severe maternal and infant morbidities, such as pre-eclampsia, abnormal infant neurodevelopment, or preterm birth. Inflammation is regulated in part by the bioactive metabolites of omega-6 (n-6) and omega-3 (n-3) fatty acids (FAs). N-6 FAs have been shown to promote pro-inflammatory cytokine environments in adults, while n-3 FAs have been shown to contribute to the resolution of inflammation; however, how these metabolites affect maternal and infant inflammation is still uncertain. The objective of this study was to predict the influence of n-6 and n-3 FA metabolites on inflammatory biomarkers in maternal and umbilical cord plasma at the time of delivery. METHODS: Inflammatory biomarkers (IL-1ß, IL-2, IL-6, IL-8, IL-10, and TNFα) for maternal and umbilical cord plasma samples in 39 maternal-infant dyads were analyzed via multi-analyte bead array. Metabolites of n-6 FAs (arachidonic acid and linoleic acid) and n-3 FAs (eicosapentaenoic acid and docosahexaenoic acid) were assayed via liquid chromatography-mass spectrometry. Linear regression models assessed relationships between maternal and infant inflammatory markers and metabolite plasma concentrations. RESULTS: Increased plasma concentrations of maternal n-6 metabolites were predictive of elevated pro-inflammatory cytokine concentrations in mothers; similarly, higher plasma concentrations of umbilical cord n-6 FA metabolites were predictive of elevated pro-inflammatory cytokine concentrations in infants. Higher plasma concentrations of maternal n-6 FA metabolites were also predictive of elevated pro-inflammatory cytokines in infants, suggesting that maternal n-6 FA status has an intergenerational impact on the inflammatory status of the infant. In contrast, maternal and cord plasma concentrations of n-3 FA metabolites had a mixed effect on inflammatory status in mothers and infants, which may be due to the inadequate maternal dietary intake of n-3 FAs in our study population. CONCLUSIONS: Our results reveal that maternal FA status may have an intergenerational impact on the inflammatory status of the infant. Additional research is needed to identify how dietary interventions that modify maternal FA intake prior to or during pregnancy may impact maternal and infant inflammatory status and associated long-term health outcomes.

APOA-5 genetic variant and a hypocaloric diet enriched in ω-6 fatty acids with Mediterranean pattern.

OBJECTIVE: The APOA5-1131C allele is related to a worse lipid profile and metabolic response to diet interventions. The present study was designed to investigate the effect of SNP rs662799 on the lipid profile of patients with obesity after a hypocaloric diet with a Mediterranean pattern enriched in ω-6 polyunsaturated fatty acids (PUFA). PATIENTS AND METHODS: A population of 362 Caucasian patients with obesity was evaluated. Anthropometric evaluation and serum parameters (lipid profile, insulin, homeostasis model assessment (HOMA-IR), glucose, C reactive protein, and adipokines) were measured at basal time and after 12 weeks. All subjects were genotyped rs662799. RESULTS: The APOA5 variant distribution among the 362 patients with obesity was the following: 87.2% (n=316) (TT) were homozygous for the T allele, 12.2% (n=44) (TC) were heterozygous, and 0.6% (n=2) (CC) were homozygous for the C allele. There were only significant differences in triglyceride levels between genotype groups. After 12 weeks of intervention, the following parameters improved in both genotype groups: adiposity parameters, systolic blood pressure, total cholesterol, LDL cholesterol, leptin, adiponectin, and ratio leptin/adiponectin. Insulin levels (delta: -3.5±0.2 UI/L vs. -1.2±0.6 UI/L; p=0.03), HOMA-IR (delta: -1.6±0.1 units vs. -0.3±0.2 units; p=0.01) and triglyceride levels (delta: -18.8±4.1 mg/dl vs. -3.7 ±3.0 mg/dl; p=0.02) decreased in non-C allele carriers. CONCLUSIONS: Our data demonstrate that the minor C allele of the APOA5 gene (rs662799) produces a worse response in triglyceride levels, insulin levels, and HOMA-IR after a ω-6 PUFA enriched hypocaloric diet with Mediterranean pattern.

The causal relationship between human blood metabolites and the risk of visceral obesity: a mendelian randomization analysis.

BACKGROUND: We aimed to explore the causal relationship between blood metabolites and the risk of visceral obesity, as measured by visceral adipose tissue (VAT). METHODS: Summary statistics for 486 blood metabolites and total, as well as sex-stratified, MRI-derived VAT measurements, adjusted for body mass index (BMI) and height, were collected from previous genome-wide association studies (GWAS). A two-sample Mendelian Randomization (MR) design was used. Comprehensive evaluation was further conducted, including sensitivity analysis, linkage disequilibrium score (LDSC) regression, Steiger test, and metabolic pathway analysis. RESULTS: After multiple testing correction, arachidonate (20:4n6) has been implicated in VAT accumulation (ß = 0.35, 95%CI:0.18-0.52, P < 0.001; FDR = 0.025). Additionally, several blood metabolites were identified as potentially having causal relationship (FDR < 0.10). Among them, lysine (ß = 0.67, 95%CI: 0.28-1.06, P < 0.001; FDR = 0.074), proline (ß = 0.30, 95%CI:0.13-0.48, P < 0.001; FDR = 0.082), valerate (ß = 0.50, 95%CI:0.23-0.78, P < 0.001, FDR = 0.091) are associated with an increased risk of VAT accumulation. On the other hand, glycine (ß=-0.21, 95%CI: -0.33-0.09), P < 0.001, FDR = 0.076) have a protective effect against VAT accumulation. Most blood metabolites showed consistent trends between different sexes. Multivariable MR analysis demonstrated the effect of genetically predicted arachidonate (20:4n6) and proline on VAT remained after accounting for BMI and glycated hemoglobin (HbA1c). There is no evidence of heterogeneity, pleiotropy, and reverse causality. CONCLUSION: Our MR findings suggest that these metabolites may serve as biomarkers, as well as for future mechanistic exploration and drug target selection of visceral obesity.

Fatty acids and their metabolites (resolvins) are altered in women with gestational diabetes mellitus (GDM).

The maternal fatty acid status plays a key role in influencing pregnancy outcomes. Omega-3 fatty acids are the precursors for E-series (RvE) and D-series resolvins (RvD) and possess anti-inflammatory properties. Pregnancy complications like gestational diabetes mellitus (GDM) are associated with excess maternal inflammation. This study reports the levels of maternal fatty acids across gestation in GDM and non-GDM women, placental fatty acids, resolvins and their association with the maternal fatty acid status. Pregnant women were recruited at 11-14 (V1) weeks and followed at 18-22 (V2) and 26-28 (V3) weeks and at delivery (V4). A total of 209 women who were diagnosed as GDM and 207 non-GDM women were included in this study. Fatty acids were estimated using gas chromatography. The protein levels of resolvins (RvE1, RvE2, RvD1 and RvD2) were measured using ELISA kits. Total PUFAs, eicosapentaenoic acid (EPA), omega-6 fatty acids, linoleic acid (LA) and arachidonic acid (AA) were lower, while saturated fatty acid (SFA) and alpha-linolenic acid (ALA) levels were higher in GDM women at 18-22 weeks. Placental AA was lower (p < 0.05) in women with GDM. Placental protein levels of RvE1, RvD1 and RvD2 were lower (p < 0.001 for all) in the GDM group. The maternal delta 5 desaturase index was positively associated, while erythrocyte omega-3 and omega-6 fatty acids were negatively associated with RvE2 at 11-14 weeks. Placental LA and ALA were positively associated with RvD1 and RvD2 (p < 0.05, for both), respectively. Our findings suggest that the maternal fatty acid status influences pro-resolving mediators which may lead to increased inflammation in GDM.

Maternal Diet High in Linoleic Acid Alters Offspring Lipids and Hepatic Regulators of Lipid Metabolism in an Adolescent Rat Model.

Linoleic acid (LA), an n-6 polyunsaturated fatty acid (PUFA), is essential for fetal growth and development. A maternal high LA (HLA) diet alters cardiovascular development in adolescent rats and hepatic function in adult rats in a sex-specific manner. We investigated the effects of an HLA diet on adolescent offspring hepatic lipids and hepatic lipid metabolism gene expression, and the ability of the postnatal diet to alter these effects. Female Wistar Kyoto rats were fed low LA (LLA; 1.44% energy from LA) or high LA (HLA; 6.21% energy from LA) diets during pregnancy and gestation/lactation. Offspring, weaned at postnatal day (PN) 25, were fed LLA or HLA and euthanised at PN40 (n = 6-8). Maternal HLA increased circulating uric acid, decreased hepatic cholesterol and increased hepatic Pparg in males, whereas only hepatic Srebf1 and Hmgcr increased in females. Postnatal (post-weaning) HLA decreased liver weight (% body weight) and increased hepatic Hmgcr in males, and decreased hepatic triglycerides in females. Maternal and postnatal HLA had an interaction effect on Lpl, Cpt1a and Pparg in females. These findings suggest that an HLA diet both during and after pregnancy should be avoided to improve offspring disease risk.

Impaired Detoxification of Trans, Trans-2,4-Decadienal, an Oxidation Product from Omega-6 Fatty Acids, Alters Insulin Signaling, Gluconeogenesis and Promotes Microvascular Disease.

Omega-6 fatty acids are the primary polyunsaturated fatty acids in most Western diets, while their role in diabetes remains controversial. Exposure of omega-6 fatty acids to an oxidative environment results in the generation of a highly reactive carbonyl species known as trans, trans-2,4-decadienal (tt-DDE). The timely and efficient detoxification of this metabolite, which has actions comparable to other reactive carbonyl species, such as 4-hydroxynonenal, acrolein, acetaldehyde, and methylglyoxal, is essential for disease prevention. However, the detoxification mechanism for tt-DDE remains elusive. In this study, the enzyme Aldh9a1b is identified as having a key role in the detoxification of tt-DDE. Loss of Aldh9a1b increased tt-DDE levels and resulted in an abnormal retinal vasculature and glucose intolerance in aldh9a1b-/- zebrafish. Transcriptomic and metabolomic analyses revealed that tt-DDE and aldh9a1b deficiency in larval and adult zebrafish induced insulin resistance and impaired glucose homeostasis. Moreover, alterations in hyaloid vasculature is induced by aldh9a1b knockout or by tt-DDE treatment can be rescued by the insulin receptor sensitizers metformin and rosiglitazone. Collectively, these results demonstrated that tt-DDE is the substrate of Aldh9a1b which causes microvascular damage and impaired glucose metabolism through insulin resistance.

Omega-3 and omega-6 fatty acids food intake and metabolic syndrome in adolescents 12 to 17 years old: A school-based cross-sectional study.

BACKGROUND & AIMS: Fatty acids (FAs) of the omega-3 and omega-6 family are considered essential, and adequate intake seems to be associated with lower risk of developing chronic non-communicable diseases. The objective was to evaluate the association of omega-3 and omega-6 FAs dietary intake with the prevalence of MS and its components waist circumference (WC), blood pressure (BP), fasting blood glucose, triglycerides and High Density Lipoprotein - cholesterol (HDL-c) in Brazilian adolescents aged 12-17 years. METHODS: This is a school-based cross-sectional investigation, using data from the Study of Cardiovascular Risks in Adolescents (ERICA), carried out between 2013 and 2014. The following variables were collected and assessed: 1) sociodemographic (sex, age, type of school, school location whether urban or rural and region of the country); 2) food consumption was measured through a 24-h Food Recall (24 hR), and a second 24 hR was applied to 7% of the total sample; 3) anthropometrics (weight, height, WC), BP and biochemical (glycemia, triglycerides and HDL-c) were also assessed. Logistic regression analysis was performed according to gender and age group. RESULTS: A total of 36,751 adolescents participated in the study. The intake of omega-3 FAs in the total population was 1.71 g/day and of omega-6 FAs, 13.56 g/day, with an omega-6/omega-3 ratio of 7.93:1. It was found that higher intake of omega-3 FAs was associated with an 53% lower chance of low HDL-c. For omega-6 FAs, no significant results were found. CONCLUSIONS: The findings indicated an association between omega-3 FAs and HDL-c. More studies are needed to elucidate the effects of omega-6 FAs.

The relationship between the intake of dietary fatty acids and minerals with sperm parameters in infertile men.

BACKGROUND & AIMS: Infertility has been increasing among Iranian couples. Some epidemiological studies have reported a relationship between infertility and lifestyle patterns, including dietary habits. Our objective was to evaluate the relationship between sperm parameters and the intake of dietary fatty acids and minerals among Iranian infertile men. METHODS: This cross-sectional was performed on 400 newly diagnosed infertile men at Yazd Reproductive Sciences Institute from July to December 2019. Men whose infertility was confirmed by an andrologist based on the World Health Organization (WHO) criteria were selected. They delivered a semen sample and answered a 168-item semi-quantitative food frequency questionnaire. All data were analyzed using SPSS and STATA software. A p-value of less than 0.5 was considered significant. RESULTS: In the adjusted model, a significant negative association between sperm motility and the 3rd quartile (Q) of poly-unsaturated fatty acids compared to the 1st quartile) P = 0.02). Also, in the adjusted model, total mobility was significantly increased in the second, third and last quartiles of omega-3 fatty acids compared to the first quartile (P < 0.001, P = 0.02, P < 0.001, respectively). Furthermore, omega-6 fatty acid intake in the last quartile were positively associated with sperm motility (P = 0.01). Moreover, there was a significant association between omega-3 fatty acid intake in the second, third, and last quartiles and sperm normal morphology (P = 0.003, P = 0.018, and P = 0.005, respectively) compared with the first quartile. Further, we observed a significant association between omega-6 fatty acid intake and sperm normal morphology in the last quartile compared with the reference quartile (P = 0.04). Also, the findings showed a significant negative association between the second quartile of sodium and calcium intake and sperm volume compared with the first quartile (P = 0.04, for both) in the adjusted model. CONCLUSIONS: We concluded that dietary polyunsaturated fatty acid, sodium, and calcium intake are related to sperm morphology, volume, and total motility in Iranian infertile men. However, more research is needed to confirm these relationships and provide evidence to exert these findings into clinical practice.

Differential Interventional Effects of Omega-6 and Omega-3 Polyunsaturated Fatty Acids on High Fat Diet-Induced Obesity and Hepatic Pathology.

Current Dietary Guidelines for Americans recommend replacing saturated fat (SFA) intake with polyunsaturated fatty acids (PUFAs) and monosaturated fatty acids (MUFAs) but do not specify the type of PUFAs, which consist of two functionally distinct classes: omega-6 (n-6) and omega-3 (n-3) PUFAs. Given that modern Western diets are already rich in n-6 PUFAs and the risk of chronic disease remains high today, we hypothesized that increased intake of n-3 PUFAs, rather than n-6 PUFAs, would be a beneficial intervention against obesity and related liver diseases caused by high-fat diets. To test this hypothesis, we fed C57BL/6J mice with a high-fat diet (HF) for 10 weeks to induce obesity, then divided the obese mice into three groups and continued feeding for another 10 weeks with one of the following three diets: HF, HF+n-6 (substituted half of SFA with n-6 PUFAs), and HF+n-3 (substituted half of SFA with n-3 PUFAs), followed by assessment of body weight, fat mass, insulin sensitivity, hepatic pathology, and lipogenesis. Interestingly, we found that the HF+n-6 group, like the HF group, had a continuous increase in body weight and fat mass, while the HF+n-3 group had a significant decrease in body weight and fat mass, although all groups had the same calorie intake. Accordingly, insulin resistance and fatty liver pathology (steatosis and fat levels) were evident in the HF+n-6 and HF groups but barely seen in the HF+n-3 group. Furthermore, the expression of lipogenesis-related genes in the liver was upregulated in the HF+n-6 group but downregulated in the HF+n-3 group. Our findings demonstrate that n-6 PUFAs and n-3 PUFAs have differential effects on obesity and fatty liver disease and highlight the importance of increasing n-3 PUFAs and reducing n-6 PUFAs (balancing the n-6/n-3 ratio) in clinical interventions and dietary guidelines for the management of obesity and related diseases.

Association between the intake of dietary n3 and n6 fatty acids and stroke in US adults: A cross-sectional study of NHANES 2007-2018.

BACKGROUND: The association between the intake of dietary n3 and n6 fatty acids and the risk of stroke is subject to debate. The primary objective of the present research was to establish the correlation in a large sample of American adults. METHODS: Using data from the National Health and Nutrition Examination Survey (NHANES) between 2007 and 2018, the association of the intake of dietary n3 and n6 fatty acids with stroke events was analyzed in a sample of 29,459 adults. The intake of n3 and n6 fatty acids intake was assessed though two 24-h dietary recalls. Stroke outcomes were identified based on the responses provided in self-reported questionnaire. Logistic regression was fitted to evaluate the correlation of dietary n3, n6 fatty acids intake with stroke events. RESULTS: Subjects in the highest tertile (T3) of dietary n3 (OR: 0.67, 95% CI: 0.49-0.93), n6 (OR: 0.65, 95% CI: 0.45-0.95) fatty acids intake were found to have obviously lower risk of stroke compared to those in the lowest tertile (T1), but the n6:n3 ratio was not found to be associated with a stroke event. Results from stratified analysis demonstrated that dietary n3 fatty acids had an inverse correlation of stroke in both male and female, but dietary n6 fatty acids only had this correlation in male. Moreover, findings were made that the interaction was significant in terms of age in the subgroup analysis, and the negative relationship between the intake of dietary n3 and n6 fatty acids and stroke event were particularly pronounced among participants aged ≥60. CONCLUSIONS: The present results suggested that increased dietary n3, n6 fatty acids intake correlated with a lower risk of stroke.

The Role of Polyunsaturated Fatty Acids in Osteoarthritis: Insights from a Mendelian Randomization Study.

The prior observational research on the impact of polyunsaturated fatty acid (PUFA) supplementation on osteoarthritis (OA) patients had yielded inclusive outcomes. This study utilized the Mendelian randomization (MR) approach to explore potential causal relationships between PUFAs and OA. The MR study was performed using GWAS summary statistics for PUFAs, encompassing omega-3 and omega-6 fatty acids, and for knee OA (KOA) and hip OA (HOA). The primary inverse-variance-weighted (IVW) method and two supplementary MR approaches were used to establish robust causality. Heterogeneity and horizontal pleiotropy were assessed using Cochrane's Q and MR-Egger intercept tests. Additionally, a range of sensitivity analyses were conducted to strengthen the precision and reliability of the results. The IVW method indicated a potential genetic association between omega-3 fatty acids and KOA risk (odd ratio (OR) = 0.94, 95% confidence interval (CI): 0.89-1.00, p = 0.048). No significant correlation was found between omega-3 levels and HOA. Moreover, genetically predicted higher levels of omega-6 fatty acids were associated with a decreased risk of KOA (OR = 0. 93, 95% CI: 0.86-1.00, p = 0.041) and HOA (OR = 0.89, 95% CI: 0.82-0.96; p = 0.003). The MR-Egger intercept evaluation showed no horizontal pleiotropy affecting the MR analysis (all p > 0.05). Our findings supported the causal relationship between PUFAs and OA susceptibility and offered a novel insight that high omega-6 fatty acids may reduce the risk of KOA and HOA. These results underscore the importance of maintaining optimal levels of PUFAs, particularly omega-6 fatty acids, in individuals with a genetic predisposition to OA. Future research is necessary to validate these findings and elucidate the underlying mechanisms involved.

Systemic Lupus Erythematosus and the Ratio of Omega-3 to Omega-6 Fatty Acids Consumption among Women in the Adventist Health Study-2.

OBJECTIVE: To assess the associations of omega-3 and omega-6 fatty acids consumption, and the ratio between the two, with self-reported doctor told Systemic Lupus Erythematosus (SLE) diagnosis. Further, to assess whether initiation of omega-3 supplements intake was related to time/year of SLE diagnosis. METHODS: Data from 42,398 women in the Adventist Health Study-2 cohort were used for this cross-sectional study. Unconditional logistic regression modeling was used for all analyses with the following candidate covariates: age, race, education, smoking, and body mass index (BMI). RESULTS: Compared to non-cases, participants with a diagnosis of SLE reported higher intakes of total omega-3 fatty acids and about the same intakes of omega-6 fatty acids. Overall, they had higher ratios of omega-3 to omega-6 fatty acids. When assessing odds ratios of SLE diagnosis by quartiles of omega-3 to omega-6 and DHA+EPA to omega-6, there was a positive significant trend (p trend = 0.005). Additionally, among those reporting intake of fish oil, 87% had initiated fish oil consumption around the time of SLE diagnosis. SLE was more likely to occur among Black women compared to White women, among ever smokers compared to never smokers, among overweight women compared to women with normal/underweight, and among women 50-59 years compared to those 30-49 year old. When a smaller 6 year follow-up study identified 64 incident SLE cases and assessed their omega-3 intake at baseline (6 years earlier and before the SLE diagnosis) their intake of omega-3 and fish oil was no different than among non-cases. CONCLUSION: We observed a significant positive association between the ratio of omega-3 to omega-6 fatty acids consumption and prevalence of SLE. Among those with prevalent SLE, their year of starting supplementation of omega-3 and fish oil was closely linked to year of SLE diagnosis. Further, baseline intake of omega-3 fatty acids was not increased among 64 incident SLE cases identified during 6 years of follow-up. Our surprising finding can best be explained by reverse causation. This could be an example of how public health information is assimilated and acted upon by a health conscious public.

Crystalline silica-induced proinflammatory eicosanoid storm in novel alveolar macrophage model quelled by docosahexaenoic acid supplementation.

Introduction: Phagocytosis of inhaled crystalline silica (cSiO2) particles by tissue-resident alveolar macrophages (AMs) initiates generation of proinflammatory eicosanoids derived from the ω-6 polyunsaturated fatty acid (PUFA) arachidonic acid (ARA) that contribute to chronic inflammatory disease in the lung. While supplementation with the ω-3 PUFA docosahexaenoic acid (DHA) may influence injurious cSiO2-triggered oxylipin responses, in vitro investigation of this hypothesis in physiologically relevant AMs is challenging due to their short-lived nature and low recovery numbers from mouse lungs. To overcome these challenges, we employed fetal liver-derived alveolar-like macrophages (FLAMs), a self-renewing surrogate that is phenotypically representative of primary lung AMs, to discern how DHA influences cSiO2-induced eicosanoids. Methods: We first compared how delivery of 25 µM DHA as ethanolic suspensions or as bovine serum albumin (BSA) complexes to C57BL/6 FLAMs impacts phospholipid fatty acid content. We subsequently treated FLAMs with 25 µM ethanolic DHA or ethanol vehicle (VEH) for 24 h, with or without LPS priming for 2 h, and with or without cSiO2 for 1.5 or 4 h and then measured oxylipin production by LC-MS lipidomics targeting for 156 oxylipins. Results were further related to concurrent proinflammatory cytokine production and cell death induction. Results: DHA delivery as ethanolic suspensions or BSA complexes were similarly effective at increasing ω-3 PUFA content of phospholipids while decreasing the ω-6 PUFA arachidonic acid (ARA) and the ω-9 monounsaturated fatty acid oleic acid. cSiO2 time-dependently elicited myriad ARA-derived eicosanoids consisting of prostaglandins, leukotrienes, thromboxanes, and hydroxyeicosatetraenoic acids in unprimed and LPS-primed FLAMs. This cSiO2-induced eicosanoid storm was dramatically suppressed in DHA-supplemented FLAMs which instead produced potentially pro-resolving DHA-derived docosanoids. cSiO2 elicited marked IL-1α, IL-1ß, and TNF-α release after 1.5 and 4 h of cSiO2 exposure in LPS-primed FLAMs which was significantly inhibited by DHA. DHA did not affect cSiO2-triggered death induction in unprimed FLAMs but modestly enhanced it in LPS-primed FLAMs. Discussion: FLAMs are amenable to lipidome modulation by DHA which suppresses cSiO2-triggered production of ARA-derived eicosanoids and proinflammatory cytokines. FLAMs are a potential in vitro alternative to primary AMs for investigating interventions against early toxicant-triggered inflammation in the lung.

Fatty Acid Positions in Triacylglycerol of Iridescent Shark Fish Oil (Pangasius sp.), Focusing on Omega-3 and Omega-6 Fatty Acids.

<b>Background and Objective:</b> Considering the many health benefits of fish oil, the potential of Indonesian fisheries needs to be mapped to find local fish oil sources that have the opportunity to be used as a source of omega-3 and 6. This research aimed to ascertain the glyceride profile of iridescent shark fish oil hydrolyzed by immobilized lipase from <i>Thermomyces lanuginosus</i> at the sn-1,3 position and identify the position of omega-3 and omega-6 fatty acids. <b>Materials and Methods:</b> To extract the fish oil from the iridescent shark, the soxhletation method was utilized. The analysis of the fatty acid composition that was carried out using gas chromatography (GC) was previously esterified with BF₃ before it was carried out to position the fatty acid hydrolysis that was carried out using lipase enzymes to position the fatty acid composition. <b>Results:</b> The sample had more unsaturated fatty acids than saturated ones. Omega-3 and omega-6 fatty acids are more concentrated in the fat molecule's sn-2 position than in the sn-1+sn-3 location. Iridescent shark fish oil meets the recommended ratio of omega-3 to omega-6 (1:1) or better (2:1). <b>Conclusion:</b> It has been discovered that iridescent shark fish oil is rich in omega-3 and omega-6 fatty acids, especially those in the sn-2 position. This makes it a great food choice for those trying to get more omega-3 unsaturated fatty acids into their diets.

n-6 fatty acid biomarkers and incident atrial fibrillation: an individual participant-level pooled analysis of 11 international prospective studies.

BACKGROUND: The presence of atrial fibrillation (AF) is associated with an over 2-fold increased risk of stroke, heart failure, and cardiovascular mortality. Long chain n-6 PUFAs have been suggested to have a variety of beneficial biologic effects that may reduce AF development; however, prior studies evaluating this relationship are limited. OBJECTIVES: We prospectively evaluated the association between circulating levels of linoleic acid (LA) and arachidonic acid (AA) with incident AF. METHODS: We used participant-level data from a global consortium of 11 prospective cohort studies with measurements of LA and AA in adults (aged ≥18 y). Participating studies conducted de novo analyses using a prespecified analytical plan with harmonized definitions for exposures, outcomes, covariates, and subgroups. Associations were pooled using inverse-variance weighted meta-analysis. RESULTS: Among 41,335 participants, 6173 incident cases of AF were ascertained, with median follow-up time of 14 y. In multivariable analysis, per interquintile range (difference between the 10th and 90th percentiles for each fatty acid), circulating n-6 levels were not associated with incident AF. For LA, the hazard ratio per interquintile range was 0.96 (95% confidence interval [CI]: 0.89, 1.04), and for AA, 1.02 (95% CI: 0.94, 1.10), with little evidence of heterogeneity between cohorts. Associations were similarly nonsignificant across subgroups of age, race, and biomarker fraction. CONCLUSIONS: Biomarkers of n-6 fatty acids including LA and AA are not associated with incident AF. These findings suggest that overall effects of n-6 PUFAs on influencing AF development are neutral.

Eicosapentaenoic Acid Influences the Lipid Profile of an In Vitro Psoriatic Skin Model Produced with T Cells.

Psoriasis is a skin disease characterized by epidermal hyperplasia and an inappropriate activation of the adaptive immunity. A dysregulation of the skin's lipid mediators is reported in the disease with a predominance of the inflammatory cascade derived from n-6 polyunsaturated fatty acids (n-6 PUFAs). Bioactive lipid mediators derived from arachidonic acid (AA) are involved in the inflammatory functions of T cells in psoriasis, whereas n-3 PUFAs' derivatives are anti-inflammatory metabolites. Here, we sought to evaluate the influence of a supplementation of the culture media with eicosapentaenoic acid (EPA) on the lipid profile of a psoriatic skin model produced with polarized T cells. Healthy and psoriatic skin substitutes were produced following the auto-assembly technique. Psoriatic skin substitutes produced with or without T cells presented increased epidermal and dermal linolenic acid (LA) and AA levels. N-6 PUFA lipid mediators were strongly measured in psoriatic substitutes, namely, 13-hydroxyoctadecadienoic acid (13-HODE), prostaglandin E2 (PGE2) and 12-hydroxyeicosatetraenoic acid (12-HETE). The added EPA elevated the amounts of EPA, n-3 docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA) in the epidermal and dermal phospholipids. The EPA supplementation balanced the production of epidermal lipid mediators, with an increase in prostaglandin E3 (PGE3), 12-hydroxyeicosapentaenoic acid (12-HEPE) and N-eicosapentaenoyl-ethanolamine (EPEA) levels. These findings show that EPA modulates the lipid composition of psoriatic skin substitutes by encouraging the return to a cutaneous homeostatic state.

Therapeutic effect of cannabidiol on myocardial arachidonic acid content in various lipid fractions in a rat model of obesity.

The study explored the potential protective influence of cannabidiol (CBD) on myocardial inflammation state, with a special focus on arachidonic acid (AA), and oxidative balance in lipid overload conditions. The 7-week experiment was conducted on male Wistar rats receiving standard or high-fat diet (HFD) with intraperitoneal CBD injections for the last 14 days. The n-3 and n-6 polyunsaturated fatty acids (PUFAs) activities and AA concentration in selected fractions were evaluated by gas-liquid chromatography (GLC). The expression of proteins was determined by Western blot and the concentration of different parameters by ELISA, colorimetric, or multiplex assay kits. Our results revealed that CBD increased n-3 PUFAs activity in phospholipid and triacylglycerol fractions, and decreased AA content in the HFD group, especially in the phospholipid pool. Simultaneously, CBD decreased the expression of nuclear factor kappa B, cyclooxygenase-1, and - 2, resulting in the reduction of prostaglandin E2 and the increment of prostaglandin I2. CBD appears to be relatively safe for the treatment of obesity-induced heart disease, as it has anti-inflammatory and partially antioxidative properties.

Dietary Linoleic Acid: An Omega-6 Fatty Acid Essential for Liver Regeneration in Buffalo Rats.

Rodents are currently the most common animals used for hepatic surgical resection studies that investigate liver regeneration, chronic liver disease, acute liver failure, hepatic metastasis, hepatic function, and hepatic cancer. Our previous work has shown that dietary consumption of linoleic acid (LA) stimulates the growth of rodent and human tumors in vivo. Here we compared 3 diets - a 5% corn oil diet (control), a diet deficient in essential fatty acids (EFAD), and an EFAD supplemented with LA in amounts equal to those in the control diet (EFAD+LA). We hypothesized that consumption of the LA provided in the EFAD+LA diet would elevate plasma levels of LA and stimulate regeneration in rats after a 70% hepatectomy (HPX), and that regeneration would not occur in the EFAD rats. Each diet group was comprised of 30 male and 30 female Buffalo rats (BUFF/CrCrl). Rats were fed one of the 3 diets and water ad libitum. After 8 wk on the assigned diet, rats were underwent a 70% HPX. On days 4 and 21 after HPX, 30 male and 30 female rats from each diet group were anesthetized for in vivo study and then were euthanized for tissue collection. For the in vivo study, arterial and venous blood samples were collected from the liver. LA-, glucose-, and O2 -uptake, and lactate- and CO2 -output were significantly higher in LA-replete rats as compared with LA-deficient rats. After a 70% HPX, the remaining liver mass in control and EFAD+LA groups had doubled at day 4, reaching 60% of the original total weight, and had regenerated completely at day 21. However, no regeneration occurred in the EFAD group. At day 4 the portions of livers removed from the control and EFAD+LA groups had significantly higher content of LA, protein, cAMP, and DNA as compared with their livers on day 21. [³ H]thymidine incorporation into liver DNA was significantly higher in the 2 LA-replete groups, with male values greater than female values, as compared with LA-deficient group. These data indicate that liver regeneration after HPX is dependent on dietary LA. Understanding the mechanisms of LA-dependent liver regeneration in rats supports our current efforts to enhance successful surgical resection therapies in humans.