Plasma Levels Of Polyunsaturated Fatty Acids Research Articles

Gender-related and PUFA-related differences in lipoprotein-associated phospholipase A2 levels in patients with type 2 diabetes and atherosclerotic cardiovascular disease.

Lipoprotein-associated phospholipase A2 (Lp-PLA2) may play an important role in the development of atherosclerotic cardiovascular disease (ASCVD). Increased plasma levels of Lp-PLA2 may predict future cardiovascular (CV) events in type 2 diabetes (T2D). The potential beneficial effects of polyunsaturated fatty acids (PUFA) on ASCVD have been widely investigated. However, the impact of different PUFA concentrations on Lp-PLA2 remains uncertain. We sought to determine the intergender differences in a population of patients with both T2D and ASCVD regarding Lp-PLA2 mass and the association between Lp-PLA2 mass and plasma levels of PUFA. In this cross-sectional study, we measured the Lp-PLA2 mass, PUFA concentrations and inflammatory markers in 74 patients (49 males and 25 females) with T2D and ASCVD. In this very high-risk population, males had, on average, 33.6% higher levels of Lp-PLA2 than females. The Lp-PLA2 mass was positively associated with interleukin 6 (IL-6) (r = 0.27, p = 0.019), creatinine (r = 0.29, p = 0.03) and triglyceride levels (r = 0.41, p = 0.002). Additionally, male gender and higher levels of triglycerides, leptin, oxidized low-density lipoprotein (oxLDL), and intercellular adhesion molecule 1 (ICAM-1) were independent predictors for an increased Lp-PLA2. Moreover, arachidonic acid (AA) negatively correlated with Lp-PLA2 (r = -0.26, p = 0.024), which was especially apparent in the female subgroup. In the population of patients with ASCVD and T2D, males present with higher plasma levels of Lp-PLA2 than females. Additionally, higher plasma levels of AA were associated with lower Lp-PLA2 levels. Our findings support the utilization of Lp-PLA2 as a novel biomarker in ASCVD risk assessment in a very high CV risk population.

Relationship between ω3 and ω6 polyunsaturated fatty acids and atrial fibrillation in acute ischemic stroke

Some ω3 polyunsaturated fatty acids (PUFAs) are said to demonstrate a dose-related risk of atrial fibrillation (AF), conversely, some ω6 PUFAs might have AF protective potential. However, few investigated the relation among ischemic strokes. Primarily, we aimed to examine a relation between ω3 and ω6 PUFAs and the presence of AF in ischemic strokes. Further, since, some PUFAs are said to affect the cardiac load, we secondarily aimed to investigate the association between ω3 and ω6 PUFAs and brain natriuretic peptide (BNP) and the occurrence of cerebral large vessel occlusion (LVO) in ischemic strokes with AF. Consecutive patients with ischemic stroke admitted between 2012 and 2022 were retrospectively screened. Plasma levels of PUFAs, including eicosapentaenoic acid (EPA), docosahexaenoic acid, dihomo-γ-linolenic acid (DGLA) and arachidonic acid (AA), were assayed. Data were analyzed using a Poisson regression analysis with a robust variance estimator and a multiple linear regression analysis. We screened 2112 consecutive ischemic strokes, including 1574 (1119 [71%] males, median age 69 years). Lower DGLA (prevalence ratio (PR) 0.885, 95% CI 0.811-0.966, p=0.006), lower AA (PR 0.797, 95% CI 0.649-0.978, p=0.030), and higher EPA/AA ratio (PR 1.353, 95% CI 1.036-1.767, p=0.026) were associated with AF. Checking the linearity between AF and PUFAs, negative linear trends were observed between DGLA quartiles (Q1: PR 1.901, Q2: PR 1.550, Q3: PR 1.423, Q4: 1.000, p<0.001 for trend) and AA quartiles (Q1: PR 1.499, Q2: PR 1.204, Q3: PR 1.125, Q4: 1.000, p=0.004 for trend), with positive linear trends between EPA/AA ratio quartiles (Q1: 1.000, Q2: PR 1.555, Q3: PR 1.612, Q4: PR 1.797, p=0.001 for trend). Among patients with AF, a negative association between AA and BNP (unstandardized coefficient-1.316, 95% CI -2.290∼-0.342, p=0.008) was observed, and lower AA was associated with LVO (PR 0.707, 95% CI 0.527-0.950, p=0.021). Lower DGLA and AA and a higher EPA/AA ratio might be related to the development of AF in ischemic strokes. Further, AA might have a cardio-cerebrovascular protective role in ischemic strokes with AF.

Plasma Levels of Polyunsaturated Fatty Acids and Adverse Kidney Outcomes

Many studies have reported polyunsaturated fatty acids (PUFA) as significant predictors of cardiovascular disease, but little is known about the relationship between PUFA levels and chronic kidney disease (CKD). This study explored this relationship among individuals with and without CKD. Prospective observational cohort study. 78,950 participants without CKD (cohort 1) and 7,233 participants with CKD (cohort 2) in the UK Biobank Study with PUFA levels measured between 2007 and 2010. Percentage of plasma PUFA, omega-3 fatty acid (FA), omega-6 FA, docosahexaenoic acid (DHA), and linoleic acid relative to total fatty acid. Incident CKD for cohort 1 and incident kidney failure requiring replacement therapy (KFRT) for cohort 2. Cox proportional hazards regression analyses, including a cause-specific competing risk model. In cohort 1, individuals with higher quartiles of plasma PUFA levels had healthier lifestyles and fewer comorbidities. During 841,007 person-years of follow-up (median 11.9 years), incident CKD occurred in 4.5% of participants (incidence rate, 39.1 per 10,000 person-years). For incident CKD in cohort 1, the adjusted cause-specific hazard ratios (HR) (95% CIs) for quartiles 2, 3, and 4 were 0.83 (0.75-0.92), 0.85 (0.76-0.96), 0.71 (0.62-0.82), respectively, compared with quartile 1. This inverse relationship was consistently observed for all PUFA types. In cohort 2, although, total PUFA levels were not associated with KFRT, higher PUFA subtype levels of DHA were associated with a lower risk of KFRT. Observational design and limited generalizability to individuals with higher disease severity; no data on eicosapentaenoic acid. Among individuals without CKD, higher plasma PUFA levels and all four PUFA components were associated with a lower risk of incident CKD. In individuals with CKD, only the omega-3 component of PUFA, DHA, was associated with a lower risk of KFRT.

Abstract WP242: Acute Ischemic Stroke With Atrial Fibrillation: Relation Between ω3/ω6 Poly Unsaturated Fatty Acids

Background &amp; Aims: Some poly unsaturated fatty acids (PUFA) are said to be associated with the development of atrial fibrillation (AF). Our aim is to elucidate the relation between PUFA and AF in acute ischemic stroke. Methods: Consecutive patients with ischemic stroke admitted between October 2012 and February 2022 were retrospectively screened. The inclusion criteria were as follows: 1) onset to door time within 7 days; and 2) availability of PUFA measurements from the day of the hospital visit or the next day. Plasma levels of PUFA, including eicosapentaenoic acid (ω3: EPA) docosahexaenoic acid (ω3: DHA), dihomo-γ-linolenic acid (ω6: DGLA), and arachidonic acids (ω6: AA), were assayed by gas chromatography. We investigated the association between each of PUFA levels and AF among the acute ischemic stroke patients. Results: We screened 2,122 consecutive ischemic stroke patients. Of them, 1,574 were identified (1,119 [71%] males, median age 69 years). In Poisson regression analysis with a robust variance estimator, factors associated with AF were lower DGLA level (prevalence ration (PR) 0.885, 95% CI 0.811 to 0.966, p = 0.006), lower AA level (PR 0.797, 95% CI 0.649 to 0.978, p = 0.029), and higher EPA/AA ratio (PR 1.353, 95% CI 1.036 to 1.766, p = 0.026). In Poisson regression analysis with a robust variance estimator for AF using PUFA quartile as indicator variables, negative linear trends were observed between the quartile of DGLA (Quartile 1: PR 1.884, Quartile 2: PR 1.530, Quartile 3: PR 1.429, Quartile 4: reference) and AA (Quartile 1: PR 1.499, Quartile 2: PR 1.199, Quartile 3: PR 1.137, Quartile 4: reference), and a positive linear trend between the quartile of EPA/AA ratio (Quartile 1: reference, Quartile 2: PR 1.544, Quartile 3: PR 1.629, Quartile 4: PR 1.781, Figure). Conclusions: In acute ischemic stroke, lower ω6 level and higher ω3/ω6 ratio were associated with the presence of AF. ω3/ω6 PUFA may have contrasting effects on the incidence of AF in acute ischemic stroke.

Association between plasma polyunsaturated fatty acids and depressive among US adults.

Depression is associated with greater functional impairment and high societal costs than many other mental disorders. Research on the association between plasma polyunsaturated fatty acids (PUFAs) levels and depression have yielded inconsistent results. To evaluate whether plasma n-3 and n-6 PUFAs levels are associated with depression in American adults. A cross-sectional study included 2053 adults (aged ≥20 y) in the National Health and Nutrition Examination Survey (NHANES), 2011-2012. The level of plasma n-3 and n-6 PUFAs were obtained for analysis. Self-reported Patient Health Questionnaire-9 (PHQ-9) was used to identify the depression status. Binary logistic regression analysis was performed to evaluate the association between quartiles of plasma n-3 and n-6 PUFAs and depression after adjustments for confounders. The study of 2053 respondents over 20 years of age with a weighted depression prevalence of 7.29% comprised 1,043 men (weighted proportion, 49.13%) and 1,010 women (weighted, 50.87%), with a weighted mean (SE) age of 47.58 (0.67) years. Significantly increased risks of depression over non-depression were observed in the third quartiles (OR = 1.65, 95% CI = 1.05-2.62) for arachidonic acid (AA; 20:4n-6); the third quartiles (OR = 2.20, 95% CI = 1.20-4.05) for docosatetraenoic acid (DTA; 22:4n-6); the third (OR = 2.33, 95% CI = 1.34-4.07), and highest quartiles (OR = 1.83, 95% CI = 1.03-3.26) for docosapentaenoic acid (DPAn-6; 22:5n-6); and the third (OR = 2.18, 95% CI = 1.18-4.03) and highest quartiles (OR = 2.47, 95% CI = 1.31-4.68) for docosapentaenoic acid (DPAn-3; 22:5n-3); the second (OR = 2.13, 95% CI = 1.24-3.66), third (OR = 2.40, 95% CI = 1.28-4.50), and highest quartiles (OR = 2.24, 95% CI = 1.08-4.69) for AA/docosahexaenoic acid (DHA; 22:6n-3) ratio compared with the lowest quartile after adjusting for confounding factors. Higher plasma levels of AA, DTA, DPAn-6, DPAn-3 PUFAs, and AA/DHA ratio may be potential risk factors for depression in US adults.

Sex differences in the association between plasma polyunsaturated fatty acids levels and moderate-to-severe plaque psoriasis severity: a cross-sectional and longitudinal study

BackgroundPsoriasis is a chronic inflammatory skin disease with metabolic abnormalities serving as important contributors for pathogenesis and progression. Polyunsaturated fatty acids (PUFAs) have been found to be associated with human diseases, including psoriasis. However, differences and controversies exist regarding their content and roles.MethodsPlasma PUFAs concentrations were measured in 296 patients with moderate-to-severe plaque psoriasis from the Shanghai Psoriasis Effectiveness Evaluation CoHort. Disease severity was assessed using Clinician-Reported Outcomes (ClinROs), including Psoriasis Area and Severity Index (PASI), Body Surface Area (BSA) and Physician Global Assessment (PGA), as well as Patient-Reported Outcomes (PROs), including Patient Global Assessment (PtGA) and Dermatology Life Quality Index (DLQI). Multivariate generalized linear regression models (GLMs), subgroup and interaction analysis, and restricted cubic spline were used to estimate the cross-sectional associations between PUFAs concentrations and disease severity. Longitudinal assessments of PASI scores and PASI response were conducted at a 12-week follow-up. Associations between baseline plasma PUFAs levels and prospective PASI scores or PASI response were assessed using multivariate GLMs or logistic regression models.ResultsMales suffered severer psoriasis and presented lower plasma docosahexaenoic acid (DHA) and arachidonic acid (ARA) levels compared to females. Among males, plasma eicosadienoic acid (EDA) level was positively associated with PASI, BSA and PGA scores, while total Omega-3 PUFAs and/or eicosapentaenoic acid (EPA) levels exhibited non-linear associations with PASI and/or BSA scores. α-Linolenic acid (ALA) was negatively, whereas ARA was positively, associated with DLQI scores. In females, Omega-3 PUFAs, including EPA, DHA, and total Omega-3 PUFAs, showed inverse associations with PASI and BSA scores. Longitudinally, plasma total Omega-6 PUFAs were positively associated with the likelihood of achieving PASI 100 at 12 weeks in males. In females, concentrations of dohomo-γ-linolenic acid were prospectively associated with an increase in PASI scores, and DHA was associated with the likelihood of achieving PASI 75 and PASI 90 decline.ConclusionsSex differences cross-sectionally exist in disease severity and plasma PUFAs levels. The association between PUFAs and psoriasis severity also varies cross-sectionally and longitudinally between males and females. Sex differences should be considered when studying the function and clinical application of PUFAs in psoriasis.

Association of Polyunsaturated Fatty Acids and Clinical Progression in Patients With ALS: Post Hoc Analysis of the EMPOWER Trial.

Polyunsaturated fatty acids (PUFAs) have neuroprotective and anti-inflammatory effects and could be beneficial in amyotrophic lateral sclerosis (ALS). Higher dietary intake and plasma levels of PUFAs, in particular alpha-linolenic acid (ALA), have been associated with a lower risk of ALS in large epidemiologic cohort studies, but data on disease progression in patients with ALS are sparse. We examined whether plasma levels of ALA and other PUFAs contributed to predicting survival time and functional decline in patients with ALS. We conducted a study among participants in the EMPOWER clinical trial who had plasma samples collected at the time of randomization that were available for fatty acid analyses. Plasma fatty acids were measured using gas chromatography. We used Cox proportional hazards models and linear regression to evaluate the association of individual fatty acids with risk of death and joint rank test score of functional decline and survival. Fatty acid analyses were conducted in 449 participants. The mean (SD) age of these participants at baseline was 57.5 (10.7) years, and 293 (65.3%) were men; 126 (28.1%) died during follow-up. Higher ALA levels were associated with lower risk of death (age-adjusted and sex-adjusted hazard ratio comparing highest vs lowest quartile 0.50, 95% CI 0.29-0.86, p-trend = 0.041) and higher joint rank test score (difference in score according to 1 SD increase 10.7, 95% CI 0.2-21.1, p = 0.045), consistent with a slower functional decline. The estimates remained similar in analyses adjusted for body mass index, race/ethnicity, symptom duration, site of onset, riluzole use, family history of ALS, predicted upright slow vital capacity, and treatment group. Higher levels of the n-3 fatty acid eicosapentaenoic acid and the n-6 fatty acid linoleic acid were associated with a lower risk of death during follow-up. Higher levels of ALA were associated with longer survival and slower functional decline in patients with ALS. These results suggest that ALA may have a favorable effect on disease progression in patients with ALS.

Differential progression of unhealthy diet-induced hepatocellular carcinoma in obese and non-obese mice.

BackgroundNon-alcoholic fatty liver disease (NAFLD) ranks first among liver diseases in Western countries. NAFLD is typically associated with obesity and diabetes, however it also develops in lean individuals without metabolic syndrome. The prevalence of lean NAFLD is 7 percent in the U.S. and 25–30 percent in some Asian countries. NAFLD starts with excess liver fat accumulation (NAFL), progresses to nonalcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma (HCC). The pathogenesis of lean NASH-HCC and how it differs from obese NASH-HCC is not well understood.MethodsIn this work, we generated a mouse model of lean and obese NASH-HCC using a choline deficient/high trans-fat/fructose/cholesterol diet and a choline supplemented/high trans-fat/fructose/cholesterol diet, respectively, to compare progression to NASH-HCC in lean versus obese mice. Comparisons were made at the organismal, histological, and molecular level by investigating fatty acid metabolism in the plasma of these mice.ResultsObese mice showed more pronounced glucose intolerance and insulin resistance, higher levels of plasma cholesterol and triglycerides, and higher penetrance of NASH compared to lean mice. Despite the abnormal metabolic profile of obese mice, male obese and lean mice developed HCC with similar penetrance (53.3% and 53.8%, respectively), albeit lean mice showed faster tumor progression as evidenced by the larger tumor size and lower HCC-free survival. None of the female lean mice developed HCC, while 50% of female obese mice developed HCC. Both groups of mice showed a reduction in plasma polyunsaturated fatty acids (PUFAs), however, the levels were higher towards the endpoint in obese mice compared to lean mice.ConclusionsUnhealthy diet composition appears to drive progression to NASH-HCC rather than the organismal effects of obesity. PUFA levels may increase due to systemic inflammation in obese mice and act as suppressors of tumor progression, thus delaying HCC progression in obese mice compared to lean mice. These models could be used to further dissect the molecular pathogenesis of lean and obese NASH-HCC and address the mechanisms whereby PUFAs may be implicated in hepatocarcinogenesis.

Causal analysis of serum polyunsaturated fatty acids with juvenile idiopathic arthritis and ocular comorbidity.

To investigate the causal effects of plasma Polyunsaturated fatty acids (PUFAs) on the risk of juvenile idiopathic arthritis (JIA) and ocular comorbidity through Mendelian randomization (MR) analysis. Genetic variants (formerly single nucleotide polymorphisms, SNPs) that are strongly associated with PUFAs levels (P < 5×10-8) were selected as instrumental variables. Summary-level MR was performed with outcome estimates for JIA (n = 31,142) and JIA associated iridocyclitis (n = 94,197). The inverse variance-weighted (IVW) method was employed as the main approach to combine the estimation for each SNP. Two set of models with summary statistics were conducted and multiple sensitivity analyses were applied for testing of pleiotropic bias. In model 1, genetically predicted n-6 PUFAs linoleic acid (LA) and arachidonic acid (AA) were associated with lower and higher risk of JIA associated iridocyclitis using IVW (ORLA = 0.940, 95% CI: 0.895-0.988, P = 0.015; ORAA = 1.053, 95% CI: 1.007-1.101, P = 0.024). No such association was observed between each plasma PUFAs and JIA susceptibility (P > 0.05). In further MR analysis, results from model 2 also showed a consistent trend. Besides, multiple sensitivity analyses revealed that there was no obvious evidence for unknown pleiotropy (P > 0.05). Our MR study provides genetic evidence on the possible causality that plasma LA level might protect against JIA associated iridocyclitis, whereas AA was responsible for opposite effect.

FADS1 and FADS2 Gene Polymorphisms Modulate the Relationship of Omega-3 and Omega-6 Fatty Acid Plasma Concentrations in Gestational Weight Gain: A NISAMI Cohort Study.

The polymorphisms of fatty acid desaturase genes FADS1 and FADS2 have been associated with an increase in weight gain. We investigated FADS1 and FADS2 gene polymorphisms and the relation between ω-3 and ω-6 fatty acid plasma concentrations and gestational weight gain. A prospective cohort study of 199 pregnant women was followed in Santo Antônio de Jesus, Brazil. Plasma levels of polyunsaturated fatty acids (PUFAs) were measured at baseline and gestational weight gain during the first, second, and third trimesters. Fatty acid recognition was carried out with the aid of gas chromatography. Single nucleotide polymorphisms (SNPs) were genotyped using real-time PCR. Statistical analyses included Structural Equation Modelling. A direct effect of FADS1 and FADS2 gene polymorphisms on gestational weight was observed; however, only the SNP rs174575 (FADS2) showed a significant positive direct effect on weight over the course of the pregnancy (0.106; p = 0.016). In terms of the influence of SNPs on plasma levels of PUFAs, it was found that SNP rs174561 (FADS1) and SNP rs174575 (FADS2) showed direct adverse effects on plasma concentrations of ω-3 (eicosapentaenoic acid and alpha-linoleic acid), and only SNP rs174575 had positive direct effects on plasma levels of ARA and the ARA/LA (arachidonic acid/linoleic acid) ratio, ω-6 products, while the SNP rs3834458 (FADS2) had an adverse effect on plasma concentrations of EPA, leading to its increase. Pregnant women who were heterozygous and homozygous for the minor allele of the SNP rs3834458 (FADS2), on the other hand, showed larger concentrations of series ω-3 substrates, which indicates a protective factor for women’s health.

Effect of plasma polyunsaturated fatty acid levels on leukocyte telomere lengths in the Singaporean Chinese population

BackgroundShorter telomere length (TL) has been associated with poor health behaviors, increased risks of chronic diseases and early mortality. Excessive shortening of telomere is a marker of accelerated aging and can be influenced by oxidative stress and nutritional deficiency. Plasma n6:n3 polyunsaturated fatty acid (PUFA) ratio may impact cell aging. Increased dietary intake of marine n-3 PUFA is associated with reduced telomere attrition. However, the effect of plasma PUFA on leukocyte telomere length (LTL) and its interaction with genetic variants are not well established.MethodsA nested coronary artery disease (CAD) case-control study comprising 711 cases and 638 controls was conducted within the Singapore Chinese Health Study (SCHS). Samples genotyped with the Illumina ZhongHua-8 array. Plasma n-3 and n-6 PUFA were quantified using mass spectrometry (MS). LTL was measured with quantitative PCR method. Linear regression was used to test the association between PUFA and LTL. The interaction between plasma PUFAs and genetic variants was assessed by introducing an additional term (PUFA×genetic variant) in the regression model. Analysis was carried out in cases and controls separately and subsequently meta-analyzed using the inverse-variance weighted method. We further assessed the association of PUFA and LTL with CAD risk by Cox Proportional-Hazards model and whether the effect of PUFA on CAD was mediated through LTL by using structural equation modeling.ResultsHigher n6:n3 ratio was significantly associated with shorter LTL (p = 0.018) and increased CAD risk (p = 0.005). These associations were mainly driven by elevated plasma total n-3 PUFAs, especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (p < 0.05). There was a statistically significant interaction for an intergenic single nucleotide polymorphism (SNP) rs529143 with plasma total n-3 PUFA and DHA on LTL beyond the genome-wide threshold (p < 5 × 10− 8). Mediation analysis showed that PUFA and LTL affected CAD risk independently.ConclusionsHigher plasma n6:n3 PUFA ratio, and lower EPA and DHA n-3 PUFAs were associated with shorter LTL and increased CAD risk in this Chinese population. Furthermore, genetic variants may modify the effect of PUFAs on LTL. PUFA and LTL had independent effect on CAD risk in our study population.

Cardiovascular Risk Factors are Inversely Associated With Omega-3 Polyunsaturated Fatty Acid Plasma Levels in Pediatric Kidney Transplant Recipients

High plasma levels of the omega-3 fatty acids eicosapentaenoic acid (EPA), docosahexaenoic acid, and docosapentaenoic acid associates with positive outcomes in adult renal transplant recipients. However, data from pediatric populations are scarce. The aim of the study was to assess the fatty acid profile in a pediatric renal transplantation cohort and to examine the associations between plasma omega-3 fatty acids and cardiovascular disease (CVD) risk factors. In this cross-sectional study comprising 53 children (median age, 12.2years; 32 boys) with a renal transplant, we assessed the prevalence of CVD risk factors as well as markers of end organ damage: carotid intima-media thickness (cIMT) and left ventricular mass index. The associations between plasma omega-3 fatty acids and CVD risk factors were assessed. Twenty-five (47%) patients were preemptively transplanted. Seventy-six percent had dyslipidemia and 51% had hypertension. The mean left ventricular mass index was 40.4±14.3g/m2.7, and 14% had left ventricular hypertrophy. The mean cIMT was 0.41±0.04mm. In a multivariate linear regression, EPA levels were inversely associated to blood pressure (β coeff.=-0.37, P=.007), triglycerides (β coeff.=-0.44, P=.01), and high-density lipoprotein cholesterol (β coeff.=-0.41, P=.01). EPA levels are inversely associated with components of the metabolic syndrome, which may provide support for specific dietary advice or supplementation in this patient population. cIMT is less pronounced in our cohort than in comparable cohorts with lower rate of preemptive transplantations. Our results need replication in prospective cohorts.

Bidirectional longitudinal associations of omega-3 polyunsaturated fatty acid plasma levels with depressive disorders

BackgroundTemporality of the association of low omega-3 polyunsaturated fatty acid (n-3 PUFA) plasma levels with depression remains questionable. To determine the underlying nature of these associations, this study examined the bidirectional longitudinal associations of n-3 PUFA plasma levels with (presence, onset and course of) depressive disorders and symptoms. MethodsBaseline (n = 2912, 28.6% with current depressive disorder) and 6-year follow-up data (n = 1966, 13.0% with current depressive disorder) of the Netherlands Study of Depression and Anxiety (NESDA) were used. Depression diagnoses and symptoms were based on psychiatric interviews and self-report questionnaires. N-3 PUFA levels (ratio of total fatty acids (mmol%)), were assessed using nuclear magnetic resonance. ResultsUsing two waves of data, n-3 PUFA levels were lower among depressed persons, as compared to healthy controls (Beta = −0.047, SE = 0.011, p < .001). Nevertheless, baseline n-3 PUFA levels were not consistently associated with subsequent change in depressive symptoms, onset or remission of depressive disorders over 6 years. Furthermore, the difference in n-3 PUFA levels detected at baseline between depressed and non-depressed participants tended to dissipate over 6 years (depression-by-time estimate: p = .011). Finally, subjects depressed both at baseline and at 6-year follow up had consistently lower n-3 PUFA levels over the entire follow-up as compared to those who had never been depressed. Change in depressive disorders across waves was not consistently accompanied by change in n-3 PUFA levels over time. LimitationsNo data on intermediate time points and EPA levels were available. ConclusionsDespite significant cross-sectional associations between n-3 PUFA plasma levels and depressive disorders and severity, this 6-year longitudinal study could not confirm an uni- or bidirectional association over time. The association between depression and n-3 PUFA plasma levels is unlikely to be causal.

Reduction of Polyunsaturated Fatty Acids with Tumor Progression in a Lean Non-Alcoholic Steatohepatitis-Associated Hepatocellular Carcinoma Mouse Model.

Background and Aim: Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in Western countries. While obesity and diabetes are the hallmarks of NAFLD, it also develops in lean individuals in the absence of metabolic syndrome, with a prevalence of 7 percent in the U.S. and 25-30 percent in some Asian countries. NAFLD represents the spectrum of liver disease, starting with excess liver fat accumulation (NAFL) that can progress to nonalcoholic steatohepatitis (NASH), cirrhosis and ultimately hepatocellular carcinoma (HCC). To date, the pathogenesis of lean NASH-HCC is poorly understood and a mouse model is lacking. We aimed to develop a mouse model of lean NASH-HCC using a choline deficient and high trans-fat/sucrose/cholesterol diet to enable better understanding of its molecular pathogenesis.Methods: C57BL/6N mice were fed this diet starting at 4 weeks of age for 52 weeks and were compared to mice fed an isocaloric low fat control diet for the same duration. C57BL/6N mice were chosen instead of the C57BL/6J mice due to the high susceptibility of C57BL/6J mice to diet-induced obesity. The plasma and tumor fatty acid profile of these mice was also investigated.Results: Nearly 61% of the mice developed lean NASH-HCC. These mice showed reduction of plasma polyunsaturated fatty acids (PUFAs) (linolenic acids (α and γ, ω-3 and ω-6, respectively), eicosapentanoic acid (ω-3), docosahexanoic acid (ω-3), and linoleic acid (ω-6)) and increasing levels over time in mice with pre-malignant lesions.Conclusions: We developed a novel high penetrance diet-induced lean NASH-HCC mouse model. Plasma PUFA levels were reduced with tumor progression in parallel with reduced expression of genes controlling desaturase expression suggesting their potential use as biomarkers for lean NASH-HCC progression as well as chemopreventive molecules.

Prediagnostic plasma polyunsaturated fatty acids and the risk of amyotrophic lateral sclerosis.

To examine the association between prediagnostic plasma polyunsaturated fatty acids levels (PUFA) and amyotrophic lateral sclerosis (ALS). We identified 275 individuals who developed ALS while enrolled in 5 US prospective cohorts, and randomly selected 2 controls, alive at the time of the case diagnosis, matched on cohort, birth year, sex, ethnicity, fasting status, and time of blood draw. We measured PUFA, expressed as percentages of total fatty acids, using gas liquid chromatography and used conditional logistic regression to estimate risk ratios (RR) and 95% confidence intervals (CI) for the association between PUFA and ALS. There was no association between total, n-3, and n-6 PUFA, eicosapentaenoic acid, or docosapentaenoic acid levels and ALS. Higher plasma α-linolenic acid (ALA) in men was associated with lower risk of ALS in age- and matching factor-adjusted analyses (top vs bottom quartile: RR = 0.21 [95% CI 0.07, 0.58], p for trend = 0.004). In women, higher plasma arachidonic acid was associated with higher risk (top vs bottom quartile: RR = 1.65 [95% CI 0.99, 2.76], p for trend = 0.052). Multivariable adjustment, including correlated PUFA, did not change the findings for ALA and arachidonic acid. In men and women combined, higher plasma docosahexaenoic acid (DHA) was associated with higher risk of ALS (top vs bottom quartile: RR = 1.56 [95% CI 1.01, 2.41], p for trend = 0.054), but in multivariable models the association was only evident in men. The majority of individual PUFAs were not associated with ALS. In men, ALA was inversely and DHA was positively related to risk of ALS, while in women arachidonic acid was positively related. These findings warrant confirmation in future studies.

Factors associated with plasma n-3 and n-6 polyunsaturated fatty acid levels in Tanzanian infants.

To identify factors associated with plasma polyunsaturated fatty acid (PUFA) levels among 3-month-old Tanzanian infants. Infants (n = 238) and mothers (n = 193) randomly selected from participants in the neonatal vitamin A supplementation randomized controlled trial. A cross-sectional study of maternal-infant pairs at 3 months postpartum. All infant total, n-3, n-6, and individual PUFA levels were correlated with maternal levels. Infant plasma n-3 PUFA levels were higher when maternal n-3 PUFA levels were higher (mean difference in infant % fatty acid per unit increase in maternal levels ± standard error: 0.79 ± 0.08; P < 0.01). Infant plasma docosahexaenoic acid (DHA) levels were positively associated with maternal DHA levels (0.77 ± 0.09; P < 0.01) but were lower for twin births (-0.55 ± 0.27; P = 0.03). Greater birth weight in kilograms (1.00 ± 0.43; P = 0.02) and higher maternal n-6 PUFA levels (0.20 ± 0.07; P < 0.01) were positively associated with higher infant n-6 PUFA levels, whereas maternal mono-unsaturated fatty acid (MUFA) levels (-0.26 ± 0.08; P < 0.01), maternal mid upper arm circumference (MUAC) (-0.22 ± 0.11; P = 0.04), and male sex (-0.99 ± 0.45; P = 0.03) were associated with lower infant plasma n-6 PUFA levels. Infant plasma arachidonic acid (AA) levels were positively associated with maternal plasma AA levels (0.38 ± 0.09; P < 0.01), but inversely associated with twin births (-1.37 ± 0.67; P = 0.04). Greater birth weight and higher maternal plasma PUFA levels at 3 months postpartum were significantly associated with higher infant plasma PUFA levels at 3 months age. Twin births, male sex, and higher maternal MUFA levels were associated with lower infant plasma PUFA levels. Nutrition counseling for optimal intake of PUFA-rich foods, to lactating mothers in resource-limited settings may be beneficial for improved infant health.

The Impact of FADS Variants on Responses to Diet in Patients With ALI

Nutritional support in the intensive care unit (ICU) is a vital element of patient care. Polyunsaturated fatty acids (PUFAs) like γ‐linolenic acid (GLA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been recommended in immunomodulatory diets because of their anti‐inflammatory effects. However, clinical trials have failed to show unanimous benefit with PUFA‐rich diets. Metabolic conversion of these PUFAs are dependent on fatty acid desaturase (FADS) and elongase (ELOVL) enzymes, which are unequal across humans. In fact, several genetic variants within FADS and ELOVL genes have been shown to impact PUFA metabolism. Select variants are also differentially expressed in African Americans. We hypothesize that these genetic variants may help explain the differential responses to PUFA‐rich diets. In this study, we aimed to investigate gene‐diet interactions in patients with acute lung injury (ALI).Banked DNA and plasma samples from the OMEGA randomized clinical trial (NCT00609180) were used to conduct a secondary analysis on genetic variants within FADS and ELOVL regions; 43 SNPs were genotyped. Plasma PUFA levels were quantified using gas chromatography. Of the 272 enrolled, 143 received omega‐rich vs. 129 placebo diets. All statistical analyses were stratified by race and adjusted for age and gender.Several SNPs were associated with PUFA levels. Notably, SNP rs174537 had a significant impact on arachidonic acid (ARA). Caucasian T allele carriers on the omega‐rich diet had lower ARA levels (p=0.022, Fig. 1). Interestingly, this SNP had a major impact on PUFAs within African Americans on both placebo and omega‐rich diets. ARA levels were significantly higher and DHA levels were low (p=0.0007) in African Americans. Genotype at rs174537 was associated with patient outcomes; Caucasians with the T allele had significantly more VENT‐free and ICU‐free days (~&gt;12%) than GGs, but this was not observed within African Americans. Instead, a significant interaction between gender and diet was seen, with African American women on placebo diet having 40% fewer VENT‐free (p=0.009) and ICU‐free days (p=0.022) than African American men. Mortality was highest in GGs receiving omega‐rich diets in both races, however this was not statistically significant. These data suggest strong ethnic, gender and genetic factors influencing the response to omega‐rich diets. Further investigation on other gene‐gene interactions (e.g. between FADS and ELOVL variants), and epigenetic modifications are needed to understand the underlying mechanisms regulating PUFA metabolism and biosynthesis in critically injured and ill patients.Support or Funding InformationNIH K25 HL133611This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Dietary and Plasma Polyunsaturated Fatty Acids Are Inversely Associated with Asthma and Atopy in Early Childhood

Polyunsaturated fatty acids (PUFAs) influence immune function and risk of allergic disease. Prior evidence of the effect of PUFA intake on childhood asthma and allergy is inconclusive. To investigate associations of PUFA plasma levels and dietary intake with asthma and allergy at age 3 years in this ancillary study of the Vitamin D Antenatal Asthma Reduction Trial. Plasma PUFA levels were reported as relative abundances from mass spectrometry profiling, and dietary PUFA intake was derived from food frequency questionnaire responses. Associations between PUFA and outcomes, including asthma and/or recurrent wheeze, allergic sensitization, and total IgE at age 3 years, were evaluated in adjusted regression models. Additional regression models analyzed the combined effects of antenatal vitamin D and early childhood PUFA on outcomes. Total, omega-3, and omega-6 plasma PUFA relative abundances were significantly (P < .05) inversely associated with both asthma and/or recurrent wheeze and allergic sensitization. Likewise, dietary PUFA intake was inversely associated with asthma and/or recurrent wheeze (P < .05 for omega-6 PUFA only). For both dietary and plasma measures of total, omega-3, and omega-6 PUFAs, inverse associations with outcomes were strongest among subjects with both high umbilical cord blood 25-hydroxyvitamin D and high PUFA at age 3 years. PUFA dietary intake and plasma levels are inversely associated with asthma and/or recurrent wheeze and atopy at age 3 years. Antenatal vitamin D could modulate the effect of early childhood PUFA on risk of asthma and allergy.

Investigation into the plasma concentration of ω3 polyunsaturated fatty acids in Japanese attention-deficit hyperactivity disorder patients.

Several studies report that patients with attention-deficit hyperactivity disorder (ADHD) have a low plasma concentration of polyunsaturated fatty acids (PUFAs). Since fish intake varies among countries and is high in Japan, those results may not apply to Japanese patients with ADHD. However, there is currently not enough evidence to support this. We compared the plasma PUFAs levels of patients with ADHD with the standard reference levels for healthy subjects, and examined the relationship between those PUFAs levels and the subject's psychological evaluation. The subjects were 24 patients (age < 20years) previously diagnosed with ADHD (according to the DSM-IV-TR criteria) at the psychiatric department of the Nagasaki University Hospital, between November 2010 and November 2015. The plasma concentrations of docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and arachidonic acid (AA) were measured using gas chromatography. Data pertaining to global assessment of functioning (GAF), clinical global impressions, ADHD Rating Scale-IV, and the drug used for treatment (atomoxetine or methylphenidate) were obtained from the medical records. The plasma concentrations of DHA, EPA, and EPA/AA were significantly lower than the normal reference range, indicating that ADHD patients present an imbalance in PUFAs levels. This trend is similar to ADHD patients in other countries and replacement therapy in Japanese ADHD patients may be useful.

Variation in the Plasma Levels of Polyunsaturated Fatty Acids in Control vis-à-vis Nonalcoholic Fatty Liver Disease Subjects and Its Possible Association with Gut Microbiome.

Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are becoming a major cause of chronic liver diseases globally. Polyunsaturated fatty acids (PUFA) have been postulated as a potential treatment for NAFLD. They can be obtained from diet and are also endogenously synthesized by enzymes delta-6-desaturase (D6D), delta-5-desaturase, and elongases. The current study is aimed at investigating the differences in the intake and levels of plasma PUFA between NAFLD patients and controls in Asian Indians. This correlation further propelled a pilot study to check for the differences in the gut microbiome of NASH subjects versus controls. One hundred forty-seven subjects were recruited and were grouped into healthy controls and cases. Subjects filled a food frequency questionnaire to assess PUFA intake. Plasma samples were subjected to gas chromatography analysis. For characterizing the gut microbiome, fecal samples of 20 NASH and healthy controls were analyzed by 16s rRNA gene sequencing. Alpha and beta diversity metrics and taxonomic analysis were carried out. Plasma levels of eicosapentaenoic acid, γ-linoleic acid and D6D enzyme activity were significantly lower in cases. Dietary intake of total n-6 and n-3 PUFA did not differ between the two groups. Relative abundance of Streptococcus and Clostridium ramosum was significantly higher in NASH patients compared with healthy controls. This study demonstrates, for the first time, decreased D6D enzyme activity and plasma PUFA levels in NAFLD patients. Furthermore, it demonstrates gut dysbiosis in histologically proven NASH patients vis-à-vis healthy controls.