The association of desaturase 9 and plasma fatty acid composition with insulin resistance-associated factors in female adolescents

Desaturase 9 (Δ9), which converts saturated fatty acids (SFAs) into monounsaturated fatty acids, is an important component in leptin-mediated energy homeostasis in rodent models. Few human studies, however, have been performed regarding the clinical relevance of Δ9, particularly whether Δ9 is involved in the relationship between blood fatty acid profiles and insulin resistance-associated factors. The aim of the present study was to examine fatty acid data from 178 apparently healthy female adolescents and determine whether (a) Δ9 has independent associations with adiposity, insulin resistance level, and fasting plasma polyunsaturated fatty acids (PUFAs); (b) Δ9 is a predictor of fasting blood lipid profile; and (c) the associations between fasting plasma fatty acid component and insulin resistance level are independent of abdominal obesity level. Desaturase 9-16 (surrogate of Δ9 as calculated by plasma ratio C16:1 n-7/C16:0) correlated with waist girth (r = .160, P < .05), homeostasis model assessment of insulin resistance (HOMA-IR) (r = .201, P < .01), plasma PUFAs (eg, C20:4 n-6 [r = −.269, P < .001], C22:6 n-3 [r = −.274, P < .001]). After adjustment for dietary SFAs, Δ9-16 had stronger correlation with waist (r = .227, P < .01) and significant correlation with PUFAs, whereas it had a nonsignificant correlation with HOMA-IR. The same pattern was observed with Δ9-18 (surrogate of Δ9 as calculated by plasma ratio C18:1 n-9/C18:0). After adjustment for dietary SFAs, waist, and HOMA-IR, Δ9-16 and Δ9-18 were still positive predictors of triglyceride (both P < .001) and apolipoprotein B (Δ9-18, P < .001; Δ9-16, P = .052). After adjustment for waist, HOMA-IR only remained a positive determinant of medium-chain SFAs (C14:0, P < .001; C16:0, P < .05); but it emerged to be inversely related to C20:4 n-6 (P < 0.1). The positive and independent associations of medium-chain SFAs with insulin resistance level suggest their vital roles in diabetes pathogenesis, whereas certain PUFAs such as C20:4 n-6 appear to be protective. The observed associations of Δ9 with adiposity and plasma lipid profile in these apparently healthy female adolescents support the concept derived from rodent models that Δ9 activity is independently reflective of higher body mass index and higher circulatory triglyceride levels.     

Genetic variations in polyunsaturated fatty acid metabolism--implications for child health?

Sufficient nutritional supply with polyunsaturated fatty acids (PUFAs) has long been considered as beneficial for child health, especially in regard to neuronal development and allergic diseases. In recent years, genetic association studies showed that in addition to nutritional influences, the genetic background is highly important for PUFA composition in human tissues. Specifically, polymorphisms in the fatty acid desaturase genes or FADS determine the efficiency of how PUFAs are processed endogenously. Recent gene-nutrition interaction studies suggest that these polymorphisms modulate the effect of nutritional fatty acid intake on complex phenotypes such as cognitive outcomes and asthma risk in children. These early results may provide the basis for future well-specified dietary recommendations to achieve optimal health benefit for all children. This article presents results from recent gene-nutrition interaction studies, discusses its implications for child health, and gives an outlook how this association might translate into clinical practice in the future.     

Genes regulating levels of ω-3 long-chain polyunsaturated fatty acids are associated with alcohol use disorder and consumption,and broader externalizing behavior in humans

Background

Individual variation in the physiological response to alcohol is predictive of an individual's likelihood to develop alcohol use disorder (AUD). Evidence from diverse model organisms indicates that the levels of long-chain polyunsaturated omega-3 fatty acids (ω-3 LC-PUFAs) can modulate the behavioral response to ethanol and therefore may impact the propensity to develop AUD. While most ω-3 LC-PUFAs come from diet, humans can produce these fatty acids from shorter chain precursors through a series of enzymatic steps. Natural variation in the genes encoding these enzymes has been shown to affect ω-3 LC-PUFA levels. We hypothesized that variation in these genes could contribute to the susceptibility to develop AUD.

Methods

We identified nine genes (FADS1, FADS2, FADS3, ELOVL2, GCKR, ELOVL1, ACOX1, APOE, and PPARA) that are required to generate ω-3 LC-PUFAs and/or have been shown or predicted to affect ω-3 LC-PUFA levels. Using both set-based and gene-based analyses we examined their association with AUD and two AUD-related phenotypes, alcohol consumption, and an externalizing phenotype.

Results

We found that the set of nine genes is associated with all three phenotypes. When examined individually, GCKR, FADS2, and ACOX1 showed significant association signals with alcohol consumption. GCKR was significantly associated with AUD. ELOVL1 and APOE were associated with externalizing.

Conclusions

Taken together with observations that dietary ω-3 LC-PUFAs can affect ethanol-related phenotypes, this work suggests that these fatty acids provide a link between the environmental and genetic influences on the risk of developing AUD.

     

Erythrocyte membrane docosapentaenoic acid levels are associated with islet autoimmunity: the Diabetes Autoimmunity Study in the Young

Aims/hypotheses

We previously reported that lower n-3 fatty acid intake and levels in erythrocyte membranes were associated with increased risk of islet autoimmunity (IA) but not progression to type 1 diabetes in children at increased risk for diabetes. We hypothesise that specific n-3 fatty acids and genetic markers contribute synergistically to this increased risk of IA in the Diabetes Autoimmunity Study in the Young (DAISY).

Methods

DAISY is following 2,547 children at increased risk for type 1 diabetes for the development of IA, defined as being positive for glutamic acid decarboxylase (GAD)₆₅, IA-2 or insulin autoantibodies on two consecutive visits. Using a case-cohort design, erythrocyte membrane fatty acids and dietary intake were measured prospectively in 58 IA-positive children and 299 IA-negative children.

Results

Lower membrane levels of the n-3 fatty acid, docosapentaenoic acid (DPA), were predictive of IA (HR 0.23; 95% CI 0.09, 0.55), while α-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were not, adjusting for HLA and diabetes family history. We examined whether the effect of dietary intake of the n-3 fatty acid ALA on IA risk was modified by fatty acid elongation and desaturation genes. Adjusting for HLA, diabetes family history, ethnicity, energy intake and questionnaire type, ALA intake was significantly more protective for IA in the presence of an increasing number of minor alleles at FADS1 rs174556 (p_interaction?=?0.017), at FADS2 rs174570 (p_interaction?=?0.016) and at FADS2 rs174583 (p_interaction?=?0.045).

Conclusions/interpretation

The putative protective effect of n-3 fatty acids on IA may result from a complex interaction between intake and genetically controlled fatty acid desaturation.     

Polyunsaturated fatty acids are involved in regulatory mechanism of fatty acid homeostasis via daf-2/insulin signaling in Caenorhabditis elegans

The development of the dauer form of Caenorhabditis elegans daf-2(e1370) enhances the expression of genes such as fatty acid desaturase fat-6 and fat-7 and fatty acid elongase elo-2, and increases the level of triglyceride (TAG). RNA interference (RNAi) of the fat-6, fat-7, and elo-2 genes lowers fat accumulation in the nematode. We recently clarified the fact that RNAi of fat-related genes, especially fat-2, reduced fat accumulation and activated DAF-16.     

Associated factors of estimated desaturase activity in the EPIC-Potsdam study

Background and aimsAltered activity of desaturase enzymes may be involved in the development of metabolic diseases like type 2-diabetes. Desaturase activities might be modifiable by diet and lifestyle-related factors, but no study has systematically investigated such factors so far. We aimed to evaluate the association of demographic, anthropometric, dietary and lifestyle characteristics with estimated Δ5-, Δ6- and Δ9-desaturase activity.Methods and resultsA subsample (n = 1782) of the EPIC-Potsdam study was used for a cross-sectional analysis, involving men and women, mainly aged 35–65 years. Fatty acid (FA) product-to-precursor ratios, derived from the FA composition of erythrocyte membrane phospholipids, were used to estimate desaturase activities. Multiple linear regression models were used with estimated Δ5-, Δ6- and Δ9-desaturase activity as outcome and demographic (age, sex), anthropometric (BMI, WHR), dietary intake (FAs, carbohydrates) and lifestyle (physical activity, smoking, alcohol consumption) factors as exposure variables.Alcohol intake was positively associated with estimated Δ6- (explained variance in desaturase activity: 1.52%) and estimated Δ9-desaturase activity (explained variance: 5.53%). BMI and WHR showed a weak inverse association with estimated Δ5-desaturase activity (explained variance: BMI: 1.07%; WHR: 1.02%) and weak positive associations with estimated Δ6-(explained variance: BMI: 1.17%; WHR: 1.19%) and estimated Δ9-desaturase activities (explained variance: BMI: 0.70%; WHR: 0.96%). Age, sex, physical activity, smoking and dietary factors were only weakly associated with the estimated desaturase activities.ConclusionOur findings suggest that alcohol intake as well as obesity measures are associated with the FA ratios reflecting desaturase activity.     

Plasma polyunsaturated fatty acid profile and delta-5 desaturase activity are altered in patients with type 2 diabetes

Objective

The association between imbalance of polyunsaturated fatty acids (PUFAs), especially low plasma n-3 to n-6 PUFA ratio, and risk of cardiovascular diseases is well known. A balance of plasma PUFAs is determined not only by dietary fatty acid intake, but also by the endogenous fatty acid metabolism, which could be dysregulated by diabetes. In this study, we investigated the plasma n-3 and n-6 PUFA profile and fatty acid desaturase activity in patients with type 2 diabetes (T2D).

Materials/Methods

The subjects were 396 patients with T2D and 122 healthy controls. Plasma eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), arachidonic acid (AA), and dihomo-γ-linolenic acid (DGLA) levels were measured by capillary gas chromatography.

Results

Plasma DHA, AA, and DGLA levels were significantly higher, and EPA levels tended to be lower in patients with T2D than in the controls. Patients with T2D also exhibited significantly lower EPA/AA, DHA/AA, and (EPA + DHA)/AA ratios, and a higher AA/DGLA ratio than the controls. Multiple regression analyses, including age, sex, body mass index, and metabolic parameters in the total population, revealed that the presence of T2D was independently associated with elevated plasma DHA, AA, and DGLA levels and decreased EPA/AA, DHA/AA, and (EPA + DHA)/AA ratios. Furthermore, T2D was independently and positively related to the AA/DGLA ratio, which serves as an estimate of delta (Δ)-5 desaturase activity.

Conclusions

Elevated plasma AA levels and decreased n-3 PUFA/AA ratios in T2D are attributable, at least partly, to Δ5 desaturase activation.     

Age-associated changes in circulatory fatty acids: new insights on adults and long-lived individuals

Long-lived individuals (LLIs) are considered an ideal model to study healthy human aging. Blood fatty acid (FA) profile of a cohort of LLIs (90–111 years old, n?=?49) from Sicily was compared to adults (18–64 years old, n?=?69) and older adults (65–89 years old, n?=?54) from the same area. Genetic variants in key enzymes related to FA biosynthesis and metabolism were also genotyped to investigate a potential genetic predisposition in determining the FA profile. Gas chromatography was employed to determine the FA profile, and genotyping was performed using high-resolution melt (HRM) analysis. Blood levels of total polyunsaturated FA (PUFA) and total trans-FA decreased with age, while the levels of saturated FA (SFA) remained unchanged. Interestingly, distinctively higher circulatory levels of monounsaturated FA (MUFA) in LLIs compared to adults and older adults were observed. In addition, among LLIs, rs174537 in the FA desaturase 1/2 (FADS1/2) gene was associated with linoleic acid (LA, 18:2n-6) and docosatetraenoic acid (DTA, 22:4n-6) levels, and the rs953413 in the elongase of very long FA 2 (ELOVL2) was associated with DTA levels. We further observed that rs174579 and rs174626 genotypes in FADS1/2 significantly affect delta-6 desaturase (D6D) activity. In conclusion, our results suggest that the LLIs have a different FA profile characterized by high MUFA content, which indicates reduced peroxidation while maintaining membrane fluidity.

     

Fatty acid desaturases in human adipose tissue: relationships between gene expression, desaturation indexes and insulin resistance

Aims/hypothesis Fatty acid desaturases introduce double bonds into growing fatty acid chains. The key desaturases in humans are Δ⁵-desaturase (D5D), Δ⁶-desaturase (D6D) and stearoyl-CoA desaturase (SCD). Animal and human data implicate hepatic desaturase activities in insulin resistance, obesity and dyslipidaemia. However, the role of desaturase activity in adipose tissue is uncertain. We therefore evaluated relationships between adipose mRNA expression, estimated desaturase activities (fatty acid ratios) in adipose tissue and insulin resistance. Methods Subcutaneous adipose tissue mRNA expression of D5D (also known as FADS1), D6D (also known as FADS2) and SCD was determined in 75 individuals representative of the study population of 294 healthy 63-year-old men. Desaturation indexes (product/substrate fatty acid ratios) were generated from adipose tissue fatty acid composition in all individuals. Insulin resistance was defined as the upper quartile of the updated homeostasis model assessment (HOMA-2) index. Results The relevant desaturation indexes (16:1/16:0, 18:1/18:0, 20:4/20:3 and 18:3/18:2) reflected expression of SCD, but not of D5D or D6D in adipose tissue. Insulin-resistant individuals had a higher adipose tissue 18:1/18:0, but not 16:1/16:0 ratio than insulin-sensitive individuals. Individuals with a high adipose tissue 18:1/18:0 ratio were 4.4-fold (95% CI 1.8–11.8) more likely to be insulin resistant [threefold (95% CI 1.1–8.6) after adjustment for waist circumference and plasma triacylglycerol]. In a multiple regression model predicting HOMA-2, the independent effect of the 18:1/18:0 ratio was borderline (p = 0.086). Conclusions/interpretation Adipose tissue desaturation indexes of SCD reflect the expression of the gene encoding the enzyme in this tissue. Elevated SCD activity within adipose tissue is closely coupled to the development of insulin resistance.     

MAT1A variants modulate the effect of dietary fatty acids on plasma homocysteine concentrations

Background and AimDietary n-3 polyunsaturated fatty acids (PUFAs) are associated with decreased plasma homocysteine (Hcy), an important biomarker for cardiovascular disease. The S-adenosylmethionine synthetase type-1 (MAT1A), an essential enzyme in the conversion of methionine to S-adenosylmethionine, plays a key role in homocysteine metabolism. This study investigated the interaction between dietary fatty acids and MAT1A genotypes on plasma Hcy concentrations among Boston Puerto Ricans.Methods and ResultsPlasma Hcy and MAT1A genotypes were determined in 994 subjects of the Boston Puerto Rican Health Study. Dietary fatty acid intakes were assessed by interviews using a questionnaire adapted from the NCI/Block food frequency form.ResultIn the cross-sectional analysis, genetic variant MAT1A 3U1510 displayed a significant interaction with dietary n-3:n-6 PUFA ratio in determining plasma Hcy (p-value for interaction = 0.025). 3U1510G homozygotes had significantly lower plasma Hcy concentration than major allele homozygotes and heterozygotes (AA + AG) (p-value for trend = 0.019) when the n-3:n-6 ratio was >0.09. Two other MAT1A variants, d18777 and i15752, also showed significant interactions with different constituents of dietary fat influencing Hcy concentrations. Furthermore, haplotypes consisting of three variants displayed a strong interaction with n3:n6 ratio influencing Hcy concentrations.ConclusionsOur results suggest that MAT1A genotypes appear to modulate effects of dietary fat on plasma Hcy.     

Adenoviral gene transfer of Caenorhabditis elegans n--3 fatty acid desaturase optimizes fatty acid composition in mammalian cells

Omega--3 polyunsaturated fatty acids (PUFAs) are essential components required for normal cellular function and have been shown to exert many preventive and therapeutic actions. The amount of n--3 PUFAs is insufficient in most Western people, whereas the level of n--6 PUFAs is relatively too high, with an n--6/n--3 ratio of >18. These two classes of PUFAs are metabolically and functionally distinct and often have important opposing physiological functions; their balance is important for homeostasis and normal development. Elevating tissue concentrations of n--3 PUFAs in mammals relies on chronic dietary intake of fat rich in n--3 PUFAs, because mammalian cells lack enzymatic activities necessary either to synthesize the precursor of n--3 PUFAs or to convert n--6 to n--3 PUFAs. Here we report that adenovirus-mediated introduction of the Caenorhabditis elegans fat-1 gene encoding an n--3 fatty acid desaturase into mammalian cells can quickly and effectively elevate the cellular n--3 PUFA contents and dramatically balance the ratio of n--6/n--3 PUFAs. Heterologous expression of the fat-1 gene in rat cardiac myocytes rendered cells capable of converting various n--6 PUFAs to the corresponding n--3 PUFAs, and changed the n--6/n--3 ratio from about 15:1 to 1:1. In addition, an eicosanoid derived from n--6 PUFA (i.e., arachidonic acid) was reduced significantly in the transgenic cells. This study demonstrates an effective approach to modifying fatty acid composition of mammalian cells and also provides a basis for potential applications of this gene transfer in experimental and clinical settings.     

Effects of saturated and unsaturated fatty acids on estimated desaturase activities during a controlled dietary intervention

Background and aimsDirect measurement of desaturase activities are difficult to obtain in humans. Consequently, surrogate measures of desaturase activity (estimated desaturase activities) have been frequently used in observational studies, and estimated Δ⁹- (or stearoyl-CoA-desaturase (SCD)), Δ⁶- and Δ⁵-desaturase activities have been associated with cardiometabolic disease. Data on how the markers of desaturase activities are modified by changes in dietary fat quality are lacking and therefore warrant examination.Methods and resultsIn a two-period (three weeks) strictly controlled cross-over study, 20 subjects (six women and 14 men) consumed a diet high in saturated fat (SAT-diet) and a rapeseed oil diet (RO-diet), rich in oleic acid (OA), linoleic acid (LA) and α-linolenic acid (ALA). Estimated desaturase activities were calculated as precursor to product FA ratios in serum cholesteryl esters and phospholipids. The estimated SCD [16:1 n-7/16:0] and Δ⁶-desaturase [20:3 n-6/18:2 n-6] was significantly higher while Δ⁵-desaturase [20:4 n-6/20:3 n-6] was significantly lower in the SAT-diet (P < 0.001 for all), compared to the RO-diet. The serum proportions of palmitic, stearic, palmitoleic and dihomo-γ-linolenic acids were significantly higher in the SAT-diet while the proportions of LA and ALA were significantly higher in the RO-diet.ConclusionThis is the first study to demonstrate that surrogate measures of desaturase activities change as a consequence of an alteration in dietary fat quality. Both the [16:1/16:0]-ratio and 16:1 seem to reflect changes in saturated fat intake and may be useful markers of saturated fat intake in Western countries.     

Association between serum fatty acids and lipoprotein subclass profile in healthy young adults: Exploring common genetic and environmental factors

Objective

Little is known about the associations of serum fatty acids with lipoprotein profile and the underlying genetic and environmental etiology of these relationships. We aimed to analyze the phenotypic association of serum n-6 and n-3 polyunsaturated (PUFAs), monounsaturated (MUFAs) and saturated (SFAs) fatty acids (relative proportion to total fatty acids) with lipids and lipoproteins, and to quantify common genetic and environmental factors determining their covariation.

Methods

Two cohorts of healthy Finnish twins were assessed in young adulthood. Data were available for 1269 individual twins including 561 complete pairs. Serum metabolites were measured by nuclear magnetic resonance spectroscopy. Bivariate quantitative genetic models were used to decompose the phenotypic covariance between the pairs of traits into genetic and environmental components.

Results

Among the strongest correlations observed, serum total n-6 PUFAs and linoleic acid were inversely (max. r = −0.65) and MUFAs positively (max. r = 0.63) correlated with triglycerides and very low-density lipoprotein (VLDL) particle concentration, particularly with large VLDL (for n-6 PUFAs) and medium VLDL (for MUFAs). Genetic factors significantly contributed to their covariance with bivariate heritability estimates ranging from 44% to 56% for n-6 PUFAs and 58% to 66% for MUFAs. Genetic correlations with lipid traits were moderate to high (max. r_A = −0.59 and 0.70 for n-6 PUFAs and MUFAs, respectively). Statistically significant, but substantially weaker phenotypic correlations of total n-3 PUFAs, docosahexaenoic acid (DHA) and SFAs with lipoprotein profile were not decomposed into their genetic and environmental components.

Conclusion

Shared genetic factors are important in explaining why higher concentrations of serum n-6 PUFAs and lower concentrations of serum MUFAs strongly associate with lower triglyceride and VLDL particle concentrations.     

Common variants in the CLDN2-MORC4 and PRSS1-PRSS2 loci confer susceptibility to acute pancreatitis

Background/Objectives

Acute pancreatitis (AP) is one of the most common gastrointestinal disorders often requiring hospitalization. Frequent aetiologies are gallstones and alcohol abuse. In contrast to chronic pancreatitis (CP) few robust genetic associations have been described. Here we analysed whether common variants in the CLDN2-MORC4 and the PRSS1-PRSS2 locus that increase recurrent AP and CP risk associate with AP.

Expression of a borage desaturase cDNA containing an N-terminal cytochrome b5 domain results in the accumulation of high levels of Δ6-desaturated fatty acids in transgenic tobacco

γ-Linolenic acid (GLA; C18:3 Δ^6,9,12) is a component of the seed oils of evening primrose (Oenothera spp.), borage (Borago officinalis L.), and some other plants. It is widely used as a dietary supplement and for treatment of various medical conditions. GLA is synthesized by a Δ⁶-fatty acid desaturase using linoleic acid (C18:2 Δ^9,12) as a substrate. To enable the production of GLA in conventional oilseeds, we have isolated a cDNA encoding the Δ⁶-fatty acid desaturase from developing seeds of borage and confirmed its function by expression in transgenic tobacco plants. Analysis of leaf lipids from a transformed plant demonstrated the accumulation of GLA and octadecatetraenoic acid (C18:4 Δ^6,9,12,15) to levels of 13.2% and 9.6% of the total fatty acids, respectively. The borage Δ⁶-fatty acid desaturase differs from other desaturase enzymes, characterized from higher plants previously, by the presence of an N-terminal domain related to cytochrome b₅.     

Relations of Plasma Polyunsaturated Fatty Acids With Blood Pressures During the 26th and 28th Week of Gestation in Women of Chinese,Malay, and Indian Ethnicity

Observational and intervention studies have reported inconsistent results of the relationship between polyunsaturated fatty acids (PUFAs) and hypertension during pregnancy. Here, we examined maternal plasma concentrations of n-3 and n-6 PUFAs between the 26th and the 28th week of gestation in relation to blood pressures and pregnancy-associated hypertension.We used data from a birth cohort study of 751 Chinese, Malay, and Indian women. Maternal peripheral systolic blood pressure (SBP) and diastolic blood pressure (DBP) were taken from the brachial arm, and central SBP and pulse pressures (PPs) were derived from radial artery pressure waveforms between the 26th and the 28th week of gestation. Pregnancy-associated hypertension (including gestational hypertension and preeclampsia) was ascertained from medical records. Plasma phosphatidylcholine n-3 and n-6 PUFAs were measured by gas chromatography and expressed as percentage of total fatty acids.Peripheral SBP was inversely associated with total n-3 PUFAs [−0.51 (95% confidence interval, CI, −0.89 to −0.13) mm Hg] and long-chain n-3 PUFAs [−0.52 (CI −0.92 to −0.13) mmHg]. Similar but weaker associations were observed for central SBP and PP. Dihomo-γ-linolenic acid was marginally positively associated with peripheral SBP, central SBP, and PP, whereas linoleic acid and total n-6 PUFAs showed no significant associations with blood pressures. We identified 28 pregnancy-associated hypertension cases, and 1% increase in total n-3 PUFAs was associated with a 24% lower odds of pregnancy-associated hypertension (odds ratio 0.76; 95% CI 0.60 to 0.97). Maternal ethnicity modified the PUFAs–blood pressure relations, with stronger inverse associations with n-3 PUFAs in Chinese women, and stronger positive associations with n-6 PUFAs in Indian women (P values for interaction ranged from 0.02 to 0.07).Higher n-3 PUFAs at midgestation are related to lower maternal blood pressures and pregnancy-associated hypertension in Asian women, and the ethnicity-related variation between PUFAs and blood pressures deserves further investigation.     

Association of plasma polyunsaturated fatty acids with arterial blood pressure: A Mendelian randomization study

High polyunsaturated fatty acids (PUFAs) intake is recommended for primary and secondary prevention of cardiovascular disease (CVD). However, the association of PUFAs with blood pressure (BP) is still controversial. In the present study, two-sample Mendelian randomization (MR) analysis was performed to investigate the causal relationship of PUFAs with BP, including systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP).Genetic instruments and summary statistics for two-sample MR analysis were obtained from 3 large-scale genome-wide association studies (GWASs). Eight single nucleotide polymorphisms (SNPs) significantly (P < 5 × 10⁻⁸) related to 6 PUFAs were used as instrumental variables. Conventional inverse-variance weighted method was adopted to evaluate the causality of PUFAs with BP; the Weighted Median, MR-egger, and Leave-one-out method were used for sensitivity analyses.As a result, there was no evidence of a causal association between all PUFAs and SBP. In addition, arachidonic acid (AA, β = −0.04, P < .001) and eicosapentaenoic acid (EPA, β = −0.47, P = .02) were negatively associated with DBP, while linoleic acid (LA, β = 0.03, P = .005) and α-linolenic acid (ALA, β = 3.83, P < .001) were positively associated with DBP. There was no evidence of a causal relationship between either docosapentaenoic acid (DPA) or docosahexaenoic acid (DHA) with DBP.In conclusion, a genetic predisposition to plasma polyunsaturated fatty acid (PUFA) had a divergent effect on DBP, independent of SBP. It suggested that it is helpful for lower DBP level to supplemental intake of AA and EPA or promote the conversion of LA and ALA to AA and EPA respectively, which need to be further validated with randomized controlled studies.     

Polyunsaturated fatty acids effect on serum triglycerides concentration in the presence of metabolic syndrome components. The Alaska-Siberia Project

Serum fatty acids (FAs) have wide effects on metabolism: Serum saturated fatty acids (SFAs) increase triglyceride (TG) levels in plasma, whereas polyunsaturated fatty acids (PUFAs) reduce them. Traditionally, Eskimos have a high consumption of omega-3 fatty acids (ω3 FAs); but the Westernization of their food habits has increased their dietary SFAs, partly reflected in their serum concentrations. We studied the joint effect of serum SFAs and PUFAs on circulating levels of TGs in the presence of metabolic syndrome components. We included 212 men and 240 women (age, 47.9 ± 15.7 years; body mass index [BMI], 26.9 ± 5.3) from 4 villages located in Alaska for a cross-sectional study. Generalized linear models were used to build surface responses of TG as functions of SFAs and PUFAs measured in blood samples adjusting by sex, BMI, and village. The effects of individual FAs were assessed by multiple linear regression analysis, and partial correlations (r) were calculated. The most important predictors for TG levels were glucose tolerance (r = 0.116, P = .018) and BMI (r = 0.42, P < .001). Triglyceride concentration showed negative associations with 20:3ω6 (r = −0.16, P = .001), 20:4ω6 (r = −0.14, P = .005), 20:5ω3 (r = −0.17, P < .001), and 22:5ω3 (r = −0.26, P < .001), and positive associations with palmitic acid (r = 0.16, P < .001) and 18:3ω3 (r = 0.15, P < .001). The surface response analysis suggested that the effect of palmitic acid on TG is blunted in different degrees according to the PUFA chemical structure. The long-chain ω3, even in the presence of high levels of saturated fat, was associated with lower TG levels. Eicosapentaenoic acid (20:5ω3) had the strongest effect against palmitic acid on TG. The total FA showed moderate association with levels of TG, whereas SFA was positively associated and large-chain PUFA was negatively associated. The Westernized dietary habits among Eskimos are likely to change their metabolic profile and increase comorbidities related to metabolic disease.     

Erythrocyte-derived measures of membrane lipid composition in healthy men: associations with arachidonic acid at low to moderate but not high insulin sensitivity

The lipid composition of erythrocyte membranes was explored as a surrogate for that of skeletal muscle in investigations into the influence of membrane fatty acid composition on insulin sensitivity. In a preliminary study (study 1), erythrocyte and monocyte/platelet membrane fatty acid percentages were compared with those of muscle membrane in 10 otherwise healthy men undergoing orthopedic surgery. In a further study (study 2), relationships between erythrocyte membrane fatty acid concentrations and insulin sensitivity, S(I), measured using the intravenous glucose tolerance test (IVGTT), were evaluated in 30 asymptomatic men. In study 1, significant positive correlations were found between muscle and erythrocyte membrane fatty acid percentages for 16:0 saturated fatty acid (r = 0.92, P <.001), and for the 18:2n-6, 20:4n-6, 20:5n-3, and 22:5n-3 polyunsaturated fatty acids (PUFAs) (r = 0.67 to 0.83, P <.05 to.01). There were fewer and weaker associations between muscle and monocyte/platelet membrane fatty acid compositions. In study 2, highly insulin-sensitive individuals (n = 8) had significantly lower erythrocyte membrane fatty acid concentrations than those with low/normal S(I). Among those with low/normal S(I) (n = 22), S(I) correlated positively with erythrocyte membrane arachidonic acid concentration (r = 0.57, P <.01) and with total PUFAs (r = 0.46, P <.05). Indices of delta 6 and delta 5 desaturase activities were significantly higher and lower, respectively, in high compared with low/normal S(I) individuals. For a range of fatty acids, erythrocyte membrane fatty acid composition shows close associations with that of muscle membranes. Measurements in erythrocyte membranes support a role for membrane arachidonic acid content in the modulation of insulin sensitivity, specifically at low/normal insulin sensitivities.     

Comparison of fatty acid proportions in serum cholesteryl esters among people with different glucose tolerance status: the CoDAM study

Background and aimAltered fatty acid patterns in blood may be associated with insulin resistance and related disorders. We investigated whether serum proportions of cholesteryl fatty acids and desaturase activity are associated with glucose tolerance status and insulin resistance.Methods and resultsData were obtained from a cross-sectional study among 471 Dutch participants aged ≥40 years. Individual fatty acids in serum cholesteryl esters were determined and endogenous conversions by desaturases were estimated from product-to-precursor ratios. Proportions of fatty acids were compared among participants with normal glucose tolerance, impaired glucose metabolism and newly diagnosed type 2 diabetes. Partial Spearman correlation coefficients between fatty acids and homeostasis model assessment-insulin resistance (HOMA-IR) were calculated. Adjustments were made for lifestyle and nutritional factors.The proportions of total saturated, mono-unsaturated, trans- and poly-unsaturated fatty acids did not differ significantly between groups, but several individual fatty acids did; the proportions of C18:0 and C20:3n6 were higher, whereas those of C18:1n7 and C20:4n6 were lower in participants with type 2 diabetes compared with those with normal glucose tolerance. Activity of Δ5-desaturase, that is, ratio of C20:4n6 to C20:3n6, was lower (p < 0.01) in participants with type 2 diabetes (7.4) than with normal glucose tolerance (8.4). HOMA-IR was correlated positively with Δ9-desaturase activity (r = 0.11, p < 0.01) and inversely with Δ5-desaturase activity (r = ?0.21, p < 0.01).ConclusionThe observed lower Δ5-desaturase activity in participants with type 2 diabetes and its inverse association with HOMA-IR suggest that changes in fatty-acid metabolism may play a role in the aetiology of type 2 diabetes.