Gender-based heterogeneity of FAHFAs in trained runners.

Fatty acid esters of hydroxy fatty acid (FAHFA) are anti-diabetic and anti-inflammatory lipokines. Recently FAHFAs were also found to predict cardiorespiratory fitness in a cross-sectional study of recreationally trained runners. Here we report the influences of body composition and gender on static FAHFA abundances in circulation. We compared the association between circulating FAHFA concentrations and body composition, determined by dual x-ray absorptiometry, in female recreational runners who were lean (BMI < 25 kg/m2, n = 6), to those who were overweight (BMI ≥ 25 kg/m2, n = 7). To characterize the effect of gender we also compared circulating FAHFAs in lean male recreational runners (n = 8) to recreationally trained lean female (n = 6) runner group. Circulating FAHFAs were increased in females in a manner that was modulated by specific adipose depot sizes, blood glucose, and lean body mass. As expected, circulating FAHFAs were diminished in the overweight group, but strikingly, within the lean cohort, increases in circulating FAHFAs were promoted by increased fat mass, relative to lean mass, while the overweight group showed a significantly attenuated relationship. These studies suggest multimodal regulation of circulating FAHFAs and raise hypotheses to test endogenous FAHFA dynamic sources and sinks in health and disease, which will be essential for therapeutic target development. Baseline circulating FAHFA concentrations could signal sub-clinical metabolic dysfunction in metabolically healthy obesity.

Circulating fatty acids and risk of hepatocellular carcinoma and chronic liver disease mortality in the UK Biobank.

Nuclear magnetic resonance (NMR)-based plasma fatty acids are objective biomarkers of many diseases. Herein, we aim to explore the associations of NMR-based plasma fatty acids with the risk of hepatocellular carcinoma (HCC) and chronic liver disease (CLD) mortality in 252,398 UK Biobank participants. Here we show plasma levels of n-3 poly-unsaturated fatty acids (PUFA) and n-6 PUFA are negatively associated with the risk of incident HCC [HRQ4vsQ1: 0.48 (95% CI: 0.33-0.69) and 0.48 (95% CI: 0.28-0.81), respectively] and CLD mortality [HRQ4vsQ1: 0.21 (95% CI: 0.13-0.33) and 0.15 (95% CI: 0.08-0.30), respectively], whereas plasma levels of saturated fatty acids are positively associated with these outcomes [HRQ4vsQ1: 3.55 (95% CI: 2.25-5.61) for HCC and 6.34 (95% CI: 3.68-10.92) for CLD mortality]. Furthermore, fibrosis stage significantly modifies the associations between PUFA and CLD mortality. This study contributes to the limited prospective evidence on the associations between plasma-specific fatty acids and end-stage liver outcomes.

Differences in Plasma Fatty Acid Composition Related to Chronic Pancreatitis: A Pilot Study.

OBJECTIVES: Chronic pancreatitis (CP) is an inflammatory disease affecting the absorption of fat-soluble nutrients. Signaling in pancreatic cells that lead to inflammation may be influenced by fatty acids (FAs) through diet and de novo lipogenesis. Here, we investigated the relationship between plasma FA composition in CP with heterogeneity of etiology and complications of CP. MATERIALS AND METHODS: Blood and clinical parameters were collected from subjects with CP (n = 47) and controls (n = 22). Plasma was analyzed for FA composition using gas chromatography and compared between controls and CP and within CP. RESULTS: Palmitic acid increased, and linoleic acid decreased in CP compared with controls. Correlations between age or body mass index and FAs are altered in CP compared with controls. Diabetes, pancreatic calcifications, and substance usage, but not exocrine pancreatic dysfunction, were associated with differences in oleic acid and linoleic acid relative abundance in CP. De novo lipogenesis index was increased in the plasma of subjects with CP compared with controls and in calcific CP compared with noncalcific CP. CONCLUSIONS: Fatty acids that are markers of de novo lipogenesis and linoleic acid are dysregulated in CP depending on the etiology or complication. These results enhance our understanding of CP and highlight potential pathways targeting FAs for treating CP.

The shift in the fatty acid composition of the circulating lipidome in Alzheimer's disease.

INTRODUCTION: Fatty acids (FAs) are the building blocks of complex lipids and signaling compounds; the role of the lipidome fatty acid profile (LFA) in AD progression remains unclear. METHODS: The LFA of plasma and cerebrospinal fluid (CSF) samples from 289 participants (103 AD patients, 92 MCI patients, and 94 controls) was determined by GC-FID. The MCI subjects were followed up for 58 ± 12.5 months. RESULTS: In controls, CSF has a more neuroprotective LFA than plasma. In CSF, a higher content of docosahexaenoic acid was associated with a reduced risk of MCI-to-AD progression. In plasma, higher oleic acid content was associated with lower risk of AD, MCI, and MCI-to-AD progression, whereas higher levels of vaccenic acid and docosahexaenoic acid were associated with greater risk of AD and MCI, and higher rate of MCI-to-AD progression, respectively. DISCUSSION: The circulating LFA is involved in the pathogenesis and progression of AD. HIGHLIGHTS: The lipidome fatty acid profile in CSF and plasma was markedly different. Higher levels of vaccenic acid and lower levels of oleic acid in plasma were associated with greater risk of Alzheimer's disease. In plasma, higher levels of oleic acid were associated with a reduced risk of MCI-to-AD progression. Higher levels of docosahexaenoic acid in CSF were associated with a lower risk of MCI-to-AD progression. Higher levels of docosahexaenoic acid in plasma were associated with a greater rate of MCI-to-AD progression.

Substitution of dietary monounsaturated fatty acids from olive oil for saturated fatty acids from lard increases low-density lipoprotein apolipoprotein B-100 fractional catabolic rate in subjects with dyslipidemia associated with insulin resistance: a randomized controlled trial.

BACKGROUND: The substitution of monounsaturated acids (MUFAs) for saturated fatty acids (SFAs) is recommended for cardiovascular disease prevention but its impact on lipoprotein metabolism in subjects with dyslipidemia associated with insulin resistance (IR) remains largely unknown. OBJECTIVES: This study aimed to evaluate the impact of substituting MUFAs for SFAs on the in vivo kinetics of apolipoprotein (apo)B-containing lipoproteins and on the plasma lipidomic profile in adults with IR-induced dyslipidemia. METHODS: Males and females with dyslipidemia associated with IR (n = 18) were recruited for this crossover double-blind randomized controlled trial. Subjects consumed, in random order, a diet rich in SFAs (SFAs: 13.4%E; MUFAs: 14.4%E) and a diet rich in MUFAs (SFAs: 7.1%E; MUFAs: 20.7%E) in fully controlled feeding conditions for periods of 4 wk each, separated by a 4-wk washout. At the end of each diet, fasting plasma samples were taken together with measurements of the in vivo kinetics of apoB-containing lipoproteins. RESULTS: Substituting MUFAs for SFAs had no impact on triglyceride-rich lipoprotein apoB-48 fractional catabolic rate (FCR) (Δ = -8.9%, P = 0.4) and production rate (Δ = 0.0%, P = 0.9), although it decreased very low-density lipoprotein apoB-100 pool size (PS) (Δ = -22.5%; P = 0.01). This substitution also reduced low-density lipoprotein cholesterol (LDL-C) (Δ = -7.0%; P = 0.01), non-high-density lipoprotein cholesterol (Δ = -2.5%; P = 0.04), and LDL apoB-100 PS (Δ = -6.0%; P = 0.05). These differences were partially attributed to an increase in LDL apoB-100 FCR (Δ = +1.6%; P = 0.05). The MUFA diet showed reduced sphingolipid concentrations and elevated glycerophospholipid levels compared with the SFA diet. CONCLUSIONS: This study demonstrated that substituting dietary MUFAs for SFAs decreases LDL-C levels and LDL PS by increasing LDL apoB-100 FCR and results in an overall improved plasma lipidomic profile in individuals with IR-induced lipidemia. TRIAL REGISTRATION: This trial was registered as clinicaltrials.gov as NCT03872349.

Neurotensin accelerates atherosclerosis and increases circulating levels of short-chain and saturated triglycerides.

BACKGROUND AND AIMS: Obesity and type 2 diabetes are significant risk factors for atherosclerotic cardiovascular disease (CVD) worldwide, but the underlying pathophysiological links are poorly understood. Neurotensin (NT), a 13-amino-acid hormone peptide, facilitates intestinal fat absorption and contributes to obesity in mice fed a high-fat diet. Elevated levels of pro-NT (a stable NT precursor produced in equimolar amounts relative to NT) are associated with obesity, type 2 diabetes, and CVD in humans. Whether NT is a causative factor in CVD is unknown. METHODS: Nt+/+ and Nt-/- mice were either injected with adeno-associated virus encoding PCSK9 mutants or crossed with Ldlr-/- mice and fed a Western diet. Atherosclerotic plaques were analyzed by en face analysis, Oil Red O and CD68 staining. In humans, we evaluated the association between baseline pro-NT and growth of carotid bulb thickness after 16.4 years. Lipidomic profiles were analyzed. RESULTS: Atherosclerotic plaque formation is attenuated in Nt-deficient mice through mechanisms that are independent of reductions in circulating cholesterol and triglycerides but associated with remodeling of the plasma triglyceride pool. An increasing plasma concentration of pro-NT predicts atherosclerotic events in coronary and cerebral arteries independent of all major traditional risk factors, indicating a strong link between NT and atherosclerosis. This plasma lipid profile analysis confirms the association of pro-NT with remodeling of the plasma triglyceride pool in atherosclerotic events. CONCLUSIONS: Our findings are the first to directly link NT to increased atherosclerosis and indicate the potential role for NT in preventive and therapeutic strategies for CVD.

Systemic Neutrophil Gelatinase-Associated Lipocalin Alterations in Chronic Pancreatitis: A Multicenter, Cross-Sectional Study.

INTRODUCTION: Chronic pancreatitis (CP) is a progressive fibroinflammatory disorder lacking therapies and biomarkers. Neutrophil gelatinase-associated lipocalin (NGAL) is a proinflammatory cytokine elevated during inflammation that binds fatty acids (FAs) such as linoleic acid. We hypothesized that systemic NGAL could serve as a biomarker for CP and, with FAs, provide insights into inflammatory and metabolic alterations. METHODS: NGAL was measured by immunoassay, and FA composition was measured by gas chromatography in plasma (n = 171) from a multicenter study, including controls (n = 50), acute and recurrent acute pancreatitis (AP/RAP) (n = 71), and CP (n = 50). Peripheral blood mononuclear cells (PBMCs) from controls (n = 16), AP/RAP (n = 17), and CP (n = 15) were measured by cytometry by time-of-flight. RESULTS: Plasma NGAL was elevated in subjects with CP compared with controls (area under the curve [AUC] = 0.777) or AP/RAP (AUC = 0.754) in univariate and multivariate analyses with sex, age, body mass index, and smoking (control AUC = 0.874; AP/RAP AUC = 0.819). NGAL was elevated in CP and diabetes compared with CP without diabetes ( P < 0.001). NGAL + PBMC populations distinguished CP from controls (AUC = 0.950) or AP/RAP (AUC = 0.941). Linoleic acid was lower, whereas dihomo-γ-linolenic and adrenic acids were elevated in CP ( P < 0.05). Linoleic acid was elevated in CP with diabetes compared with CP subjects without diabetes ( P = 0.0471). DISCUSSION: Elevated plasma NGAL and differences in NGAL + PBMCs indicate an immune response shift that may serve as biomarkers of CP. The potential interaction of FAs and NGAL levels provide insights into the metabolic pathophysiology and improve diagnostic classification of CP.

Maternal Blood Fatty Acid Levels in Fetal Growth Restriction.

OBJECTIVE: To assess the maternal blood levels of fatty acids (FAs) in pregnancies with fetal growth restriction (FGR). METHODS: This prospective cross-sectional study included pregnant women with gestational age between 26 and 37 + 6 weeks with FGR and appropriate for gestational age (AGA) fetuses. The levels of saturated, trans, monounsaturated, and polyunsaturated FAs were measured using centrifugation and liquid chromatography. The Student's t-test, Mann-Whitney test, and general linear model, with gestational age and maternal weight as covariants, were used to compare FA levels and the FGR and AGA groups. The Chi-square was used to evaluate the association between groups and studied variables. RESULTS: Maternal blood sample was collected from 64 pregnant women, being 24 FGR and 40 AGA. A weak positive correlation was found between the palmitoleic acid level and maternal weight (r = 0.285, p = 0.036). A weak negative correlation was found between the gamma-linoleic acid level and gestational age (r = - 0.277, p = 0.026). The median of the elaidic acid level (2.3 vs. 4.7 ng/ml, p = 0.045) and gamma-linoleic acid (6.3 vs. 6.6 ng/ml, p = 0.024) was significantly lower in the FGR than the AGA group. The palmitoleic acid level was significantly higher in the FGR than AGA group (50.5 vs. 47.6 ng/ml, p = 0.033). CONCLUSION: Pregnant women with FGR had lower elaidic acid and gamma-linoleic acid levels and higher palmitoleic acid levels than AGA fetuses.

OBJETIVO: Avaliar os níveis sanguíneos maternos de ácidos graxos (AGs) em gestações com restrição de crescimento fetal (RCF). MéTODOS:: Este estudo prospectivo transversal incluiu gestantes com idade gestacional entre 26 e 37 semanas e 6 dias com RCF e fetos adequados para a idade gestacional (AIG). Os níveis de ácidos graxos saturados, trans, monoinsaturados e poliinsaturados foram medidos usando centrifugação e cromatografia líquida. O teste t-Student, o teste de Mann-Whitney e o modelo linear geral, com idade gestacional e peso materno como covariantes, foram utilizados para comparar os níveis de AGs e os grupos RCF e AIG. O teste Qui-quadrado foi utilizado para avaliar a associação entre os grupos e as variáveis estudadas. RESULTADOS: Amostra de sangue materno foi coletada de 64 gestantes, sendo 24 RCF e 40 AIG. Uma correlação positiva fraca foi encontrada entre o nível de ácido palmitoleico e o peso materno (r = 0,285, p = 0,036). Uma correlação negativa fraca foi encontrada entre o nível de ácido gama-linoleico e a idade gestacional (r = − 0,277, p = 0,026). A mediana do nível de ácido elaídico (2,3 vs. 4,7 ng/ml, p = 0,045) e ácido gama-linoleico (6,3 vs. 6,6 ng/ml, p = 0,024) foram significativamente menores no grupo RCF do que no grupo AIG. O nível de ácido palmitoleico foi significativamente maior no grupo RCF do que no grupo AIG (50,5 vs. 47,6 ng/ml, p = 0,033). CONCLUSãO:: Gestantes com RCF apresentaram níveis mais baixos de ácido elaídico e ácido gama-linoleico e níveis mais elevados de ácido palmitoleico do que os fetos AIG.

Effect of Diets on Plasma and Aorta Lipidome: A Study in the apoE Knockout Mouse Model.

SCOPE: Specific lipid molecules circulating in plasma at low concentrations have emerged as biomarkers of atherosclerotic risk. The aim of the present study is that of evaluating, in an athero-prone mouse model, how different diets can affect plasma and aorta lipidome. METHODS AND RESULTS: Thirty-six apoE knockout mice are divided in three groups and feed 12 weeks with diets differing for cholesterol and fatty acid content. Atherosclerosis is measured at the aortic sinus and aorta. Lipids are quantified in plasma and aorta with mass spectrometry. The cholesterol content of the diets is the main driver of lipid accumulation in plasma and aorta. The fatty acid composition of the diets affects plasma levels both of essential (linoleic acid) and nonessential (myristic and arachidonic acid) ones. Lipidomics show a comparable distribution, in plasma and aorta, of the main lipid components of oxidized LDL, including cholesteryl esters and lysophosphatidylcholines. Interestingly, lactosylceramide, glucosyl/galactosylceramide, and individual ceramide species are found to accumulate in diseased aortic segments. CONCLUSION: Both the cholesterol and fatty acid content of the diets profoundly affect plasma lipidome. Aorta lipidome is likewise affected with the accumulation of specific lipids known as markers of atherosclerosis.

Unexpected role for IGF-1 in starvation: Maintenance of blood glucose.

Wild-type (WT) mice maintain viable levels of blood glucose even when adipose stores are depleted by 6 d of 60% calorie restriction followed by a 23-h fast (hereafter designated as "starved" mice). Survival depends on ghrelin, an octanoylated peptide hormone. Mice that lack ghrelin suffer lethal hypoglycemia when subjected to the same starvation regimen. Ghrelin is known to stimulate secretion of growth hormone (GH), which in turn stimulates secretion of IGF-1 (insulin-like growth factor-1). In the current study, we found that starved ghrelin-deficient mice had a 90% reduction in plasma IGF-1 when compared with starved WT mice. Injection of IGF-1 in starved ghrelin-deficient mice caused a twofold increase in glucose production and raised blood glucose to levels seen in starved WT mice. Increased glucose production was accompanied by increases in plasma glycerol, fatty acids and ketone bodies, and hepatic triglycerides. All of these increases were abolished when the mice were treated with atglistatin, an inhibitor of adipose tissue triglyceride lipase. We conclude that IGF-1 stimulates adipose tissue lipolysis in starved mice and that this lipolysis supplies energy and substrates that restore hepatic gluconeogenesis. This action of IGF-1 in starved mice is in contrast to its known action in inhibiting adipose tissue lipase in fed mice. Surprisingly, the ghrelin-dependent maintenance of plasma IGF-1 in starved mice was not mediated by GH. Direct injection of GH into starved ghrelin-deficient mice failed to increase plasma IGF-1. These data call attention to an unsuspected role of IGF-1 in the adaptation to starvation.

Association of placental fatty acid desaturase 2 (FADS2) methylation with maternal fatty acid levels in women with preeclampsia.

INTRODUCTION: Biosynthesis of long-chain polyunsaturated fatty acids requires sequential activities of desaturases and elongases for conversion of fatty acid precursors to products. The delta-6 desaturase enzyme, encoded by FADS2 gene, is a rate limiting enzyme in this pathway. Alterations in D6D enzyme activity can lead to altered fatty acid profiles. OBJECTIVES: To examine differences in placental DNA methylation (DNAm) and expression of FADS2 gene in preeclampsia women compared to normal women and their association with maternal variables (plasma fatty acids, desaturase enzyme index, blood pressure), placental weight and birth outcomes. METHODS: DNAm and expression of FADS2 gene were examined in placentae of normotensive (n = 100) control and preeclampsia (n = 100) women using pyrosequencing and quantitative real-time PCR respectively. Women with preeclampsia included those delivering at term (n = 43, gestation ≥ 37 weeks; T-PE) or preterm (n = 57, gestation < 37 weeks; PT-PE). A total of 26 CpGs in FADS2 promoter and region around it, were analysed in two PCR reactions (region 1 and 2). RESULTS: Out of 13 CpGs in region 1, significant hypermethylation was noted at CpG3 in T-PE (p = 0.03) and of 13 CpGs in region 2, CpG2 (p = 0.008), CpG11 (p = 0.04), CpG12 (p = 0.001) were hypomethylated and CpG13 (p = 0.001) was hypermethylated in preeclampsia group, as compared to controls. FADS2 expression was lower in PT-PE as compared to controls (p = 0.04). DNAm at various CpGs in the FADS2 were associated with maternal plasma FADS2 enzyme index and also associated with maternal fatty acid levels. However, we did not observe any association of DNAm with maternal blood pressure, placental weight and birth outcomes. CONCLUSIONS: This study for the first time reports differential methylation of FADS2 and its association with impaired maternal fatty acid metabolism in preeclampsia and provides a mechanistic basis to our earlier observations of altered maternal LCPUFA levels in women with preeclampsia.

Serum fatty acid profiling in patients with SDHx mutations: New advances on cellular metabolism in SDH deficiency.

Apart from the oncometabolite succinate, little studies have appeared on extra-mitochondrial pathways in Succinate Dehydrogenase (SDH) genetic deficiency. The role of NADH/NAD+ redox status and dependent pathways was recently emphasized. Therein, fatty acid (FA) metabolism data were collected here in 30 patients with a loss of function (LOF) variant in one SDHx gene (either with a pheochromocytoma/paraganglioma (PPGL) or asymptomatic) and in 22 wild-type SDHx controls (with PPGL or asymptomatic). Blood acylcarnitines in two patients, peroxisomal biomarkers, very long-chain saturated FA (VLCFA), and C20 to C24 n-3 polyunsaturated fatty acids (PUFA), in all patients were measured by mass spectrometry. Preliminary data showed elevated even and odd long- and very long-chain acylcarnitines in two patients with a SDHB variant. In the whole series, no abnormalities were observed in biomarkers of peroxisomal ß-oxidation (C27-bile acids, VLCFAs and phytanic/pristanic acids) in SDHx patients. However, an increased hexaene to pentaene PUFA ratio ([TetraHexaenoic Acid + DocosaHexaenoic Acid]/[n-3 DocosaPentaenoic Acid + EicosaPentaenoic Acid]) was noticed in patients with SDHC/SDHD variants vs patients with SDHA/SDHB variants or controls, suggesting a higher degree of unsaturation of PUFAs. Within the group with a SDHx variant, Eicosapentaenoate/Tetracosahexaenoate ratio, as an empiric index of shortening/elongation balance, discriminated patients with PPGL from asymptomatic ones. Present findings argue for stimulated elongation of saturated FAs, changes in shortening/elongation balance and desaturation rates of C20-C24 PUFAs in SDH-deficient patients with PPGL. Overall, oxidation of NADH sustained by these pathways might reflect or impact glycolytic NAD+ recycling and hence tumor proliferation.

TNF-alpha, IL-6, IL-10 and fatty acids in rheumatoid arthritis patients receiving cDMARD and bDMARD therapy.

OBJECTIVE: The present study aimed to examine the effects of cDMARD and bDMARD therapy on both gene expressions and protein levels of TNF-α, IL-6, IL-10 and fatty acid levels in patients with RA. METHOD: Plasma TNF-α, IL-6, and IL-10 levels were examined by the ELISA method, while TNF-α, IL-6, and IL-10 gene expression levels were examined by RT-qPCR, and fatty acid levels were examined by GC/MS. RESULTS: IL-10 gene expression levels significantly increased in RA patients receiving cDMARD treatment compared to those of the control group. Also, eicosadienoic acid, myristoleic acid and capric acid levels were significantly lower in the patient groups compared to those in the control group. CONCLUSION: The drugs used in the treatment of RA had no effect on the fatty acid levels whereas had effects on the mRNA and protein levels of the target cytokines.

Metabolomic response to collegiate football participation: Pre- and Post-season analysis.

Contact sports participation has been shown to have both beneficial and detrimental effects on health, however little is known about the metabolic sequelae of these effects. We aimed to identify metabolite alterations across a collegiate American football season. Serum was collected from 23 male collegiate football athletes before the athletic season (Pre) and after the last game (Post). Samples underwent nontargeted metabolomic profiling and 1131 metabolites were included for univariate, pathway enrichment, and multivariate analyses. Significant metabolites were assessed against head acceleration events (HAEs). 200 metabolites changed from Pre to Post (P < 0.05 and Q < 0.05); 160 had known identity and mapped to one of 57 pre-defined biological pathways. There was significant enrichment of metabolites belonging to five pathways (P < 0.05): xanthine, fatty acid (acyl choline), medium chain fatty acid, primary bile acid, and glycolysis, gluconeogenesis, and pyruvate metabolism. A set of 12 metabolites was sufficient to discriminate Pre from Post status, and changes in 64 of the 200 metabolites were also associated with HAEs (P < 0.05). In summary, the identified metabolites, and candidate pathways, argue there are metabolic consequences of both physical training and head impacts with football participation. These findings additionally identify a potential set of objective biomarkers of repetitive head injury.

Effects of marine-derived and plant-derived omega-3 polyunsaturated fatty acids on erythrocyte fatty acid composition in type 2 diabetic patients.

BACKGROUND: Dietary fatty acids intake affects the composition of erythrocyte fatty acids, which is strongly correlated with glycolipid metabolism disorders. This study aimed at investigating the different effects of marine-derived and plant-derived omega-3 polyunsaturated fatty acid (n-3 PUFA) on the fatty acids of erythrocytes and glycolipid metabolism in patients with type 2 diabetes mellitus (T2DM). METHODS: The randomized double-blinded trial that was performed on 180 T2DM patients. The participants were randomly assigned to three groups for the six-month intervention. The participants were randomly assigned to three groups for the six-month intervention. The fish oil (FO) group was administered with FO at a dose of 3 g/day containing eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), the perilla oil (PO) group was administered with PO at a dose of 3 g/day containing α-linolenic (ALA), the linseed and fish oil (LFO) group was administered with mixed linseed and fish oil at a dose of 3 g/day containing EPA, DHA and ALA. Demographic information were collected and anthropometric indices, glucose and lipid metabolism indexes, erythrocyte fatty acid composition were measured. Statistical analyses were performed using two-way ANOVA. RESULTS: A total of 150 patients finished the trial, with 52 of them in the FO group, 50 in the PO group and 48 in the LFO group. There were significant effects of time × treatment interaction on fast blood glucose (FBG), insulin, HOMA-IR and C-peptide, TC and triglyceride (TG) levels (P < 0.001). Glucose and C-peptide in PO and LFO groups decreased significantly and serum TG in FO group significantly decreased (P < 0.001) after the intervention. Erythrocyte C22: 5 n-6, ALA, DPA, n-6/n-3 PUFA, AA/EPA levels in the PO group were significantly higher than FO and LFO groups, while EPA, total n-3 PUFA and Omega-3 index were significantly higher in the FO and LFO groups compared to PO group. CONCLUSION: Supplementation with perilla oil decreased FBG while fish oil supplementation decreased the TG level. Marine-based and plant-based n-3 PUFAs exhibit different effects on fatty acid compositions of erythrocytes and regulated glycolipid metabolism. TRIAL REGISTRATION: This trial was recorded under Chinese Clinical Trial Registry Center (NO: ChiCTR-IOR-16008435 ) on May 28 2016.

Single nucleotide polymorphism of fatty acid desaturase gene and breast cancer risk in estrogen receptor subtype.

BACKGROUND: Breast cancer (BC) is the most common cancer of women and the second most common cancer overall globally. Data suggest that the plasma concentration of omega fatty acids (n-3 and n-6) and the impact of the genetic variant are associated with diet-related inflammatory disease, BC. This study was aimed to find an association between genetic variant rs174537 of fatty acid desaturase gene 1(FADS 1) and breast cancer estrogen receptor subtype. METHODOLOGY: Hundred and two blood samples from women were quantified for fatty acids by gas chromatography. SNP rs 174537(G > T) showed maximum variability and the strongest genetic determinant in the Genome-wide association study were genotyped using Sanger sequencing. RESULTS: The highest tertile of ALA showed a significantly reduced risk of BC compared to the lowest tertile (OR = 0.2, 95 %CL = 0.1-1.14, P = 0.03). Median values of ALA were higher in GT/TT genotype in ER +ve molecular subtype (P = 0.03) and DPA was higher in GG genotype of ER-ve molecular subtype (P = 0.037). When both the groups were put together the highest tertile of GG tertile showed significantly reduced risk of BC compared with the other lowest tertiles of GG and GT/TT genotypes (OR, 95% CL = 0.45(0.2-0.9). CONCLUSION: The high levels of arachidonic acid and low levels of n-3 fatty acids result in a pro-inflammatory milieu and that these pro-inflammatory effects might contribute to BC. We conclude that the individuals with genetically determined lower activity of FADS1(minor allele T) will derive greater advantage from n-3 FAs than those with higher FADS1 activity (G allele) and reduce the BC risk.

ER Unfolded Protein Response in Liver In Vivo Is Characterized by Reduced, Not Increased, De Novo Lipogenesis and Cholesterol Synthesis Rates with Uptake of Fatty Acids from Adipose Tissue: Integrated Gene Expression, Translation Rates and Metabolic Fluxes.

The unfolded protein response in the endoplasmic reticulum (UPRER) is involved in a number of metabolic diseases. Here, we characterize UPRER-induced metabolic changes in mouse livers in vivo through metabolic labeling and mass spectrometric analysis of lipid and proteome-wide fluxes. We induced UPRER by tunicamycin administration and measured synthesis rates of proteins, fatty acids and cholesterol, as well as RNA-seq. Contrary to reports in isolated cells, hepatic de novo lipogenesis and cholesterogenesis were markedly reduced, as were mRNA levels and synthesis rates of lipogenic proteins. H&E staining showed enrichment with lipid droplets while electron microscopy revealed ER morphological changes. Interestingly, the pre-labeling of adipose tissue prior to UPRER induction resulted in the redistribution of labeled fatty acids from adipose tissue to the liver, with replacement by unlabeled glycerol in the liver acylglycerides, indicating that the liver uptake was of free fatty acids, not whole glycerolipids. The redistribution of adipose fatty acids to the liver was not explicable by altered plasma insulin, increased fatty acid levels (lipolysis) or by reduced food intake. Synthesis of most liver proteins was suppressed under UPRER conditions, with the exception of BiP, other chaperones, protein disulfide isomerases, and proteins of ribosomal biogenesis. Protein synthesis rates generally, but not always, paralleled changes in mRNA. In summary, this combined approach, linking static changes with fluxes, revealed an integrated reduction of lipid and cholesterol synthesis pathways, from gene expression to translation and metabolic flux rates, under UPRER conditions. The reduced lipogenesis does not parallel human fatty liver disease. This approach provides powerful tools to characterize metabolic processes underlying hepatic UPRER in vivo.

Serum sex hormone-binding globulin levels are reduced and inversely associated with intrahepatic lipid content and saturated fatty acid fraction in adult patients with glycogen storage disease type 1a.

PURPOSE: De novo lipogenesis has been inversely associated with serum sex hormone-binding globulin (SHBG) levels. However, the directionality of this association has remained uncertain. We, therefore, studied individuals with glycogen storage disease type 1a (GSD1a), who are characterized by a genetic defect in glucose-6-phosphatase resulting in increased rates of de novo lipogenesis, to assess the downstream effect on serum SHBG levels. METHODS: A case-control study comparing serum SHBG levels in patients with GSD1a (n = 10) and controls matched for age, sex, and BMI (n = 10). Intrahepatic lipid content and saturated fatty acid fraction were quantified by proton magnetic resonance spectroscopy. RESULTS: Serum SHBG levels were statistically significantly lower in patients with GSD1a compared to the controls (p = 0.041), while intrahepatic lipid content and intrahepatic saturated fatty acid fraction-a marker of de novo lipogenesis-were significantly higher in patients with GSD1a (p = 0.001 and p = 0.019, respectively). In addition, there was a statistically significant, inverse association of intrahepatic lipid content and saturated fatty acid fraction with serum SHBG levels in patients and controls combined (ß: - 0.28, 95% CI: - 0.47;- 0.09 and ß: - 0.02, 95% CI: - 0.04;- 0.01, respectively). CONCLUSION: Patients with GSD1a, who are characterized by genetically determined higher rates of de novo lipogenesis, have lower serum SHBG levels than controls.

CerS1 but Not CerS5 Gene Silencing, Improves Insulin Sensitivity and Glucose Uptake in Skeletal Muscle.

Skeletal muscle is perceived as a major tissue in glucose and lipid metabolism. High fat diet (HFD) lead to the accumulation of intramuscular lipids, including: long chain acyl-CoA, diacylglycerols, and ceramides. Ceramides are considered to be one of the most important lipid groups in the generation of skeletal muscle insulin resistance. So far, it has not been clearly established whether all ceramides adversely affect the functioning of the insulin pathway, or whether there are certain ceramide species that play a pivotal role in the induction of insulin resistance. Therefore, we designed a study in which the expression of CerS1 and CerS5 genes responsible for the synthesis of C18:0-Cer and C16:0-Cer, respectively, was locally silenced in the gastrocnemius muscle of HFD-fed mice through in vivo electroporation-mediated shRNA plasmids. Our study indicates that HFD feeding induced both, the systemic and skeletal muscle insulin resistance, which was accompanied by an increase in the intramuscular lipid levels, decreased activation of the insulin pathway and, consequently, a decrease in the skeletal muscle glucose uptake. CerS1 silencing leads to a reduction in C18:0-Cer content, with a subsequent increase in the activity of the insulin pathway, and an improvement in skeletal muscle glucose uptake. Such effects were not visible in case of CerS5 silencing, which indicates that the accumulation of C18:0-Cer plays a decisive role in the induction of skeletal muscle insulin resistance.

Circulating Fatty Acids and Genetic Predisposition to Type 2 Diabetes: Gene-Nutrient Interaction Analysis.

OBJECTIVE: To assess the relationship of circulating fatty acids (FA) with risk of type 2 diabetes (T2D) and potential interactions with genetic risk. RESEARCH DESIGN AND METHODS: A total of 95,854 participants with complete data on plasma FA from the UK Biobank were enrolled between 2006 and 2010 and were followed up to the end of 2020. Plasma concentrations of saturated fatty acids (SFA), monounsaturated fatty acids (MUFA), and polyunsaturated fatty acids (PUFA) were analyzed by a high-throughput nuclear magnetic resonance-based biomarker profiling platform. The genetic risk scores (GRS) were calculated on the basis of 424 variants associated with T2D. Pathway-specific GRS were calculated based on robust clusters of T2D loci. RESULTS: There were 3,052 instances of T2D documented after an average follow-up of 11.6 years. Plasma concentrations of SFA and MUFA were positively associated with T2D risk, while plasma PUFA were inversely associated. After adjustment for major risk factors, hazard ratios (95% CI) of T2D for 1-SD increment were 1.03 (1.02-1.04) for SFA, 1.03 (1.02-1.05) for MUFA, 0.62 (0.56-0.68) for PUFA, 0.67 (0.61-0.73) for n-6 PUFA, 0.90 (0.85-0.95) for n-3 PUFA, and 1.01 (0.98-1.04) for n-6-to-n-3 ratio. Plasma MUFA had significant interactions with the overall GRS and GRS for proinsulin and liver/lipid clusters on T2D risk. The protective associations of n-3 PUFA with T2D risk were weaker among individuals with higher obesity GRS (P interaction = 0.040) and liver/lipid GRS (P interaction = 0.012). Additionally, increased plasma n-3 PUFA concentration was associated with more reductions in T2D risk among participants carrying more docosapentaenoic acid-associated alleles (P interaction = 0.007). CONCLUSIONS: Plasma concentrations of SFA and MUFA were associated with a higher T2D risk, whereas plasma PUFA and n-6 and n-3 PUFA were related to a lower risk. Circulating MUFA and n-3 PUFA had significant interactions with genetic predisposition to T2D and FA-associated variants.