Free fatty acid receptor 4 in cardiac myocytes ameliorates ischemic cardiomyopathy.

Aims: Free fatty acid receptor 4 (Ffar4) is a receptor for long-chain fatty acids that attenuates heart failure driven by increased afterload. Recent findings suggest that Ffar4 prevents ischemic injury in brain, liver, and kidney, and therefore, we hypothesized that Ffar4 would also attenuate cardiac ischemic injury. Methods and Results: Using a mouse model of ischemia-reperfusion (I/R), we found that mice with systemic deletion of Ffar4 (Ffar4KO) demonstrated impaired recovery of left ventricular systolic function post-I/R with no effect on initial infarct size. To identify potential mechanistic explanations for the cardioprotective effects of Ffar4, we performed bulk RNAseq to compare the transcriptomes from wild-type (WT) and Ffar4KO infarcted myocardium 3-days post-I/R. In the Ffar4KO infarcted myocardium, gene ontology (GO) analyses revealed augmentation of glycosaminoglycan synthesis, neutrophil activation, cadherin binding, extracellular matrix, rho signaling, and oxylipin synthesis, but impaired glycolytic and fatty acid metabolism, cardiac repolarization, and phosphodiesterase activity. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated impaired AMPK signaling and augmented cellular senescence in the Ffar4KO infarcted myocardium. Interestingly, phosphodiesterase 6c (PDE6c), which degrades cGMP, was the most upregulated gene in the Ffar4KO heart. Further, the soluble guanylyl cyclase stimulator, vericiguat, failed to increase cGMP in Ffar4KO cardiac myocytes, suggesting increased phosphodiesterase activity. Finally, cardiac myocyte-specific overexpression of Ffar4 prevented systolic dysfunction post-I/R, defining a cardioprotective role of Ffa4 in cardiac myocytes. Conclusions: Our results demonstrate that Ffar4 in cardiac myocytes attenuates systolic dysfunction post-I/R, potentially by attenuating oxidative stress, preserving mitochondrial function, and modulation of cGMP signaling.

Effects of niacin and omega-3 fatty acids on HDL-apolipoprotein A-I exchange in subjects with metabolic syndrome.

HDL-apolipoprotein A-I exchange (HAE) measures a functional property associated with HDL's ability to mediate reverse cholesterol transport. HAE has been used to examine HDL function in case-control studies but not in studies of therapeutics that alter HDL particle composition. This study investigates whether niacin and omega-3 fatty acids induce measurable changes in HAE using a cohort of fifty-six subjects with metabolic syndrome (MetS) who were previously recruited to a double-blind trial where they were randomized to 16 weeks of treatment with dual placebo, extended-release niacin (ERN, 2g/day), prescription omega-3 ethyl esters (P-OM3, 4g/day), or the combination. HAE was assessed at the beginning and end of the study. Compared to placebo, ERN and P-OM3 alone significantly increased HAE by 15.1% [8.2, 22.0] (P<0.0001) and 11.1% [4.5, 17.7] (P<0.0005), respectively, while in combination they increased HAE by 10.0% [2.5, 15.8] (P = 0.005). When HAE was evaluated per unit mass of apoA-I ERN increased apoA-I specific exchange activity by 20% (2, 41 CI, P = 0.02) and P-OM3 by 28% (9.6, 48 CI, P<0.0006). However the combination had no statistically significant effect, 10% (-9, 31 CI, P = 0.39). With regard to P-OM3 therapy in particular, the HAE assay detected an increase in this property in the absence of a concomitant rise in HDL-C and apoA-I levels, suggesting that the assay can detect functional changes in HDL that occur in the absence of traditional biomarkers.

Oxylipin transport by lipoprotein particles and its functional implications for cardiometabolic and neurological disorders.

Lipoprotein metabolism is critical to inflammation. While the periphery and central nervous system (CNS) have separate yet connected lipoprotein systems, impaired lipoprotein metabolism is implicated in both cardiometabolic and neurological disorders. Despite the substantial investigation into the composition, structure and function of lipoproteins, the lipoprotein oxylipin profiles, their influence on lipoprotein functions, and their potential biological implications are unclear. Lipoproteins carry most of the circulating oxylipins. Importantly, lipoprotein-mediated oxylipin transport allows for endocrine signaling by these lipid mediators, long considered to have only autocrine and paracrine functions. Alterations in plasma lipoprotein oxylipin composition can directly impact inflammatory responses of lipoprotein metabolizing cells. Similar investigations of CNS lipoprotein oxylipins are non-existent to date. However, as APOE4 is associated with Alzheimer's disease-related microglia dysfunction and oxylipin dysregulation, ApoE4-dependent lipoprotein oxylipin modulation in neurological pathologies is suggested. Such investigations are crucial to bridge knowledge gaps linking oxylipin- and lipoprotein-related disorders in both periphery and CNS. Here, after providing a summary of existent literatures on lipoprotein oxylipin analysis methods, we emphasize the importance of lipoproteins in oxylipin transport and argue that understanding the compartmentalization and distribution of lipoprotein oxylipins may fundamentally alter our consideration of the roles of lipoprotein in cardiometabolic and neurological disorders.

A Genome-Wide Interaction Study of Erythrocyte ω-3 Polyunsaturated Fatty Acid Species and Memory in the Framingham Heart Study Offspring Cohort.

BACKGROUND: Cognitive decline, and more specifically Alzheimer's disease, continues to increase in prevalence globally, with few, if any, adequate preventative approaches. Several tests of cognition are utilized in the diagnosis of cognitive decline that assess executive function, short- and long-term memory, cognitive flexibility, and speech and motor control. Recent studies have separately investigated the genetic component of both cognitive health, using these measures, and circulating fatty acids. OBJECTIVES: We aimed to examine the potential moderating effect of main species of ω-3 polyunsaturated fatty acids (PUFAs) on an individual's genetically conferred risk of cognitive decline. METHODS: The Offspring cohort from the Framingham Heart Study was cross-sectionally analyzed in this genome-wide interaction study (GWIS). Our sample included all individuals with red blood cell ω-3 PUFA, genetic, cognitive testing (via Trail Making Tests [TMTs]), and covariate data (N = 1620). We used linear mixed effects models to predict each of the 3 cognitive measures (TMT A, TMT B, and TMT D) by each ω-3 PUFA, single nucleotide polymorphism (SNP) (0, 1, or 2 minor alleles), ω-3 PUFA by SNP interaction term, and adjusting for sex, age, education, APOE ε4 genotype status, and kinship (relatedness). RESULTS: Our analysis identified 31 unique SNPs from 24 genes reaching an exploratory significance threshold of 1×10-5. Fourteen of the 24 genes have been previously associated with the brain/cognition, and 5 genes have been previously associated with circulating lipids. Importantly, 8 of the genes we identified, DAB1, SORCS2, SERINC5, OSBPL3, CPA6, DLG2, MUC19, and RGMA, have been associated with both cognition and circulating lipids. We identified 22 unique SNPs for which individuals with the minor alleles benefit substantially from increased ω-3 fatty acid concentrations and 9 unique SNPs for which the common homozygote benefits. CONCLUSIONS: In this GWIS of ω-3 PUFA species on cognitive outcomes, we identified 8 unique genes with plausible biology suggesting individuals with specific polymorphisms may have greater potential to benefit from increased ω-3 PUFA intake. Additional replication in prospective settings with more diverse samples is needed.

FFAR4 regulates cardiac oxylipin balance to promote inflammation resolution in HFpEF secondary to metabolic syndrome.

Heart failure with preserved ejection fraction (HFpEF) is a complex clinical syndrome, but a predominant subset of HFpEF patients has metabolic syndrome (MetS). Mechanistically, systemic, nonresolving inflammation associated with MetS might drive HFpEF remodeling. Free fatty acid receptor 4 (Ffar4) is a GPCR for long-chain fatty acids that attenuates metabolic dysfunction and resolves inflammation. Therefore, we hypothesized that Ffar4 would attenuate remodeling in HFpEF secondary to MetS (HFpEF-MetS). To test this hypothesis, mice with systemic deletion of Ffar4 (Ffar4KO) were fed a high-fat/high-sucrose diet with L-NAME in their water to induce HFpEF-MetS. In male Ffar4KO mice, this HFpEF-MetS diet induced similar metabolic deficits but worsened diastolic function and microvascular rarefaction relative to WT mice. Conversely, in female Ffar4KO mice, the diet produced greater obesity but no worsened ventricular remodeling relative to WT mice. In Ffar4KO males, MetS altered the balance of inflammatory oxylipins systemically in HDL and in the heart, decreasing the eicosapentaenoic acid-derived, proresolving oxylipin 18-hydroxyeicosapentaenoic acid (18-HEPE), while increasing the arachidonic acid-derived, proinflammatory oxylipin 12-hydroxyeicosatetraenoic acid (12-HETE). This increased 12-HETE/18-HEPE ratio reflected a more proinflammatory state both systemically and in the heart in male Ffar4KO mice and was associated with increased macrophage numbers in the heart, which in turn correlated with worsened ventricular remodeling. In summary, our data suggest that Ffar4 controls the proinflammatory/proresolving oxylipin balance systemically and in the heart to resolve inflammation and attenuate HFpEF remodeling.

Effect of omega-3 ethyl esters on the triglyceride-rich lipoprotein response to endotoxin challenge in healthy young men.

Oxylipins are produced enzymatically from polyunsaturated fatty acids, are abundant in triglyceride-rich lipoproteins (TGRLs), and mediate inflammatory processes. Inflammation elevates TGRL concentrations, but it is unknown if the fatty acid and oxylipin compositions change. In this study, we investigated the effect of prescription ω-3 acid ethyl esters (P-OM3; 3.4 g/d EPA + DHA) on the lipid response to an endotoxin challenge (lipopolysaccharide; 0.6 ng/kg body weight). Healthy young men (N = 17) were assigned 8-12 weeks of P-OM3 and olive oil control in a randomized order crossover study. Following each treatment period, subjects received endotoxin challenge, and the time-dependent TGRL composition was observed. Postchallenge, arachidonic acid was 16% [95% CI: 4%, 28%] lower than baseline at 8 h with control. P-OM3 increased TGRL ω-3 fatty acids (EPA 24% [15%, 34%]; DHA 14% [5%, 24%]). The timing of ω-6 oxylipin responses differed by class; arachidonic acid-derived alcohols peaked at 2 h, while linoleic acid-derived alcohols peaked at 4 h (pint = 0.006). P-OM3 increased EPA alcohols by 161% [68%, 305%] and DHA epoxides by 178% [47%, 427%] at 4 h compared to control. In conclusion, this study shows that TGRL fatty acid and oxylipin composition changes following endotoxin challenge. P-OM3 alters the TGRL response to endotoxin challenge by increasing availability of ω-3 oxylipins for resolution of the inflammatory response.

Esterified Oxylipins: Do They Matter?

Oxylipins are oxygenated metabolites of fatty acids that share several similar biochemical characteristics and functions to fatty acids including transport and trafficking. Oxylipins are most commonly measured in the non-esterified form which can be found in plasma, free or bound to albumin. The non-esterified form, however, reflects only one of the possible pools of oxylipins and is by far the least abundant circulating form of oxylipins. Further, this fraction cannot reliably be extrapolated to the other, more abundant, esterified pool. In cells too, esterified oxylipins are the most abundant form, but are seldom measured and their potential roles in signaling are not well established. In this review, we examine the current literature on experimental oxylipin measurements to describe the lack in reporting the esterified oxylipin pool. We outline the metabolic and experimental importance of esterified oxylipins using well established roles of fatty acid trafficking in non-esterified fatty acids and in esterified form as components of circulating lipoproteins. Finally, we use mathematical modeling to simulate how exchange between cellular esterified and unesterified pools would affect intracellular signaling.. The explicit inclusion of esterified oxylipins along with the non-esterified pool has the potential to convey a more complete assessment of the metabolic consequences of oxylipin trafficking.

Signaling through Free Fatty Acid Receptor 4 Attenuates Cardiometabolic Disease.

A surge in the prevalence of obesity and metabolic syndrome, which promote systemic inflammation, underlies an increase in cardiometabolic disease. Free fatty acid receptor 4 is a nutrient sensor for long-chain fatty acids, like ω3-polyunsaturated fatty acids (ω3-PUFAs), that attenuates metabolic disease and resolves inflammation. Clinical trials indicate ω3-PUFAs are cardioprotective, and this review discusses the mechanistic links between ω3-PUFAs, free fatty acid receptor 4, and attenuation of cardiometabolic disease.

Free fatty acid receptor 4 responds to endogenous fatty acids to protect the heart from pressure overload.

AIMS: Free fatty acid receptor 4 (Ffar4) is a G-protein-coupled receptor for endogenous medium-/long-chain fatty acids that attenuates metabolic disease and inflammation. However, the function of Ffar4 in the heart is unclear. Given its putative beneficial role, we hypothesized that Ffar4 would protect the heart from pathologic stress. METHODS AND RESULTS: In mice lacking Ffar4 (Ffar4KO), we found that Ffar4 is required for an adaptive response to pressure overload induced by transverse aortic constriction (TAC), identifying a novel cardioprotective function for Ffar4. Following TAC, remodelling was worsened in Ffar4KO hearts, with greater hypertrophy and contractile dysfunction. Transcriptome analysis 3-day post-TAC identified transcriptional deficits in genes associated with cytoplasmic phospholipase A2α signalling and oxylipin synthesis and the reduction of oxidative stress in Ffar4KO myocytes. In cultured adult cardiac myocytes, Ffar4 induced the production of the eicosapentaenoic acid (EPA)-derived, pro-resolving oxylipin 18-hydroxyeicosapentaenoic acid (18-HEPE). Furthermore, the activation of Ffar4 attenuated cardiac myocyte death from oxidative stress, while 18-HEPE rescued Ffar4KO myocytes. Systemically, Ffar4 maintained pro-resolving oxylipins and attenuated autoxidation basally, and increased pro-inflammatory and pro-resolving oxylipins, including 18-HEPE, in high-density lipoproteins post-TAC. In humans, Ffar4 expression decreased in heart failure, while the signalling-deficient Ffar4 R270H polymorphism correlated with eccentric remodelling in a large clinical cohort paralleling changes observed in Ffar4KO mice post-TAC. CONCLUSION: Our data indicate that Ffar4 in cardiac myocytes responds to endogenous fatty acids, reducing oxidative injury, and protecting the heart from pathologic stress, with significant translational implications for targeting Ffar4 in cardiovascular disease.

Aspirin and omega-3 fatty acid status interact in the prevention of cardiovascular diseases in Framingham Heart Study.

BACKGROUND: The roles of omega-3 (n3) fatty acids [eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] and low-dose aspirin in the primary prevention of ischemic cardiovascular disease (CVD) are controversial. Since omega-3 (n3) fatty acids and aspirin affect cyclooxygenase activity in platelets, there could be a clinically-relevant effect of aspirin combined with a particular n3 fatty acid level present in each individual. METHODS: RBC EPA+DHA, arachidonic acid (AA) and docosapentaenoic acid (DPA) were measured in 2500 participants without known CVD in the Framingham Heart Study. We then tested for interactions with reported aspirin use (1004 reported use and 1494 did not) on CVD outcomes. The median follow-up was 7.2 years. RESULTS: Having RBC EPA+DHA in the second quintile (4.2-4.9% of total fatty acids) was associated with significantly reduced risk for future CVD events (relative to the first quintile, <4.2%) in those who did not take aspirin (HR 0.54 (0.30, 0.98)), but in those reporting aspirin use, risk was significantly increased (HR 2.16 (1.19, 3.92)) in this quintile. This interaction remained significant when adjusting for confounders. Significant interactions were also present for coronary heart disease and stroke outcomes using the same quintiles. Similar findings were present for EPA and DHA alone but not for DPA and AA. CONCLUSIONS: There is a complex interaction between aspirin use and RBC EPA+DHA levels on CVD outcomes. This suggests that aspirin use may be beneficial in one omega-3 environment but harmful in another, implying that a personalized approach to both aspirin use and omega-3 supplementation may be needed.

Effects of inflammation and soluble epoxide hydrolase inhibition on oxylipin composition of very low-density lipoproteins in isolated perfused rat livers.

Oxylipins are metabolites of polyunsaturated fatty acids that mediate cardiovascular health by attenuation of inflammation, vascular tone, hemostasis, and thrombosis. Very low-density lipoproteins (VLDL) contain oxylipins, but it is unknown whether the liver regulates their concentrations. In this study, we used a perfused liver model to observe the effect of inflammatory lipopolysaccharide (LPS) challenge and soluble epoxide hydrolase inhibition (sEHi) on VLDL oxylipins. A compartmental model of deuterium-labeled linoleic acid and palmitic acid incorporation into VLDL was also developed to assess the dependence of VLDL oxylipins on fatty acid incorporation rates. LPS decreased the total fatty acid VLDL content by 30% [6%,47%], and decreased final concentration of several oxylipins by a similar amount (13-HOTrE, 35% [4%,55%], -1.3 nM; 9(10)-EpODE, 29% [3%,49%], -2.0 nM; 15(16)-EpODE, 29% [2%,49%], -1.6 nM; AA-derived diols, 32% [5%,52%], -2.4 nM; 19(20)-DiHDPA, 31% [7%,50%], -1.0 nM). However, the EPA-derived epoxide, 17(18)-EpETE, was decreased by 75% [49%,88%], (-0.52 nM) with LPS, double the suppression of other oxylipins. sEHi increased final concentration of DHA epoxide, 16(17)-EpDPE, by 99% [35%,193%], (2.0 nM). Final VLDL-oxylipin concentrations with LPS treatment were not correlated with linoleic acid kinetics, suggesting they were independently regulated under inflammatory conditions. We conclude that the liver regulates oxylipin incorporation into VLDL, and the oxylipin content is altered by LPS challenge and by inhibition of the epoxide hydrolase pathway. This provides evidence for delivery of systemic oxylipin signals by VLDL transport.

Mechanistic insights into cardiovascular protection for omega-3 fatty acids and their bioactive lipid metabolites.

Patients with well-controlled low-density lipoprotein cholesterol levels, but persistent high triglycerides, remain at increased risk for cardiovascular events as evidenced by multiple genetic and epidemiologic studies, as well as recent clinical outcome trials. While many trials of low-dose ω3-polyunsaturated fatty acids (ω3-PUFAs), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) have shown mixed results to reduce cardiovascular events, recent trials with high-dose ω3-PUFAs have reignited interest in ω3-PUFAs, particularly EPA, in cardiovascular disease (CVD). REDUCE-IT demonstrated that high-dose EPA (4 g/day icosapent-ethyl) reduced a composite of clinical events by 25% in statin-treated patients with established CVD or diabetes and other cardiovascular risk factors. Outcome trials in similar statin-treated patients using DHA-containing high-dose ω3 formulations have not yet shown the benefits of EPA alone. However, there are data to show that high-dose ω3-PUFAs in patients with acute myocardial infarction had reduced left ventricular remodelling, non-infarct myocardial fibrosis, and systemic inflammation. ω3-polyunsaturated fatty acids, along with their metabolites, such as oxylipins and other lipid mediators, have complex effects on the cardiovascular system. Together they target free fatty acid receptors and peroxisome proliferator-activated receptors in various tissues to modulate inflammation and lipid metabolism. Here, we review these multifactorial mechanisms of ω3-PUFAs in view of recent clinical findings. These findings indicate physico-chemical and biological diversity among ω3-PUFAs that influence tissue distributions as well as disparate effects on membrane organization, rates of lipid oxidation, as well as various receptor-mediated signal transduction pathways and effects on gene expression.

Trafficking of nonesterified fatty acids in insulin resistance and relationship to dysglycemia.

In adipose, insulin functions to suppress intracellular lipolysis and secretion of nonesterified fatty acid (NEFA) into plasma. We applied glucose and NEFA minimal models (MM) following a frequently sampled intravenous glucose tolerance test (FSIVGTT) to assess glucose-specific and NEFA-specific insulin resistance. We used total NEFA and individual fatty acids in the NEFA MM, comparing the model parameters in metabolic syndrome (MetSyn) subjects (n = 52) with optimally healthy controls (OptHC; n = 14). Results are reported as mean difference (95% confidence interval). Using the glucose MM, MetSyn subjects had lower [-73% (-82, -57)] sensitivity to insulin (Si) and higher [138% (44, 293)] acute insulin response to glucose (AIRg). Using the NEFA MM, MetSyn subjects had lower [-24% (-35, -13)] percent suppression, higher [32% (15, 52)] threshold glucose (gs), and a higher [81% (12, 192)] affinity constant altering NEFA secretion (ϕ). Comparing fatty acids, percent suppression was lower in myristic acid (MA) than in all other fatty acids, and the stearic acid (SA) response was so unique that it did not fit the NEFA MM. MA and SA percent of total were increased at 50 min after glucose injection, whereas oleic acid (OA) and palmitic acid (PA) were decreased (P < 0.05). We conclude that the NEFA MM, as well as the response of individual NEFA fatty acids after a FSIVGTT, differ between OptHC and MetSyn subjects and that the NEFA MM parameters differ between individual fatty acids.

Proceedings of the Ninth HDL (High-Density Lipoprotein) Workshop: Focus on Cardiovascular Disease.

The HDL (high-density lipoprotein) Workshop was established in 2009 as a forum for candid discussions among academic basic scientists, clinical investigators, and industry researchers about the role of HDL in cardiovascular disease. This ninth HDL Workshop was held on May 16 to 17, 2019 in Boston, MA, and included outstanding oral presentations from established and emerging investigators. The Workshop featured 5 sessions with topics that tackled the role of HDL in the vasculature, its structural complexity, its role in health and disease states, and its interaction with the intestinal microbiome. The highlight of the program was awarding the Jack Oram Award to the distinguished professor emeritus G.S. Getz from the University of Chicago. The tenth HDL Workshop will be held on May 2020 in Chicago and will continue the focus on intellectually stimulating presentations by established and emerging investigators on novel roles of HDL in cardiovascular and noncardiovascular health and disease states.

Four nights of sleep restriction suppress the postprandial lipemic response and decrease satiety.

Chronic sleep restriction, or inadequate sleep, is associated with increased risk of cardiometabolic disease. Laboratory studies demonstrate that sleep restriction causes impaired whole-body insulin sensitivity and glucose disposal. Evidence suggests that inadequate sleep also impairs adipose tissue insulin sensitivity and the NEFA rebound during intravenous glucose tolerance tests, yet no studies have examined the effects of sleep restriction on high-fat meal lipemia. We assessed the effect of 5 h time in bed (TIB) per night for four consecutive nights on postprandial lipemia following a standardized high-fat dinner (HFD). Furthermore, we assessed whether one night of recovery sleep (10 h TIB) was sufficient to restore postprandial metabolism to baseline. We found that postprandial triglyceride (TG) area under the curve was suppressed by sleep restriction (P = 0.01), but returned to baseline values following one night of recovery. Sleep restriction decreased NEFAs throughout the HFD (P = 0.02) and NEFAs remained suppressed in the recovery condition (P = 0.04). Sleep restriction also decreased participant-reported fullness or satiety (P = 0.03), and decreased postprandial interleukin-6 (P < 0.01). Our findings indicate that four nights of 5 h TIB per night impair postprandial lipemia and that one night of recovery sleep may be adequate for recovery of TG metabolism, but not for markers of adipocyte function.

Predicting the effects of supplemental EPA and DHA on the omega-3 index.

BACKGROUND: Supplemental long-chain omega-3 (n-3) fatty acids (EPA and DHA) raise erythrocyte EPA + DHA [omega-3 index (O3I)] concentrations, but the magnitude or variability of this effect is unclear. OBJECTIVE: The purpose of this study was to model the effects of supplemental EPA + DHA on the O3I. METHODS: Deidentified data from 1422 individuals from 14 published n-3 intervention trials were included. Variables considered included dose, baseline O3I, sex, age, weight, height, chemical form [ethyl ester (EE) compared with triglyceride (TG)], and duration of treatment. The O3I was measured by the same method in all included studies. Variables were selected by stepwise regression using the Bayesian information criterion. RESULTS: Individuals supplemented with EPA + DHA (n = 846) took a mean ± SD of 1983 ± 1297 mg/d, and the placebo controls (n = 576) took none. The mean duration of supplementation was 13.6 ± 6.0 wk. The O3I increased from 4.9% ± 1.7% to 8.1% ± 2.7% in the supplemented individuals ( P < 0.0001). The final model included dose, baseline O3I, and chemical formulation type (EE or TG), and these explained 62% of the variance in response (P < 0.0001). The model predicted that the final O3I (and 95% CI) for a population like this, with a baseline concentration of 4.9%, given 850 mg/d of EPA + DHA EE would be ∼6.5% (95% CI: 6.3%, 6.7%). Gram for gram, TG-based supplements increased the O3I by about 1 percentage point more than EE products. CONCLUSIONS: Of the factors tested, only baseline O3I, dose, and chemical formulation were significant predictors of O3I response to supplementation. The model developed here can be used by researchers to help estimate the O3I response to a given EPA + DHA dose and chemical form.

Predicting Risk for Incident Heart Failure With Omega-3 Fatty Acids: From MESA.

OBJECTIVES: The aim of this study was to determine if plasma eicosapentaenoic acid (EPA) abundance (%EPA) is associated with reduced hazard for primary heart failure (HF) events in the MESA (Multi-Ethnic Study of Atherosclerosis) trial. BACKGROUND: Clinical trials suggest that omega-3 polyunsaturated fatty acids (ω3 PUFAs) prevent sudden death in coronary heart disease and HF, but this is controversial. In mice, the authors demonstrated that the ω3 PUFA EPA prevents contractile dysfunction and fibrosis in an HF model, but whether this extends to humans is unclear. METHODS: In the MESA cohort, the authors tested if plasma phospholipid EPA predicts primary HF incidence, including HF with reduced ejection fraction (EF) (EF <45%) and HF with preserved EF (EF ≥45%) using Cox proportional hazards modeling. RESULTS: A total of 6,562 participants 45 to 84 years of age had EPA measured at baseline (1,794 black, 794 Chinese, 1,442 Hispanic, and 2,532 white; 52% women). Over a median follow-up period of 13.0 years, 292 HF events occurred: 128 HF with reduced EF, 110 HF with preserved EF, and 54 with unknown EF status. %EPA in HF-free participants was 0.76% (0.75% to 0.77%) but was lower in participants with HF at 0.69% (0.64% to 0.74%) (p = 0.005). Log %EPA was associated with lower HF incidence (hazard ratio: 0.73 [95% confidence interval: 0.60 to 0.91] per log-unit difference in %EPA; p = 0.001). Adjusting for age, sex, race, body mass index, smoking, diabetes mellitus, blood pressure, lipids and lipid-lowering drugs, albuminuria, and the lead fatty acid for each cluster did not change this relationship. Sensitivity analyses showed no dependence on HF type. CONCLUSIONS: Higher plasma EPA was significantly associated with reduced risk for HF, with both reduced and preserved EF. (Multi-Ethnic Study of Atherosclerosis [MESA]; NCT00005487).

Walnuts change lipoprotein composition suppressing TNFα-stimulated cytokine production by diabetic adipocyte.

Walnut consumption can provide both vascular and metabolic health benefits, and walnut-induced changes in lipoprotein particle chemical payloads may be responsible for these health benefits. To explore this possibility with a focus on metabolic health, this study investigated the impact of walnut consumption on lipoprotein lipid composition and changes in LDL anti-inflammatory properties, as reported by inflamed adipocyte. Hypercholesterolemic, postmenopausal females were treated with 40 g/day (i.e., 1.6 servings/day; n=15) of walnuts for 4 weeks. Fatty acids and their oxygenated metabolites, i.e., oxylipins, were quantified in isolated lipoproteins. Human primary adipocytes were exposed to LDL and TNFα-stimulated adipokine production was measured. Walnut treatment elevated α-linolenic acid and its epoxides in all lipoproteins and depleted mid-chain alcohols in VLDL and LDL, but not HDL. Walnuts also reduced TNFα-induced diabetic adipocyte production of IL-6 (-48%, P=.0006) and IL-8 (-30%, P=.01), changes inversely correlated with levels of α-linolenic acid-derived epoxides but not α-linolenic acid itself. In conclusion, modest walnut consumption can alter lipoprotein lipid profiles and enhance their ability to inhibit TNFα-dependent pro-inflammatory responses in human diabetic primary adipocytes. Moreover, this study suggests the oxylipins, rather than the parent fatty acids, mediate LDL action of adipocytes.

Two nights of recovery sleep restores the dynamic lipemic response, but not the reduction of insulin sensitivity, induced by five nights of sleep restriction.

Chronic inadequate sleep is associated with increased risk of cardiometabolic diseases. The mechanisms involved are poorly understood but involve changes in insulin sensitivity, including within adipose tissue. The aim of this study was to assess the effects of sleep restriction on nonesterified fatty acid (NEFA) suppression profiles in response to an intravenous glucose tolerance test (IVGTT) and to assess whether 2 nights of recovery sleep (a "weekend") is sufficient to restore metabolic health. We hypothesized that sleep restriction impairs both glucose and lipid metabolism, specifically adipocyte insulin sensitivity, and the dynamic lipemic response of adipocyte NEFA release during an IVGTT. Fifteen healthy men completed an inpatient study of 3 baseline nights (10 h of time in bed/night), followed by 5 nights of 5 h of time in bed/night and 2 recovery nights (10 h of time in bed/night). IVGTTs were performed on the final day of each condition. Reductions in insulin sensitivity without a compensatory change in acute insulin response to glucose were consistent with prior studies (insulin sensitivity P = 0.002; acute insulin response to glucose P = 0.23). The disposition index was suppressed by sleep restriction and did not recover after recovery sleep (P < 0.0001 and P = 0.01, respectively). Fasting NEFAs were not different from baseline in either the restriction or recovery conditions. NEFA rebound was significantly suppressed by sleep restriction (P = 0.01) but returned to baseline values after recovery sleep. Our study indicates that sleep restriction impacts NEFA metabolism and demonstrates that 2 nights of recovery sleep may not be adequate to restore glycemic health.

Microbiota fermentation-NLRP3 axis shapes the impact of dietary fibres on intestinal inflammation.

OBJECTIVE: Diets rich in fermentable fibres provide an array of health benefits; however, many patients with IBD report poor tolerance to fermentable fibre-rich foods. Intervention studies with dietary fibres in murine models of colonic inflammation have yielded conflicting results on whether fibres ameliorate or exacerbate IBD. Herein, we examined how replacing the insoluble fibre, cellulose, with the fermentable fibres, inulin or pectin, impacted murine colitis resulting from immune dysregulation via inhibition of interleukin (IL)-10 signalling and/or innate immune deficiency (Tlr5KO). DESIGN: Mice were fed with diet containing either cellulose, inulin or pectin and subjected to weekly injections of an IL-10 receptor (αIL-10R) neutralising antibody. Colitis development was examined by serological, biochemical, histological and immunological parameters. RESULTS: Inulin potentiated the severity of αIL10R-induced colitis, while pectin ameliorated the disease. Such exacerbation of colitis following inulin feeding was associated with enrichment of butyrate-producing bacteria and elevated levels of caecal butyrate. Blockade of butyrate production by either metronidazole or hops ß-acids ameliorated colitis severity in inulin-fed mice, whereas augmenting caecal butyrate via tributyrin increased colitis severity in cellulose containing diet-fed mice. Elevated butyrate levels were associated with increased IL-1ß activity, while inhibition of the NOD-like receptor protein 3 by genetic, pharmacologic or dietary means markedly reduced colitis. CONCLUSION: These results not only support the notion that fermentable fibres have the potential to ameliorate colitis but also caution that, in some contexts, prebiotic fibres can lead to gut dysbiosis and surfeit colonic butyrate that might exacerbate IBD.