Plasma Concentrations Of Fatty Acids Research Articles

Circulating fatty acids, genetic susceptibility and hypertension: a prospective cohort study.

Combining genetic risk factors and plasma fatty acids (FAs) can be used as an effective method of precision medicine to prevent hypertension risk. A total of 195,250 participants in the UK Biobank cohort were included in this study from 2006-2010. Polygenic risk scores (PRSs) were calculated for hypertension using single-nucleotide polymorphisms (SNPs). Concentrations of plasma FAs, including polyunsaturated fatty acids (PUFAs), monounsaturated fatty acids (MUFAs) and saturated fatty acids (SFAs), were tested by nuclear magnetic resonance. The Cox model was used to test for the main effects of PRS, different plasma FAs and their joint effects on hypertension. Relative excess risk due to interaction (RERI) and the attributable proportion due to interaction (AP) were used to test the additive interaction. Plasma PUFAs, n-3 PUFAs, MUFAs and SFAs were related to the risk of hypertension (PUFAs: HR, 0.878; 95% CI, 0.868-0.888; MUFAs: HR, 1.13; 95% CI, 1.123-1.150; SFAs: HR, 1.086; 95% CI, 1.074-1.098; n-3 PUFAs: HR, 0.984; 95% CI, 0.973-0.995). Moreover, an additive interaction was found between PRS and plasma FAs, which could contribute to an approximately 10-18% risk of hypertension, and the associations between high plasma MUFAs and a high PRS of hypertension were the strongest positive [RERI: 0.178 (95% CI: 0.062, 0.294), AP: 0.079 (95% CI: 0.027, 0.130)]. Increased plasma MUFAs or SFAs and decreased plasma PUFAs or n-3 PUFAs were associated with hypertension risk, especially among people at high genetic risk.

Fatty acids promote migration of CD4+ T cells through calcium release-activated calcium modulator ORAI1 sensitive glycolysis in dairy cows

Nutritional and metabolic state in dairy cows are important determinants of the immune response. During the periparturient period, a state of negative energy balance in the cow increases plasma concentrations of fatty acids, which are associated with inflammation. Among immune cells, CD4+ T are able to function under high fatty acid (High-FA) conditions, but the underlying mechanisms regulating these events remain unclear. The objective of this study was to clarify the functional mechanisms of CD4+ T cells under High-FA conditions. Effects of glycolysis and calcium release-activated calcium modulator 1 (ORAI1) on migration of CD4+ T cells exposed to High-FA were investigated in vivo and in vitro. CD4+ T cells were isolated from peripheral blood of healthy (n = 9) and High-FA (n = 9) Holstein cows (average 2.5 ± 0.2 lactations, 12.3 ± 0.8 d in milk). In the first experiment, real-time quantitative PCR (RT-qPCR) was used to assess chemokine receptors in isolated CD4+ T cells and migration capacity. The relative mRNA measurements results revealed downregulation of CCR1 and CXCR2, and upregulation of CCR2, CCR4, CCR5, CCR7, CCR8, CCR10, CXCR1, CXCR3, CXCR4, CX3CR1. Among them, the expression of CXCR4 was relatively high. Therefore, CXCL12, a ligand chemokine of CXCR4, was an inducer of CD4+ T cell migration. CD4+ T cells were inoculated in the upper chamber and CXCL12 (100 ng/mL, Peprotech) in RPMI1640 was added to the lower chamber and transmigrate for 3 h at 37°C and 5% CO2. The cell migration assay revealed that migration capacity of CD4+ T cells from High-FA cows was greater. RT-qPCR indicated greater abundance of the glycolysis-related targets HIF1A, HK2, PKM2, Glut1, GAPDH, LDHA and Western blotting indicated greater abundance of the glycolysis-related targets HIF1A, HK2, PKM2, Glut1, GAPDH and LDHA in CD4+ T cells of High-FA cows. To characterize specific mechanisms of CD4+ T cell migration in vitro, cells from the spleens of 3 newborn healthy female Holstein calves were isolated (1 d old, 40-50 kg) after euthanasia. Inhibition of glycolysis attenuated the migration ability of cells, but had no effect on the protein and mRNA abundance of SOCE-associated ORAI1 and STIM1. In contrast, ORAI1 was upregulated in CD4+ T cells of cows exposed to high-FA. To explore the potential mechanisms whereby an active glycolytic metabolism affects CD4+ T cells under High-FA conditions, we knocked down ORAI1 (siORAI1) using small interfering RNA. Isolated CD4+ T cells from High-FA cows with the siORAI1 had an attenuated glycolytic metabolism and migration capacity. Taken together, these data suggested that calcium ions in CD4+ T cells from cows with High-FA regulate glycolytic metabolism and influence cell migration at least in part by modulating ORAI1. Thus, these studies identified a novel mechanism of Ca2+ regulation of CD4+ T cell glycolytic metabolism affecting their migration through the SOCE pathway.

387 Impacts of rumen protected omega-6 fatty acid supplementation on cow reproduction and calf growth

Abstract Maternal nutrition during pregnancy is crucial for proper fetal development. Rumen protected omega-6 (ω-6) fatty acids (FA) may improve health and reproductive success in beef cattle. Previous research studied the effects of supplementing ω-6 on cow production either during late gestation or post-breeding but not during both stages. Our objective was to determine the effects of ω-6 supplementation during late gestation and post-breeding on cow reproduction and calf pre-weaning growth. Eighty cows were assigned to either a saturated FA control (C) or rumen protected ω-6 supplements for 40 d before parturition (PRE) and/or 35 d after artificial insemination (AI, POST) using a 2 × 2 factorial: PRE C-POST C(n = 19); PRE C-POST ω-6(n = 19); PRE ω-6-POST ω-6(n = 17); PRE ω-6-POST C(n = 18). Cows were fed ad libitum hay and water when on/off supplementation periods. Supplements were provided in low moisture tubs. Individual animal intake of supplement was measured by a GrowSafe system. Cow body weights and plasma FA concentrations were measured prior to and after supplementation during each period. Calves were weighed at birth, branding, 150 d old and weaning. Reproductive measurements included postpartum estrus activity, estrus response at fixed-time AI (FTAI), and pregnancy rates. Blood plasma for progesterone analysis was collected on d 7 post-AI on all cows. Corpus luteum (CL) area was measured on d 7 via transrectal ultrasonography on a subset of cows during the POST period (PRE ω-6-POST ω-6 n = 8; PRE C-POST C n = 8; PRE C-POST ω-6 n = 8; PRE ω-6-POST C n = 8). The relationship between supplement intake and plasma FA concentration was analyzed via linear regression, and all other variables were analyzed via ANOVA. Supplement intakes within treatments and between the PRE and POST supplemental periods were highly variable. Body weights remained similar for cows (P = 0.52), but POST ω-6 calves had larger weaning weights than POST C calves (P = 0.02). There was a positive linear relationship (r2 = 0.14, P < 0.03) between supplement intake and plasma FA for PRE ω-6 and POST ω-6. Positive linear relationships between intake and plasma ω-6 FA concentration were observed for PRE C (r2 = 0.11, P < 0.05), PRE ω-6 (r2 = 0.2, P < 0.007) and POST ω-6 (r2 = 0.31, P = 0.0005). Post-partum estrus activity was similar (P = 0.81) between PRE C and PRE ω-6 cows, and estrus response at FTAI was similar (P = 0.13) between POST C and POST ω-6 cows. POST ω-6 cows had larger CL areas than POST C cows (P = 0.03); however, blood progesterone concentrations at d 7 did not differ between treatments (P = 0.65). There was no difference in conception to FTAI between POST C and POST ω-6 (P = 0.08). These results indicate that free choice ω-6 FA supplementation during late gestation and post-AI result in large variation in intake between cows that influence plasma concentrations, but did not markedly alter reproductive measures in mature beef cows.

Role of plasma fatty acid in age-related macular degeneration: insights from a mendelian randomization analysis

BackgroundAn imbalance in lipid metabolism has been linked to the development of AMD, but the causal relationship between AMD and plasma fatty acids (FAs) remains controversial. Using a two-sample Mendelian randomization (MR) approach, we sought to evaluate the impact of specific FA plasma levels on the risk of different AMD subtypes.MethodsWe analysed genome-wide association data of circulating FAs from 115,006 European-descended individuals in the UK Biobank. These data were used in a two-sample MR framework to assess the potential role of circulating FAs in developing wet and dry AMD. Sensitivity analyses were conducted to ensure the robustness of our findings. Additional multivariable and locus-specific MR analyses were conducted to evaluate direct effects of FA on AMD subtypes, minimizing biases from lipoprotein-related traits and triglycerides.ResultsMendelian randomization revealed associations of omega-3 was associated with decreased wet (OR 0.78, 95%CI 0.66–0.92) and dry AMD (0.85, 0.74–0.97) risk, showed a protective effect on AMD. Notably, the omega-6 to omega-3 ratio showed potential causal effects on both wet (1.27, 1.03–1.56) and dry AMD (1.18, 1.02–1.37). Multivariable MR suggested that the causal relationship of omega-3, omega-6 to omega-3 ratio on wet AMD persists after conditioning on HDL, LDL and triglycerides, albeit with slightly diminished evidence strength. Locus-specific MR linked to omega-3(FADS1, 0.89, 0.82–0.98; FADS2, 0.88, 0.81–0.96) and omega-6 to omega-3 ratio (FADS1, 1.10, 1.02–1.20; FADS2, 1.11, 1.03–1.20) suggests causal effects of these factors on wet AMD.ConclusionsThe associations between plasma FA concentrations and AMD, suggest potential causal role of omega-3, and the omega-6 to omega-3 ratio in wet AMD. These results underscore the impact of an imbalanced circulating omega-3 and omega-6 FA ratio on AMD pathophysiology from MR perspective.

Saturated fatty acid concentrations are predictive of insulin sensitivity and beta cell compensation in dogs

Chronic feeding of a high fat diet (HFD) in preclinical species induces broad metabolic dysfunction characterized by body weight gain, hyperinsulinemia, dyslipidemia and impaired insulin sensitivity. The plasma lipidome is not well characterized in dogs with HFD-induced metabolic dysfunction. We therefore aimed to describe the alterations that occur in the plasma lipid composition of dogs that are fed a HFD and examine the association of these changes with the clinical signs of metabolic dysfunction. Dogs were fed a normal diet (ND) or HFD for 12 weeks. Insulin sensitivity (SI) and beta cell compensation (AIRG) were assessed through an intravenous glucose tolerance test (IVGTT) and serum biochemistry was analyzed before the introduction of HFD and again after 12 weeks of continued ND or HFD feeding. Plasma lipidomics were conducted prior to the introduction of HFD and again at week 8 in both ND and HFD-fed dogs. 12 weeks of HFD feeding resulted in impaired insulin sensitivity and increased beta cell compensation measured by SI (ND mean: 11.5 [mU/l]–1 min–1, HFD mean: 4.7 [mU/l]–1 min–1) and AIRG (ND mean: 167.0 [mU/l]min, HFD mean: 260.2 [mU/l]min), respectively, compared to dogs fed ND over the same duration. Chronic HFD feeding increased concentrations of plasma lipid species and deleterious fatty acids compared to dogs fed a ND. Saturated fatty acid (SFA) concentrations were significantly associated with fasting insulin (R2 = 0.29), SI (R2 = 0.49) and AIRG (R2 = 0.37) in all dogs after 12 weeks, irrespective of diet. Our results demonstrate that chronic HFD feeding leads to significant changes in plasma lipid composition and fatty acid concentrations associated with metabolic dysfunction. High SFA concentrations may be predictive of deteriorated insulin sensitivity in dogs.

Increased hepatic glucagon sensitivity in totally pancreatectomised patients.

The metabolic phenotype of totally pancreatectomised patients includes hyperaminoacidaemia and predisposition to hypoglycaemia and hepatic lipid accumulation. We aimed to investigate whether the loss of pancreatic glucagon may be responsible for these changes. Nine middle-aged, normal-weight totally pancreatectomised patients, nine patients with type 1 diabetes (C-peptide negative), and nine matched controls underwent two separate experimental days, each involving a 150-min intravenous infusion of glucagon (4 ng/kg/min) or placebo (saline) under fasting conditions while any basal insulin treatment was continued. Glucagon infusion increased plasma glucagon to similar high physiological levels in all groups. The infusion increased hepatic glucose production and decreased plasma concentration of most amino acids in all groups, with more pronounced effects in the totally pancreatectomised patients compared with the other groups. Glucagon infusion diminished fatty acid re-esterification and tended to decrease plasma concentrations of fatty acids in the totally pancreatectomised patients but not in the type 1 diabetes patients. Totally pancreatectomised patients were characterised by increased sensitivity to exogenous glucagon at the level of hepatic glucose, amino acid, and lipid metabolism, suggesting that the metabolic disturbances characterising these patients may be rooted in perturbed hepatic processes normally controlled by pancreatic glucagon.

Metabolic flexibility in postmenopausal women: Hormone replacement therapy is associated with higher mitochondrial content, respiratory capacity, and lower total fat mass.

To investigate effects of hormone replacement therapy in postmenopausal women on factors associated with metabolic flexibility related to whole-body parameters including fat oxidation, resting energy expenditure, body composition and plasma concentrations of fatty acids, glucose, insulin, cortisol, and lipids, and for the mitochondrial level, including mitochondrial content, respiratory capacity, efficiency, and hydrogen peroxide emission. 22 postmenopausal women were included. 11 were undergoing estradiol and progestin treatment (HT), and 11 were matched non-treated controls (CONT). Peak oxygen consumption, maximal fat oxidation, glycated hemoglobin, body composition, and resting energy expenditure were measured. Blood samples were collected at rest and during 45 min of ergometer exercise (65% VO2peak). Muscle biopsies were obtained at rest and immediately post-exercise. Mitochondrial respiratory capacity, efficiency, and hydrogen peroxide emission in permeabilized fibers and isolated mitochondria were measured, and citrate synthase (CS) and 3-hydroxyacyl-CoA dehydrogenase (HAD) activity were assessed. HT showed higher absolute mitochondrial respiratory capacity and post-exercise hydrogen peroxide emission in permeabilized fibers and higher CS and HAD activities. All respiration normalized to CS activity showed no significant group differences in permeabilized fibers or isolated mitochondria. There were no differences in resting energy expenditure, maximal, and resting fat oxidation or plasma markers. HT had significantly lower visceral and total fat mass compared to CONT. Use of hormone therapy is associated with higher mitochondrial content and respiratory capacity and a lower visceral and total fat mass. Resting energy expenditure and fat oxidation did not differ between HT and CONT.

PNPLA3 Genotype and Dietary Fat Modify Concentrations of Plasma and Fecal Short Chain Fatty Acids and Plasma Branched-Chain Amino Acids.

The GG genotype of the Patatin-like phosphatase domain-containing 3 (PNPLA3), dietary fat, short-chain fatty acids (SCFA) and branched-chain amino acids (BCAA) are linked with non-alcoholic fatty liver disease. We studied the impact of the quality of dietary fat on plasma (p) and fecal (f) SCFA and p-BCAA in men homozygous for the PNPLA3 rs738409 variant (I148M). Eighty-eight randomly assigned men (age 67.8 ± 4.3 years, body mass index 27.1 ± 2.5 kg/m2) participated in a 12-week diet intervention. The recommended diet (RD) group followed the National and Nordic nutrition recommendations for fat intake. The average diet (AD) group followed the average fat intake in Finland. The intervention resulted in a decrease in total p-SCFAs and iso-butyric acid in the RD group (p = 0.041 and p = 0.002). Valeric acid (p-VA) increased in participants with the GG genotype regardless of the diet (RD, 3.6 ± 0.6 to 7.0 ± 0.6 µmol/g, p = 0.005 and AD, 3.8 ± 0.3 to 9.7 ± 8.5 µmol/g, p = 0.015). Also, genotype relation to p-VA was seen statistically significantly in the RD group (CC: 3.7 ± 0.4 to 4.2 ± 1.7 µmol/g and GG: 3.6 ± 0.6 to 7.0 ± 0.6 µmol/g, p = 0.0026 for time and p = 0.004 for time and genotype). P-VA, unlike any other SCFA, correlated positively with plasma gamma-glutamyl transferase (r = 0.240, p = 0.025). Total p-BCAAs concentration changed in the AD group comparing PNPLA3 CC and GG genotypes (CC: 612 ± 184 to 532 ± 149 µmol/g and GG: 587 ± 182 to 590 ± 130 µmol/g, p = 0.015 for time). Valine decreased in the RD group (p = 0.009), and leucine decreased in the AD group (p = 0.043). RD decreased total fecal SCFA, acetic acid (f-AA), and butyric acid (f-BA) in those with CC genotype (p = 0.006, 0.013 and 0.005, respectively). Our results suggest that the PNPLA3 genotype modifies the effect of dietary fat modification for p-VA, total f-SCFA, f-AA and f-BA, and total p-BCAA.

The Effect of Exercise Intensity on Carbohydrate Sparing Postexercise: Implications for Postexercise Hypoglycemia.

The purpose of this study was to determine the effect of exercise intensity on the proportion and rate of carbohydrate oxidation and glucoregulatory hormone responses during recovery from exercise. Six physically active participants completed 1hr of low-intensity (LI; 50% lactate threshold) or moderate-intensity (MI; 100% lactate threshold) exercise on separate days following a randomized counterbalanced design. During exercise and for 6hr of recovery, samples of expired air were collected to determine oxygen consumption, respiratory exchange ratio, energy expenditure, and substrate oxidation rates. Blood samples were also collected to measure glucoregulatory hormones (catecholamines, GH) and metabolites (glucose, free fatty acids, lactate, pH, and bicarbonate). During exercise, respiratory exchange ratio, energy expenditure, and the proportion and rate of carbohydrate (CHO) oxidation were higher during MI compared with LI. However, during recovery from MI, respiratory exchange ratio and the proportion and rate of CHO oxidation were lower than preexercise levels and corresponding LI. During exercise and early recovery, catecholamines and growth hormone were higher in MI than LI, and there was a trend for higher levels of free fatty acids in the early recovery from MI compared with LI. In summary, CHO oxidation during exercise increases with exercise intensity but there is a preference for CHO sparing (and fat oxidation) during recovery from MI exercise compared with LI exercise. This exercise intensity-dependent shift in substrate oxidation during recovery is explained, in part, by the pattern of change of key glucoregulatory hormones including catecholamines and growth hormone and plasma fatty acid concentrations.

The effect of dietary omega-3 fatty acid supplementation on fetal growth, piglet birth weight and plasma fatty acid concentrations, using docosahexaenoic acid in early gestation in sows

The objective of the study was to test the effect of the omega-3 fatty acid docosahexaenoic acid (DHA) on fetal and placental development as well as the birth weight of piglets. A total of 238 multiparous sows were allocated to either a control diet group or a DHA diet group with an omega-6 to omega-3 ratio of 9.8 and 2.4, respectively, from mating to day 43 of gestation. A blood sample was collected and back fat thickness was measured prior to mating, on days 14, 42 and 112 of gestation. On day 43 of gestation, 14 sows were slaughtered and measurements of fetuses and placentas were taken. Piglets in some litters were weighed individually at farrowing. Dietary treatment did not affect fetal characteristics and back fat thickness (P > 0.05). Dietary treatment increased the plasma concentrations of total omega-3 fatty acids in sows (P < 0.05). Sows fed the DHA diet had a shorter gestation length compared to the control sows (P < 0.05), but the number of born piglets was not affected (P > 0.05). The average piglet birth weight and the within-litter variation in birthweight were unaffected by dietary DHA (P > 0.05), however, sows fed DHA diet had fewer piglets under 800 g at birth compared to control sows (P < 0.05). In conclusion, addition of DHA decreased the dietary ratio of omega-6 to omega-3 fatty acids, increased plasma n-3 fatty acid concentrations in sows and decreased the number of piglets weighing under 800 g at birth.

Effects of dietary camelina, flaxseed, and canola oil supplementation on plasma fatty acid concentrations and health parameters in horses

Camelina (Camelina sativa) is a hardy, low-input oilseed crop that provides a rich source of the n-3 fatty acid, α-linolenic acid (ALA). The primary purpose of the present study was to assess the effects of dietary camelina oil (CAM) consumption on various health parameters, as compared to horses fed canola oil (OLA) or flax oil (FLX). Secondly, to determine how dietary CAM, FLX, and OLA alter circulating plasma total lipids across time. Thirty horses, from three separate herds, were used for this study [14.9 years ± 5.3 years; 544 ± 66 kg calculated BW (mean ± SD)]. After a 4-week gradual acclimation period using sunflower oil mixed with soaked hay cubes, horses were balanced by location, age, sex, weight, and breed and randomly allocated to one of three treatment oils (CAM, OLA, or FLX) at an inclusion of 370 mg of oil/kg BW/day. Horses had ad libitum access to hay and/or pasture for the duration of the study. Body condition score (BCS), BW, oil intake, complete blood counts, plasma biochemical profiles, and plasma total lipids were measured on weeks 0, 2, 4, 8, and 16 throughout the 16-week treatment period. BW, BCS, and oil intake were analyzed using an ANOVA using PROC GLIMMIX in SAS Studio. Complete blood counts and biochemical profiles were analyzed using an ANCOVA, and fatty acids were analyzed using an ANOVA in PROC MIXED in SAS Studio. No differences were observed among treatment groups for BW, BCS, oil intake, complete blood counts, and biochemical parameters. Individual fatty acids that differed among treatments and/or across time were largely reflective of the different FA profiles of the oils provided. Most notably, plasma ALA was greater for FLX than OLA, but neither differed from CAM (P = 0.01). Linoleic acid did not differ among treatments or over time (P > 0.05). The n-6:n-3 ratio decreased over time for both CAM and FLX, and ratios were lower for FLX than OLA at week 16, but not different from CAM (P = 0.02). These results suggest that dietary CAM had no adverse effects on health parameters and that daily supplementation of CAM and FLX at 370 mg of oil/kg BW/day induces positive changes (a decrease) in the n-6:n-3 status of the horse. Consequently, CAM may be considered as an alternative oil to FLX in equine diets.

Peripartum factors associated with variation in voluntary postpartum hay intake in dairy cows

The objective of this research was to assess variation in postpartum hay intake when offered alongside total mixed ration (TMR) as free choice, and identify factors related to the hay intake. Twenty multiparous cows were fed a closeup TMR (21.5% starch, 39.1% neutral detergent fiber [NDF] on a dry matter [DM] basis). After calving, cows were offered free choice timothy hay (61.6% NDF, 9.6% crude protein) in addition to a fresh cow TMR (26.8% starch, 33.0% NDF) for the first 5 d postpartum. Cows were fed individually with separate mangers for TMR and hay, each offered ad libitum. Prepartum DM intake (DMI) was recorded, and baseline blood samples were collected after calving, but before the first postpartum feeding. Free choice hay intake ranged from 0 to 4.7 kg/d (DM basis) or 0 to 55.2% (% of total DMI). Cows that consumed more hay (% of total DMI) from d 1 through 5 postpartum had lower DMI 2 d before calving (r = −0.63), and greater baseline concentrations of plasma β-hydroxybutyrate (r = 0.60) and serum haptoglobin (r = 0.68). Additionally, hay intake (% of total DMI) from d 1 through 5 postpartum tended to be positively related to baseline plasma fatty acid concentration (r = 0.41). These findings suggest that cows with lower intake before calving and cows with greater ketone production and inflammation at calving may consume more hay, when offered separate from TMR.

Air pollution exposure and plasma fatty acid profile in pregnant women: a cohort study.

Air pollution exposure was known to result in body impairments by inducing inflammation and oxidation. But little is known about the associations of air pollutants with plasma fatty acid profile which may play important roles in the impairment of air pollutants based on the related mechanism, especially in pregnant women. This study aimed to explore the relationships of air pollution exposure with plasma fatty acid profile and the potential effect modification by pre-pregnancy body mass index (BMI). Based on a cohort in Wuhan, China, we measured concentrations of plasma fatty acids of 519 pregnant women enrolled from 2013 to 2016 by gas chromatography-mass spectrometry (GC-MS). Levels of exposure to air pollutants (fine particulate matter (PM2.5), inhalable particles (PM10), nitrogen dioxide (NO2), sulfur dioxide (SO2), and carbon monoxide (CO)) were estimated by using spatial-temporal land use regression models and calculated in three periods (average concentrations during 1 day, 1 week, and 1 month before the phlebotomizing day in the first trimester). Per interquartile range increment of the levels of air pollution exposure 1 day before phlebotomizing was related to 1.21-2.01% increment of omega-6 polyunsaturated fatty acids (n-6PUFA) and 0.63-1.74% decrement of omega-3 polyunsaturated fatty acids (n-3PUFA). Besides, relationships above were kept robust in the analysis during 1 week and 1 month before phlebotomizing. In women with normal BMI, plasma fatty acid profile was observed to be more sensitive to air pollutants. Our study demonstrated that increment of exposure to air pollutants was associated with higher plasma n-6PUFA known to be pro-inflammatory and lower plasma n-3PUFA known to be anti-inflammatory, which was more sensitive in pregnant women with normal BMI. Our findings suggested that changes in plasma fatty acid profile should cause concerns and may serve as biomarkers in the further studies. Future studies are needed to validate our findings and elucidate the underlying mechanisms.

Inhibition of DHCR24 activates LXRα to ameliorate hepatic steatosis and inflammation

Liver X receptor (LXR) agonism has theoretical potential for treating NAFLD/NASH, but synthetic agonists induce hyperlipidemia in preclinical models. Desmosterol, which is converted by Δ24‐dehydrocholesterol reductase (DHCR24) into cholesterol, is a potent endogenous LXR agonist with anti‐inflammatory properties. We aimed to investigate the effects of DHCR24 inhibition on NAFLD/NASH development. Here, by using APOE*3‐Leiden. CETP mice, a well‐established translational model that develops diet‐induced human‐like NAFLD/NASH characteristics, we report that SH42, a published DHCR24 inhibitor, markedly increases desmosterol levels in liver and plasma, reduces hepatic lipid content and the steatosis score, and decreases plasma fatty acid and cholesteryl ester concentrations. Flow cytometry showed that SH42 decreases liver inflammation by preventing Kupffer cell activation and monocyte infiltration. LXRα deficiency completely abolishes these beneficial effects of SH42. Together, the inhibition of DHCR24 by SH42 prevents diet‐induced hepatic steatosis and inflammation in a strictly LXRα‐dependent manner without causing hyperlipidemia. Finally, we also showed that SH42 treatment decreased liver collagen content and plasma alanine transaminase levels in an established NAFLD model. In conclusion, we anticipate that pharmacological DHCR24 inhibition may represent a novel therapeutic strategy for treatment of NAFLD/NASH.

Evaluation of plasma Short chain fatty acid levels as markers for Inflammatory bowel disease

Background Specific variations of short chain fatty acids in fecal samples have been shown for patients with inflammatory bowel disease. The aim of this study was to assess if Crohn’s disease and ulcerative colitis are associated with altered concentrations of short chain fatty acids also in blood plasma. Method Between 2016-2019, Swedish adults referred to a tertiary center for colonoscopy were asked to participate in a cross-sectional study. Individuals with Crohn’s disease or ulcerative colitis as well as individuals with no findings on the colonoscopy (defined as clean colon) were included in the study. Data on colonoscopy findings, blood samples (including haemoglobin, C-reactive protein and short chain fatty acid analysis) as well as a validated lifestyle questionnaire including 277 questions were collected from all participants. Linear regression was used to compare mean concentrations of short chain fatty acids between Crohn’s disease, ulcerative colitis and clean colon. Results The cohort consisted of 132 individuals with Crohn’s disease, 119 with ulcerative colitis and 205 with clean colon. In the crude model, succinic acid was significantly lower (p < 0.05) among patients with Crohn’s disease (mean 3.00 µM SE 0.10) and ulcerative colitis (mean 3.13 µM SE 0.10) in comparison to clean colon (mean 3.41 µM SE 0.08), however when adjusting for sex, age and diet the results did not remain statistically significant. No differences in plasma concentration of the other measured short chain fatty acids were detected. Conclusion Crohn’s disease and ulcerative colitis are not associated with altered short chain fatty acid concentrations in plasma. Further research is needed to confirm or refute our findings.

The Effect of Increasing Concentrations of Omega-3 Fatty Acids from either Flaxseed Oil or Preformed Docosahexaenoic Acid on Fatty Acid Composition, Plasma Oxylipin, and Immune Response of Laying Hens

BackgroundThere is a lack of nutrition guidelines for the feeding of omega-3 polyunsaturated fatty acids (PUFA) to laying hens. Knowledge as to whether the type and concentrations of α-linolenic acid (ALA) and/or docosahexaenoic acid (DHA) in the diet can make a difference to the birds’ immune responses when subjected to a lipopolysaccharide (LPS) challenge is limited. ObjectivesThe study was designed to determine the potential nutritional and health benefits to laying hens when receiving dietary omega-3 PUFA from either ALA or DHA. MethodsA total of 80 Lohmann LSL-Classic (white egg layer, 20 wk old) were randomly assigned to 1 of 8 treatment diets (10 hens/treatment), provided 0.2%, 0.4%, 0.6%, or 0.8% of total dietary omega-3 PUFA, provided as either ALA-rich flaxseed oil or DHA-enriched algal biomass. After an 8-wk feeding period, the birds were challenged with Escherichia coli-derived LPS (8 mg/kg; i.v. injection), with terminal sample collection 4 h after challenge. Egg yolk, plasma, liver, and spleen samples were collected for subsequent analyses. ResultsIncreasing dietary omega-3 supplementation yielded predictable responses in egg yolk, plasma, and liver fatty acid concentrations. Dietary intake of ALA contributed mainly to ALA-derived oxylipins. Meanwhile, eicosapentaenoic acid- and DHA-derived oxylipins were primarily influenced by DHA dietary intake. LPS increased the concentrations of almost all the omega-6 PUFA-, ALA-, and DHA-derived oxylipins in plasma and decreased hepatic mRNA expression of COX-2 and 5-LOX (P < 0.001) involved in the biosynthesis of oxylipins. LPS also increased mRNA expression of proinflammatory cytokine IFN-γ and receptor TLR-4 (P < 0.001) in the spleen. ConclusionsThese results revealed that dietary intake of ALA and DHA had unique impacts on fatty acid deposition and their derived oxylipins and inflammatory responses under the administration of LPS in laying hens.

Prospective Association Between Plasma Concentrations of Fatty Acids and Other Lipids, and Multimorbidity in Older Adults.

Biological mechanisms that lead to multimorbidity are mostly unknown, and metabolomic profiles are promising to explain different pathways in the aging process. The aim of this study was to assess the prospective association between plasma fatty acids and other lipids, and multimorbidity in older adults. Data were obtained from the Spanish Seniors-ENRICA 2 cohort, comprising noninstitutionalized adults ≥65 years old. Blood samples were obtained at baseline and after a 2-year follow-up period for a total of 1 488 subjects. Morbidity was also collected at baseline and end of the follow-up from electronic health records. Multimorbidity was defined as a quantitative score, after weighting morbidities (from a list of 60 mutually exclusive chronic conditions) by their regression coefficients on physical functioning. Generalized estimating equation models were employed to assess the longitudinal association between fatty acids and other lipids, and multimorbidity, and stratified analyses by diet quality, measured with the Alternative Healthy Eating Index-2010, were also conducted. Among study participants, higher concentrations of omega-6 fatty acids [coef. per 1-SD increase (95% CI) = -0.76 (-1.23, -0.30)], phosphoglycerides [-1.26 (-1.77, -0.74)], total cholines [-1.48 (-1.99, -0.96)], phosphatidylcholines [-1.23 (-1.74, -0.71)], and sphingomyelins [-1.65 (-2.12, -1.18)], were associated with lower multimorbidity scores. The strongest associations were observed for those with a higher diet quality. Higher plasma concentrations of omega-6 fatty acids, phosphoglycerides, total cholines, phosphatidylcholines, and sphingomyelins were prospectively associated with lower multimorbidity in older adults, although diet quality could modulate the associations found. These lipids may serve as risk markers for multimorbidity.

Microvascular constriction via fatty acid-mediated oxidative stress in humans

Purpose: Excess plasma lipids promote oxidative stress and impair vascular function. Herein, we examined microcirculatory blood flow and tested the hypothesis that a co-infusion of a water-soluble antioxidant (ascorbic acid, AA) would attenuate reductions in retinal arteriole lumen diameter and increase resistance resulting from acutely elevated plasma lipids in healthy adults. Methods: A 20% IV fat emulsion (Intralipid) was administered for 2 hours to 8 healthy, middle-aged adults (2 men/6 women) with and without co-infusion of ascorbic acid (separate visits) in a double-blinded, crossover study design. Co-infusion of AA was administered at 0.06g/kg fat free mass in 100 ml saline at 5 mL/min over 20 min (bolus) followed by a drip infusion at 0.02 g/kg fat-free mass in 30 ml saline at 0.33 mL/min over 90 min. Retinal arteriole lumen diameter and resistance were assessed via Laser Speckle Flowgraphy at baseline and after infusion. Results: Lipid infusion significantly increase plasma fatty acid concentrations (lipid w/o AA: +36 ± 18 vs. lipid with AA: +41 ± 13 vs. μmol/L, P=0.84). AA infusion significantly increased plasma ascorbic acid concentrations (lipid w/o AA: -1 ± 7 vs. lipid with AA: +26 ± 11 μmol/L, P=0.04). A significant increase in retinal arteriole resistance was observed following lipid infusion (lipid w/o AA: +20 ± 8 %, vs. lipid with AA: +17 ± 8 %, P=0.40). In accordance, lipid infusion significantly reduced retinal arteriole lumen diameter; however, co-infusion of AA reversed the lipid-mediated decrease in retinal arteriole diameter (lipid w/o AA: -3 ± 1 % vs. lipid with AA: +3 ± 2 %, P=0.01). Conclusions: Although microvascular resistance was increased, co-infusion of the antioxidant (ascorbic acid) reversed the fatty acid-mediated reduction in arteriole lumen diameter. Therefore, these preliminary findings suggest that acute elevations in plasma fatty acids induce microvascular constriction via an oxidative stress pathway. Funding and support: R01HL159370-01 (S.W.H.). This work was also supported by a CTSA grant from NCATS awarded to the University of Kansas for Frontiers: University of Kansas Clinical and Translational Science Institute (# UL1TR002366). The contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH or CTSA. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Impaired endothelial function via fatty acids and the potential role of oxidative stress

Purpose: Excess plasma lipids promote oxidative stress and impaired vascular function. Therefore, we tested the hypothesis that a water-soluble antioxidant (ascorbic acid, AA) would attenuate reductions in endothelium-dependent dilation resulting from acutely elevated plasma fatty acids. Methods: A 20% IV fat emulsion (Intralipid) was administered for 2 hours to 8 healthy, middle-aged adults (2 men/6 women) with and without co-infusion of ascorbic acid (separate visits) in a double-blinded, crossover study design. Co-infusion of AA was administered at 0.06g/kg fat free mass in 100 ml saline at 5 mL/min over 20 min (bolus) followed by a drip infusion at 0.02 g/kg fat-free mass in 30 ml saline at 0.33 mL/min over 90 min. Endothelium-dependent dilation was assessed via brachial artery flow-mediated dilation (FMD) and expressed as % increase in diameter from baseline before forearm occlusion. Results: Lipid infusion significantly increase plasma fatty acid concentrations (w/o AA: +36 ± 18 vs. with AA: +41 ± 13 vs. μmol/L, P=0.84). AA infusion significantly increased plasma ascorbic acid concentrations (w/o AA: -1 ± 7 vs. with AA: +26 ± 11 μmol/L, P=0.04). Compared with baseline, FMD was significantly reduced following lipid infusion at (Baseline: 9.3 ± 1.1 vs. 20 min: 4.4 ± 1.3 vs. End: 5.3 ± 2.9 %, P=0.03), and when statistically adjusting for the stimulus (shear rate area under the curve) via analysis of covariance (P=0.02). FMD was also significantly reduced following lipid infusion with co-infusion of AA (Baseline: 8.9 ± 1.0 vs. 20 min: 5.3 ± 1.0 vs. End: 6.4 ± 3.8 %, P=0.02), but not when statistically adjusting for shear rate under the curve (P=0.08). Conclusions: Elevated plasma fatty acids impair endothelium-dependent dilation in healthy adults. However, co-administration of an antioxidant (ascorbic acid) limited the reduction in FMD when correcting for shear rate. Therefore, these preliminary data suggest that fatty acids may reduce endothelium-dependent dilation via an oxidative stress mechanism. Funding and support: R01HL159370-01 (S.W.H.). This work was also supported by a CTSA grant from NCATS awarded to the University of Kansas for Frontiers: University of Kansas Clinical and Translational Science Institute (# UL1TR002366). The contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH or CTSA. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Effects of dietary organic acid and pure botanical supplementation on growth performance and circulating measures of metabolic health in Holstein calves challenged by heat stress

To evaluate the effects of heat stress environmental conditioning and dietary supplementation with organic acid and pure botanicals (OA/PB) on growth in dairy calves, we enrolled 62 bull (noncastrated) and heifer calves in a study with a completely randomized design. Calves were assigned to 1 of 5 groups (n = 11 to 14/group): (1) thermoneutral conditions (TN-Con), (2) HS conditions (HS-Con), (3) thermoneutral conditions and pair-fed to match nutrient intake with HS-Con (TN-PF), (4) HS with low-dose OA/PB [75 mg/kg of body weight (BW); 25% citric acid, 16.7% sorbic acid, 1.7% thymol, 1.0% vanillin, and 55.6% triglyceride; HS-Low], or (5) HS with high-dose OA/PB (150 mg/kg of BW; HS-High). Supplements were delivered as a twice-daily bolus via the esophagus from wk 1 through 13 of life; all calves, including those on the control treatments, received an equivalent amount of triglyceride used for microencapsulation. Calves were raised in TN conditions from birth until weaning. After weaning, calves (62 ± 2 d; 91 ± 10.9 kg of BW) were transported to a new facility and remained in TN conditions [temperature-humidity index (THI): 60 to 69] for a 7-d covariate period. Thereafter, calves remained in TN or were moved to HS conditions (THI: diurnal change 75 to 83 during night and day, respectively) for 19 d. Clinical assessments were performed thrice daily, BW was recorded weekly, and blood was sampled on d 1, 2, 3, 8, 15, and 19. Upon experiment completion, calves from HS-Con and TN-Con were euthanized, and hot carcass and visceral organ weights were recorded. The mixed model included calf as a random effect; treatment, day, hour (when appropriate) as fixed effects, and the interactions of treatment × day and treatment × hour (when appropriate). Rectal and skin temperatures and respiration rates were greater in HS-Con than in TN-Con. During heat stress exposure, dry matter intake (DMI), average daily gain (ADG), and gain to feed (G:F) were lower in HS-Con relative to TN-Con. Comparing HS-Con and TN-PF, ADG and G:F were similar. Plasma fatty acid concentrations were elevated in TN-PF compared with HS-Con and TN-Con. Despite tendencies for increased aspartate aminotransferase, HS conditions did not overtly influence liver and inflammation markers. Liver weights were lower in HS-Con relative to TN-Con. During the first week of heat exposure, DMI was greater for HS-Low relative to HS-Con. Supplementation of OA/PB at low and high levels had a similar G:F to HS-Con. We conclude that reductions in DMI accounted for production losses during HS conditioning and that dietary OA/PB supplementation was not able to improve growth performance in heat-stressed calves.