Effect of daily avocado consumption for 6 mo compared with habitual diet on red blood cell fatty acid profiles and association with cardiometabolic risk factors in individuals with abdominal obesity: a randomized trial.

BACKGROUND: Avocado intake improves dietary fat quality, but the subsequent impact on red blood cell (RBC) saturated (SFA), monounsaturated (MUFA), polyunsaturated (PUFA), and trans-fatty acid (TFA) composition and association with cardiometabolic health, has not been elucidated. OBJECTIVES: To compare the effect of consuming 1 avocado/d relative to habitual diet (HAB) on RBC-FA profiles, and their association with visceral adiposity and cardiometabolic risk factors (CMRFs) in individuals with abdominal obesity. METHODS: RBC-FA profiling at baseline, 3- and 6 mo was conducted in participants (n = 994) from the Habitual Diet and Avocado Trial (HAT). HAT was a multisite, free-living, parallel-arm intervention study in which participants were randomly assigned to either the avocado-supplemented group (AVO, usual diet with 1 avocado/d) or the HAB group (usual diet with limited avocado intake) for 6 mo. Changes in RBC-FA profiles, a secondary outcome measure, were determined within and between groups using linear regression and mixed effect models, adjusting for age, sex, BMI, clinical site, smoking status, and percentage of energy intake from fat at baseline. The association between changes in RBC-FAs with visceral adiposity measures and CMRFs was assessed after covariate and False Discovery Rate (FDR <0.05) adjustment. RESULTS: No major differences in RBC-FA profiles were observed between groups, with the exception of MUFA cis-vaccenic [18:1n-7c], which was significantly higher in AVO (ß: 0.11 [0.05, 0.17]) compared with the HAB (ß: 0.03 [-0.03, 0.08]) participants. In the HAB but not AVO group, increases in MUFA cis (18:1n-7c, oleic [18;1n-9c], erucic [22:1n-9c]) and MUFA trans (palmitelaidic [16:1n-7t], vaccenic [18:1n-7t], elaidic [18:1n-9t], and petroselaidic [18;1n-10-12t), as well as PUFA γ-linolenic [18:3n-6], dihomo-γ-linolenic [20:3n-6], arachidonic [20:4n-6], and α-linolenic [18:3n-3] were associated with unfavorable changes in visceral adiposity measures, lipid profiles, glucose, insulin and high sensitivity C-reactive protein concentrations. CONCLUSIONS: Daily avocado intake over 6-mo modified RBC-MUFA composition, notably 18:1n-7c, and potentially mitigated some of the unfavorable individual RBC-FA-CMRF associations observed over time in the HAB group. This trial was registered at https://clinicaltrials.gov/study as NCT03528031.

Effect of Incorporating 1 Avocado per Day Versus Habitual Diet on Vascular Function in Adults With Abdominal Obesity: An Ancillary Study of HAT, a Randomized Controlled Trial.

BACKGROUND: Abdominal obesity is associated with endothelial dysfunction and poorer vascular health. Avocado consumption improves postprandial endothelial function; however, the longer-term effects remain unclear. It was hypothesized that the daily addition of 1 avocado to a habitual diet for 6 months would improve flow-mediated dilation (FMD) and carotid-femoral pulse wave velocity in individuals with abdominal obesity (waist circumference ≥35 in for women, ≥40 in for men), compared with a habitual diet low in avocados. METHODS AND RESULTS: HAT (Habitual Diet and Avocado Trial) was a multicenter, randomized, controlled, parallel-arm study that investigated the health effects of adding 1 avocado per day to a habitual diet in individuals with abdominal obesity. At the Pennsylvania State University, University Park study center (n=134; age, 50 ± 13 years; women, 78%; body mass index, 32.6 ± 4.8 kg/m2), markers of vascular function were measured, including endothelial function, assessed via brachial artery flow-mediated dilation, and arterial stiffness, assessed via carotid-femoral pulse wave velocity. Between-group differences in 6-month change in flow-mediated dilation and carotid-femoral pulse wave velocity were assessed using independent t tests. Prespecified subgroup analyses were conducted using linear regression. No significant between-group differences in flow-mediated dilation (mean difference=-0.62% [95% CI, -1.70 to 0.46]) or carotid-femoral pulse wave velocity (0.25 m/s [95% CI, -0.13 to 0.63]) were observed. Results of the subgroup analyses were consistent with the primary analyses. CONCLUSIONS: Longer-term consumption of 1 avocado per day as part of a habitual diet did not improve measures of vascular function compared with a habitual diet low in avocados in individuals with abdominal obesity. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03528031.

One Avocado per Day as Part of Usual Intake Improves Diet Quality: Exploratory Results from a Randomized Controlled Trial.

Background: Few clinical trials have evaluated diet quality change as a predictor of intervention effectiveness. Objectives: The aim of this study was to examine changes in the Healthy Eating Index (HEI)-2015 after a food-based intervention, and assess the associations between HEI-2015 change and intervention effects on cardiometabolic risk-related outcomes. Methods: The Habitual Diet and Avocado Trial was a 26-wk, multicenter, randomized, controlled parallel-arm study. Participants were 1008 individuals aged ≥25 y with abdominal obesity (females ≥ 35 inches; males ≥ 40 inches). The avocado-supplemented diet group was provided 1 avocado per day, and the habitual diet group maintained their usual diet. Change in diet quality was assessed using the HEI-2015 from a single 24-h recall conducted at 4 time points. Mixed models were used for analysis. Results: The avocado-supplemented diet group had a greater increase in the HEI-2015 (4.74 points; 95% CI: 2.93, 6.55) at 26 wk than the habitual diet group. Compared with the habitual diet group, the avocado-supplemented diet group had greater increases in the following HEI-2015 components from baseline: total vegetables (0.99 points; 95% CI: 0.77, 1.21), fatty acid ratio (2.25 points; 95% CI: 1.74, 2.77), sodium (1.03 points; 95% CI: 0.52, 1.55), refined grains (0.82 points; 95% CI: 0.32, 1.31), and added sugars (0.84 points; 95% CI: 0.49, 1.19). No differences in HEI-2015 improvements were observed by race, ethnicity, study site, body mass index, or age category. In the avocado-supplemented diet compared with the habitual diet group, the HEI-2015 increased in females (6.50 points; 95% CI: 4.39, 8.62) but not in males (0.02 points; 95% CI: -3.44, 3.48). Median HEI-2015 change was not associated with intervention-related changes in cardiometabolic disease risk factors. Conclusions: Intake of 1 avocado per day for 26 wk in adults with abdominal obesity increased adherence to the Dietary Guidelines for Americans. Changes in diet quality did not predict changes in risk factors for cardiometabolic disease.This trial was registered at clinicaltrials.gov as NCT03528031 (https://clinicaltrials.gov/study/NCT03528031).

Monocyte transcriptomic profile following EPA and DHA supplementation in men and women with low-grade chronic inflammation.

BACKGROUND: Recent data indicate considerable variability in response to very long chain omega-3 fatty acid supplementation on cardiovascular disease risk. This inconsistency may be due to differential effects of EPA vs DHA and/or sex-specific responses. METHODS: Sixteen subjects (eight men and eight women) 50-75 y and with low-grade chronic inflammation participated in a randomized controlled crossover trial comparing 3 g/d EPA, 3 g/d DHA, and placebo (3 g/d high oleic acid sunflower oil). Blood monocytes were isolated at the end of each phase for RNA-sequencing. RESULTS: Sex dimorphism in monocyte gene expression was observed, therefore, data for men and women were analyzed separately. 1088 genes were differentially expressed in men and 997 in women (p < 0.05). In both men and women, EPA and DHA repressed genes involved in protein turnover and mitochondrial energy metabolism, relative to placebo. In men only, EPA and DHA upregulated genes related to wound healing and PPARα activation. In women only, EPA and DHA activated genes related to ER stress response. Relative to DHA, EPA resulted in lower expression of genes involved in inflammatory processes in men, and lower expression of genes involved in ER stress response in women. CONCLUSIONS: EPA and DHA supplementation elicited both similar and differential effects on monocyte transcriptome, some of which were sex specific. The observed variability in response to EPA and DHA in men and women could in part explain the conflicting results from previous cardiovascular clinical trials using omega-3 fatty acids.

Waist-to-height ratio associated cardiometabolic risk phenotype in children with overweight/obesity.

BACKGROUND: Childhood overweight/obesity has been associated with an elevated risk of insulin resistance and cardiometabolic disorders. Waist-to-height ratio (WHtR) may be a simple screening tool to quickly identify children at elevated risk for cardiometabolic disorders. The primary objective of the present study was to create sex-specific tertile cut points of WHtR and assess its association with Insulin resistance and elevated liver enzyme concentrations in children, factors using cross-sectional data from the randomized, controlled Family Weight Management Study. METHODS: Baseline data from 360 children (7-12 years, mean Body Mass Index (BMI) ≥ 85th percentile for age and sex) were used to calculate WHtR tertiles by sex, male: ≤ 0.55 (T1), > 0.55- ≤ 0.59 (T2), > 0.59 (T3); female: ≤ 0.56 (T1), > 0.56- ≤ 0.6 (T2), > 0.6 (T3). The Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) was used to categorize participants as insulin-resistant (HOMA-IR ≥ 2.6) and insulin-sensitive (HOMA-IR < 2.6). Liver enzymes aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were categorized as normal vs. elevated (AST of < 36.0 µkat/L or ≥ 36.0 µkat/L; ALT of < 30.0 µkat/L or ≥ 30.0 µkat/L; ALT > 26 µkat/L males, > 22 µkat/L females). We examined differences in baseline cardiometabolic risk factors by WHtR tertiles and sex-specific multivariable logistic regression models to predict HOMA-IR and elevation of liver enzymes. RESULTS: Study participants had a mean WHtR of 0.59 ([SD: 0.06]). Irrespective of sex, children in WHtR T3 had higher BMIz scores, blood pressure, triglycerides, 2-h glucose, fasting 2-h insulin, and lower high-density lipoprotein cholesterol (HDL-C) concentrations than those in T2 and T1. After adjusting for covariates, the odds of elevated HOMA-IR (> 2.6) were over five-fold higher among males in T3 versus T1 [OR, 95%CI: 5.83, 2.34-14.52] and T2 [OR, 95%CI: 4.81, 1.94-11.92] and females in T3 [OR, 95%CI: 5.06, 2.10-12.20] versus T1. The odds of elevated ALT values (≥ 30) were 2.9 [95%CI: 1.01-8.41] fold higher among females in T3 compared to T1. CONCLUSION: In public health settings, WHtR may be a practical screening tool in pediatric populations to identify children at risk of metabolic syndrome.

Comparison of Plasma Metabolome Response to Diets Enriched in Soybean and Partially-Hydrogenated Soybean Oil in Moderately Hypercholesterolemic Adults-A Pilot Study.

Partially-hydrogenated fat/trans fatty acid intake has been associated with adverse effects on cardiometabolic risk factors. Comparatively unexplored is the effect of unmodified oil relative to partially-hydrogenated fat on the plasma metabolite profile and lipid-related pathways. To address this gap, we conducted secondary analyses using a subset of samples randomly selected from a controlled dietary intervention trial involving moderately hypercholesterolemic individuals. Participants (N = 10, 63 ± 8 y, BMI, 26.2 ± 4.2 kg/m2, LDL-C, 3.9 ± 0.5 mmol/L) were provided with diets enriched in soybean oil (SO) and partially-hydrogenated soybean oil (PHSO). Plasma metabolite concentrations were determined using an untargeted approach and pathway analysis using LIPIDMAPS. Data were assessed using a volcano plot, receiver operating characteristics curve, partial least square-discrimination analysis and Pearson correlations. Among the known metabolites higher in plasma after the PHSO diet than the SO diet, the majority were phospholipids (53%) and di- and triglycerides (DG/TG, 34%). Pathway analysis indicated upregulation of phosphatidylcholine synthesis from DG and phosphatidylethanolamine. We identified seven metabolites (TG_56:9, TG_54:8, TG_54:7, TG_54:6, TG_48:5, DG_36:5 and benproperine) as potential biomarkers for PHSO intake. These data indicate that TG-related metabolites were the most affected lipid species, and glycerophospholipid biosynthesis was the most active pathway in response to PHSO compared to SO intake.

The Associations of Individual and Subclasses of Nonesterified Fatty Acids With Disability, and Mobility Limitation in Older Adults: The Cardiovascular Health Study.

BACKGROUND: We sought to determine the associations between individual nonesterified fatty acids (NEFAs) and disability and mobility limitation. METHODS: We studied 1 734 participants in the Cardiovascular Health Study (CHS), an ongoing population-based cohort study of community-living older American adults. We measured 35 individual NEFA species in fasting serum samples obtained at the 1996-1997 clinic visit. Using yearly assessments of activities of daily living and self-reported mobility, we identified participants with incident disability or mobility limitation during 15 years of follow-up. Cox proportional hazards regression models were used to determine the associations between per SD increment in the individual NEFAs and incident disability and mobility limitations with adjustment for potential confounding factors. RESULTS: Higher concentrations of total and a broad range of individual NEFA species were associated with risk of disability and mobility limitation (disability: HR per SD of total NEFA [SD = 174.70] = 1.11, 95% CI = 1.04-1.18, p = .001; mobility limitation: HR per SD of total NEFA = 1.09, 95% CI = 1.02-1.16, p = .01). Among individual saturated NEFAs (SFAs), myristic (14:0) and palmitic (16:0) acids were significantly associated with higher risk of both disability and mobility limitations, but longer-chain FAs were not. Most individual monounsaturated (MUFA), n-6 polyunsaturated fatty acids (PUFAs), and trans FAs were positively significantly associated with higher risks of both disability and mobility limitation. In contrast, most n-3 PUFA species were not associated with disability or mobility limitation. CONCLUSIONS: Higher risks of disability and mobility limitation were observed for proinflammatory intermediate-chain SFAs, MUFAs, n-6 PUFAs, and trans FAs. Our findings indicated no significant association for anti-inflammatory n-3 PUFAs.

Effect of Incorporating 1 Avocado Per Day Versus Habitual Diet on Visceral Adiposity: A Randomized Trial.

Background Excess visceral adiposity is associated with increased risk of cardiometabolic disorders. Short-term well-controlled clinical trials suggest that regular avocado consumption favorably affects body weight, visceral adiposity, and satiety. Methods and Results The HAT Trial (Habitual Diet and Avocado Trial) was a multicenter, randomized, controlled parallel-arm trial designed to test whether consuming 1 large avocado per day for 6 months in a diverse group of free-living individuals (N=1008) with an elevated waist circumference compared with a habitual diet would decrease visceral adiposity as measured by magnetic resonance imaging. Secondary and additional end points related to risk factors associated with cardiometabolic disorders were assessed. The primary outcome, change in visceral adipose tissue volume during the intervention period, was not significantly different between the Avocado Supplemented and Habitual Diet Groups (estimated mean difference (0.017 L [-0.024 L, 0.058 L], P=0.405). No significant group differences were observed for the secondary outcomes of hepatic fat fraction, hsCRP (high-sensitivity C-reactive protein), and components of the metabolic syndrome. Of the additional outcome measures, modest but nominally significant reductions in total and low-density lipoprotein cholesterol were observed in the Avocado Supplemented compared with the Habitual Diet Group. Changes in the other additional and post hoc measures (body weight, body mass index, insulin, very low-density lipoprotein concentrations, and total cholesterol:high-density lipoprotein cholesterol ratio) were similar between the 2 groups. Conclusions Addition of 1 avocado per day to the habitual diet for 6 months in free-living individuals with elevated waist circumference did not reduce visceral adipose tissue volume and had minimal effect on risk factors associated with cardiometabolic disorders. Registration URL: https://clinicaltrials.gov; Unique identifier: NCT03528031.

Plasma Metabolite Response to Simple, Refined and Unrefined Carbohydrate-Enriched Diets in Older Adults-Randomized Controlled Crossover Trial.

Food intake data collected using subjective tools are prone to inaccuracies and biases. An objective assessment of food intake, such as metabolomic profiling, may offer a more accurate method if unique metabolites can be identified. To explore this option, we used samples generated from a randomized and controlled cross-over trial during which participants (N = 10; 65 ± 8 year, BMI, 29.8 ± 3.2 kg/m2) consumed each of the three diets enriched in different types of carbohydrate. Plasma metabolite concentrations were measured at the end of each diet phase using gas chromatography/time-of-flight mass spectrometry and ultra-high pressure liquid chromatography/quadrupole time-of-flight tandem mass spectrometry. Participants were provided, in random order, with diets enriched in three carbohydrate types (simple carbohydrate (SC), refined carbohydrate (RC) and unrefined carbohydrate (URC)) for 4.5 weeks per phase and separated by two-week washout periods. Data were analyzed using partial least square-discrimination analysis, receiver operating characteristics (ROC curve) and hierarchical analysis. Among the known metabolites, 3-methylhistidine, phenylethylamine, cysteine, betaine and pipecolic acid were identified as biomarkers in the URC diet compared to the RC diet, and the later three metabolites were differentiated and compared to SC diet. Hierarchical analysis indicated that the plasma metabolites at the end of each diet phase were more strongly clustered by the participant than the carbohydrate type. Hence, although differences in plasma metabolite concentrations were observed after participants consumed diets differing in carbohydrate type, individual variation was a stronger predictor of plasma metabolite concentrations than dietary carbohydrate type. These findings limited the potential of metabolic profiling to address this variable.

Plasma Metabolite Profiles Following Consumption of Animal Protein and Soybean-Based Diet in Hypercholesterolemic Postmenopausal Women.

Subjective reporting of food intake can be unreliable. No objective method is available to distinguish between diets differing in protein type. To address this gap, a secondary analysis of a randomized controlled cross-over feeding trial was conducted. Assessed were fasting plasma metabolite profiles and their associations with cardiometabolic risk factors (CMRFs). Hypercholesterolemic post-menopausal women (N = 11) were provided with diets containing predominantly animal protein (AP) and soy protein (SP). Untargeted metabolomics were used to determine the plasma metabolite profiles at the end of each diet phase. Concentrations of identified metabolites (N = 829) were compared using paired t-tests adjusted for false discovery rate, partial least square-discrimination analysis (PLS-DA) and receiver operating characteristics (ROC). Among the identified metabolites, 58 differed significantly between the AP and SP diets; the majority were phospholipids (n = 36), then amino acids (n = 10), xenobiotics (n = 7), vitamin/vitamin-related (n = 3) and lipids (n = 2). Of the top 10 metabolites, amino acid-derived metabolites, phospholipids and xenobiotics comprised the main categories differing due to dietary protein type. ROC curves confirmed that the top 10 metabolites were potential discriminating biomarkers for AP- and SP-rich diets. In conclusion, amino acid-derived metabolites, phosphatidylethanolamine-derived metabolites and isoflavones were identified as potential metabolite biomarkers distinguishing between dietary protein type.

Spillover Effects of a Family-Based Childhood Weight-Management Intervention on Parental Nutrient Biomarkers and Cardiometabolic Risk Factors.

BACKGROUND: Parental involvement has been shown to favorably affect childhood weight-management interventions, but whether these interventions influence parental diet and cardiometabolic health outcomes is unclear. OBJECTIVES: The aim was to evaluate whether a 1-y family-based childhood weight-management intervention altered parental nutrient biomarker concentrations and cardiometabolic risk factors (CMRFs). METHODS: Secondary analysis from a randomized-controlled, parallel-arm clinical trial (NCT00851201). Families were recruited from a largely Hispanic population and assigned to either standard care (SC; American Academy of Pediatrics overweight/obesity recommendations) or SC + enhanced program (SC+EP; targeted diet/physical activity strategies, skill building, and monthly support sessions). Nutrient biomarkers (plasma carotenoids and fat-soluble vitamins, RBC fatty acid profiles) and CMRFs (BMI, blood pressure, glucose, insulin, lipid profile, inflammatory and endothelial dysfunction markers, adipokines) were measured in archived samples collected from parents of participating children at baseline and end of the 1-y intervention. RESULTS: Parents in both groups (SC = 106 and SC+EP = 99) had significant reductions in trans fatty acid (-14%) and increases in MUFA (2%), PUFA n-6 (É·-6) (2%), PUFA n-3 (7%), and ß-carotene (20%) concentrations, indicative of lower partially hydrogenated fat and higher vegetable oil, fish, and fruit/vegetable intake, respectively. Significant reductions in high-sensitivity C-reactive protein (hsCRP; -21%) TNF-α (-19%), IL-6 (-19%), and triglycerides (-6%) were also observed in both groups. An additional significant improvement in serum insulin concentrations (-6%) was observed in the SC+EP parents. However, no major reductions in BMI or blood pressure and significant unfavorable trajectories in LDL-cholesterol and endothelial dysfunction markers [P-selectin, soluble intercellular adhesion molecule (sICAM), thrombomodulin] were observed. Higher carotenoid, MUFA, and PUFA (n-6 and n-3) and lower SFA and trans fatty acid concentrations were associated with improvements in circulating glucose and lipid measures, inflammatory markers, and adipokines. CONCLUSIONS: The benefits of a family-based childhood weight-management intervention can spill over to parents, resulting in apparent healthier dietary shifts that are associated with modest improvements in some CMRFs.

Association of Serum Low-Density Lipoprotein, High-Density Lipoprotein, and Total Cholesterol With Development of Knee Osteoarthritis.

OBJECTIVE: Studies suggest an association between elevated total serum cholesterol, particularly low-density lipoprotein (LDL), and osteoarthritis (OA). The present study was undertaken to evaluate the association between total cholesterol, LDL, and high-density lipoprotein (HDL) and risk of knee OA. METHODS: We studied participants from the Multicenter Osteoarthritis study (MOST) cohort at risk of developing knee OA. From baseline through 7 years, repeated knee radiographs and magnetic resonance images (MRIs) were obtained, and knee symptoms were queried. From baseline fasting blood samples, lipids and lipoproteins were analyzed using standard assays. After excluding participants with baseline OA, we defined 2 sets of patients: those developing radiographic OA, and those developing symptomatic OA (knee pain and radiographic OA). Controls did not develop these outcomes. Additionally, we examined worsening of cartilage loss and synovitis on MRI and of knee pain using the Western Ontario and McMaster Universities Osteoarthritis Index scale. We carried out logistic regression adjusting for age, sex, body mass index, education, baseline pain, and depressive symptoms, testing total cholesterol and lipoproteins as continuous measures, and we performed sensitivity analyses examining whether commonly used thresholds for high cholesterol, LDL, or low HDL increased risk. RESULTS: We studied 337 patients with incident symptomatic OA and 283 patients with incident radiographic OA. The mean age at baseline was 62 years (55% women). Neither total cholesterol, LDL, nor HDL showed a significant association with radiographic or symptomatic OA. Additionally, we found no association of these lipid measures with cartilage loss, worsening synovitis, or worsening knee pain. CONCLUSION: Our data do not support an association between total cholesterol, LDL, or HDL with OA outcomes.

Oncogenic Integration of Nucleotide Metabolism via Fatty Acid Synthase in Non-Hodgkin Lymphoma.

Metabolic dysfunctions enabling increased nucleotide biosynthesis are necessary for supporting malignant proliferation. Our investigations indicate that upregulation of fatty acid synthase (FASN) and de novo lipogenesis, commonly observed in many cancers, are associated with nucleotide metabolic dysfunction in lymphoma. The results from our experiments showed that ribonucleotide and deoxyribonucleotide pool depletion, suppression of global RNA/DNA synthesis, and cell cycle inhibition occurred in the presence of FASN inhibition. Subsequently, we observed that FASN inhibition caused metabolic blockade in the rate-limiting step of the oxidative branch of the pentose phosphate pathway (oxPPP) catalyzed by phosphogluconate dehydrogenase (PGDH). Furthermore, we determined that FASN inhibitor treatment resulted in NADPH accumulation and inhibition of PGDH enzyme activity. NADPH is a cofactor utilized by FASN, also a known allosteric inhibitor of PGDH. Through cell-free enzyme assays consisting of FASN and PGDH, we delineated that the PGDH-catalyzed ribulose-5-phosphate synthesis is enhanced in the presence of FASN and is suppressed by increasing concentrations of NADPH. Additionally, we observed that FASN and PGDH were colocalized in the cytosol. The results from these experiments led us to conclude that NADP-NADPH turnover and the reciprocal stimulation of FASN and PGDH catalysis are involved in promoting oxPPP and nucleotide biosynthesis in lymphoma. Finally, a transcriptomic analysis of non-Hodgkin's lymphoma (n = 624) revealed the increased expression of genes associated with metabolic functions interlinked with oxPPP, while the expression of genes participating in oxPPP remained unaltered. Together we conclude that FASN-PGDH enzymatic interactions are involved in enabling oxPPP and nucleotide metabolic dysfunction in lymphoma tumors.

Serum Nonesterified Fatty Acids and Incident Stroke: The CHS.

Background Significant associations between total nonesterified fatty acid (NEFA) concentrations and incident stroke have been reported in some prospective cohort studies. We evaluated the associations between incident stroke and serum concentrations of nonesterified saturated, monounsaturated, polyunsaturated, and trans fatty acids. Methods and Results CHS (Cardiovascular Health Study) participants (N=2028) who were free of stroke at baseline (1996-1997) and had an archived fasting serum sample were included in this study. A total of 35 NEFAs were quantified using gas chromatography. Cox proportional hazards regression models were used to evaluate associations of 5 subclasses (nonesterified saturated, monounsaturated, omega (n)-6 polyunsaturated, n-3 polyunsaturated, and trans fatty acids) of NEFAs and individual NEFAs with incident stroke. Sensitivity analysis was conducted by excluding cases with hemorrhagic stroke (n=45). A total of 338 cases of incident stroke occurred during the median 10.5-year follow-up period. Total n-3 (hazard ratio [HR], 0.77 [95% CI, 0.61-0.97]) and n-6 (HR, 1.32 [95% CI, 1.01-1.73]) subclasses of NEFA were negatively and positively associated with incident stroke, respectively. Among individual NEFAs, dihomo-γ-linolenic acid (20:3n-6) was associated with higher risk (HR, 1.29 [95% CI, 1.02-1.63]), whereas cis-7-hexadecenoic acid (16:1n-9c) and arachidonic acid (20:4n-6) were associated with a lower risk (HR, 0.67 [95% CI, 0.47-0.97]; HR, 0.81 [95% CI. 0.65-1.00], respectively) of incident stroke per standard deviation increment. After the exclusion of cases with hemorrhagic stroke, these associations did not remain significant. Conclusions A total of 2 NEFA subclasses and 3 individual NEFAs were associated with incident stroke. Of these, the NEFA n-3 subclass and dihomo-γ-linolenic acid are diet derived and may be potential biomarkers for total stroke risk.

Serum Non-Esterified Fatty Acids, Carotid Artery Intima-Media Thickness and Flow-Mediated Dilation in Older Adults: The Cardiovascular Health Study (CHS).

Backgrounds and aims: Elevated common carotid artery intima-media thickness (carotid IMT) and diminished flow-mediated dilation (FMD) are early subclinical indicators of atherosclerosis. Serum total non-esterified fatty acid (NEFA) concentrations have been positively associated with subclinical atherosclerosis. The relations between individual NEFA, carotid IMT and FMD have as yet to be assessed. Methods: We investigated the associations between fasting serum individual NEFA, carotid IMT and FMD among Cardiovascular Health Study (CHS) participants with (n = 255 for carotid IMT, 301 for FMD) or without (n = 1314 for carotid IMT, 1462 for FMD) known atherosclerotic cardiovascular disease (ASCVD). Using archived samples (fasting) collected from 1996-1997 (baseline), 35 individual NEFAs were measured using gas chromatography. Carotid IMT and estimated plaque thickness (mean of maximum internal carotid IMT) were determined in 1998-1999. FMD was measured in 1997-1998. Linear regression adjusted by the Holm-Bonferroni method was used to assess relations between individual NEFA, carotid IMT and FMD. Results: In multivariable adjusted linear regression models per SD increment, the non-esterified trans fatty acid conjugated linoleic acid (trans-18:2 CLA) was positively associated with carotid IMT [ß (95% CI): 44.8 (19.2, 70.4), p = 0.025] among participants with, but not without, ASCVD [2.16 (-6.74, 11.5), p = 1.000]. Non-esterified cis-palmitoleic acid (16:1n-7c) was positively associated with FMD [19.7 (8.34, 31.0), p = 0.024] among participants without, but not with ASCVD. No significant associations between NEFAs and estimated plaque thickness were observed. Conclusions: In older adults, serum non-esterified CLA and palmitoleic acid were positively associated with carotid IMT and FMD, respectively, suggesting potential modifiable biomarkers for arteriopathy.

The design and rationale of a multi-center randomized clinical trial comparing one avocado per day to usual diet: The Habitual Diet and Avocado Trial (HAT).

Excess visceral adiposity is associated with increased risk of diabetes and cardiovascular disease. In the U.S. approximately 60% of adults have visceral obesity. Despite high calorie and fat, small, well-controlled clinical studies suggest that avocado consumption has favorable effects on body weight and visceral adiposity. Additionally, short-term studies also suggest that consuming avocados increases satiety, hence, may decrease overall energy intake. The Habitual Diet and Avocado Trial HAT is a multi-center, randomized, controlled trial designed to test whether in a large, diverse cohort providing one avocado per day for consumption for six months compared to a habitual diet essentially devoid of avocados, will result in a decrease in visceral adiposity as measured by magnetic resonance imaging (MRI) in individuals with an increased waist circumference (WC). Additional outcome measures include hepatic lipid content, plasma lipid profiles, blood pressure and high sensitivity C-reactive protein. Inclusion criteria were increased WC and not currently eating more than two avocados per month. Major exclusion criteria were not eating or being allergic to avocados, and not willing or able to undergo MRI scans. From June 27, 2018 to March 4, 2020, 1008 participants were randomized at 4 clinics. The cohort was 72% women, 53% Non-Hispanic White, and had a mean age of 50 years. Follow-up was completed in October 2020 when 936 participants had final MRI scans. HAT will provide information on the effects of avocado consumption on visceral fat adiposity and cardiometabolic disease risk in a diverse sample of participants.

Carotenoid-Rich Brain Nutrient Pattern Is Positively Correlated With Higher Cognition and Lower Depression in the Oldest Old With No Dementia.

Background: Healthy dietary patterns are related to better cognitive health in aging populations. While levels of individual nutrients in neural tissues are individually associated with cognitive function, the investigation of nutrient patterns in human brain tissue has not been conducted. Methods: Brain tissues were acquired from frontal and temporal cortices of 47 centenarians from the Georgia Centenarian Study. Fat-soluble nutrients (carotenoids, vitamins A, E, K, and fatty acids [FA]) were measured and averaged from the two brain regions. Nutrient patterns were constructed using principal component analysis. Cognitive composite scores were constructed from cognitive assessment from the time point closest to death. Dementia status was rated by Global Deterioration Scale (GDS). Pearson's correlation coefficients between NP scores and cognitive composite scores were calculated controlling for sex, education, hypertension, diabetes, and APOE ε4 allele. Result: Among non-demented subjects (GDS = 1-3, n = 23), a nutrient pattern higher in carotenoids was consistently associated with better performance on global cognition (r = 0.38, p = 0.070), memory (r = 0.38, p = 0.073), language (r = 0.42, p = 0.046), and lower depression (r = -0.40, p = 0.090). The findings were confirmed with univariate analysis. Conclusion: Both multivariate and univariate analyses demonstrate that brain nutrient pattern explained mainly by carotenoid concentrations is correlated with cognitive function among subjects who had no dementia. Investigation of their synergistic roles on the prevention of age-related cognitive impairment remains to be performed.

Associations of Serum Nonesterified Fatty Acids With Coronary Heart Disease Mortality and Nonfatal Myocardial Infarction: The CHS (Cardiovascular Health Study) Cohort.

Background Significant associations have been reported between serum total nonesterified fatty acid (NEFA) concentrations and coronary heart disease (CHD) mortality and incident nonfatal myocardial infarction (MI) in some prospective cohort studies. Little is known about whether individual or subclasses (saturated, polyunsaturated [n-6 and n-3], and trans fatty acids) of serum NEFAs relate to CHD mortality and nonfatal MI. Methods and Results CHS (Cardiovascular Health Study) participants (N=1681) who had no history of MI, angina, or revascularization or were free of MI at baseline (1996-1997) were included. NEFAs were quantified using gas chromatography. Cox regression analysis was used to evaluate associations of 5 subclasses and individual NEFAs with CHD composite (CHD mortality and nonfatal MI), CHD mortality, and incident nonfatal MI. During a median follow-up of 11.7 years, 266 cases of CHD death and 271 cases of nonfatal MI occurred. In the fully adjusted model, no significant associations were identified between individual NEFA and CHD composite. Exploratory analyses indicated that lauric acid (12:0) was negatively associated (hazard ratio [HR], 0.76; 95% CI, 0.59-0.98; P=0.0328) and dihomo-γ-linolenic acid (20:3n-6) was positively associated with CHD mortality (HR, 1.34; 95% CI, 1.02-1.76; P=0.0351). Elaidic acid (18:1n-7t) was positively associated with incident nonfatal MI (HR, 1.46; 95% CI, 1.01-2.12; P=0.0445). No significant associations were observed for NEFA subclass and any outcomes. Conclusions In CHS participants, 2 NEFAs, dihomo-γ-linolenic and elaidic acids, were positively associated with CHD mortality and nonfatal MI, respectively, suggesting potential susceptibility biomarkers for risks of CHD mortality and nonfatal MI.

Serum Individual Nonesterified Fatty Acids and Risk of Heart Failure in Older Adults.

BACKGROUND: Heart failure (HF) is highly prevalent among older adults and is associated with high costs. Although serum total nonesterified fatty acids (NEFAs) have been positively associated with HF risk, the contribution of each individual NEFA to HF risk has not been examined. OBJECTIVE: The aim of this study was to examine the association of individual fasting NEFAs with HF risk in older adults. METHODS: In this prospective cohort study of older adults, we measured 35 individual NEFAs in 2,140 participants of the Cardiovascular Health Study using gas chromatography. HF was ascertained using review of medical records by an endpoint committee. RESULTS: The mean age was 77.7 ± 4.4 years, and 38.8% were male. During a median follow-up of 9.7 (maximum 19.0) years, 655 new cases of HF occurred. In a multivariable Cox regression model controlling for demographic and anthropometric variables, field center, education, serum albumin, glomerular filtration rate, physical activity, alcohol consumption, smoking, hormone replacement therapy, unintentional weight loss, and all other measured NEFAs, we observed inverse associations (HR [95% CI] per standard deviation) of nonesterified pentadecanoic (15:0) (0.73 [0.57-0.94]), γ-linolenic acid (GLA) (0.87 [0.75-1.00]), and docosahexaenoic acid (DHA) (0.73 [0.61-0.88]) acids with HF, and positive associations of nonesterified stearic (18:0) (1.30 [1.04-1.63]) and nervonic (24:1n-9) (1.17 [1.06-1.29]) acids with HF. CONCLUSION: Our data are consistent with a higher risk of HF with nonesterified stearic and nervonic acids and a lower risk with nonesterified 15:0, GLA, and DHA in older adults. If confirmed in other studies, specific NEFAs may provide new targets for HF prevention.

Western and heart healthy dietary patterns differentially affect the expression of genes associated with lipid metabolism, interferon signaling and inflammation in the jejunum of Ossabaw pigs.

Diet quality and statin therapy are established modulators of coronary artery disease (CAD) progression, but their effect on the gastrointestinal tract and subsequent sequelae that could affect CAD progression are relatively unexplored. To address this gap, Ossabaw pigs (N = 32) were randomly assigned to receive isocaloric amounts of a Western-type diet (WD; high in saturated fat, refined carbohydrate, and cholesterol, and low in fiber) or a heart healthy-type diet (HHD; high in unsaturated fat, whole grains, fruits and vegetables, supplemented with fish oil, and low in cholesterol), with or without atorvastatin, for 6 months. At the end of the study, RNA sequencing with 100 base pair single end reads on NextSeq 500 platform was conducted in isolated pig jejunal mucosa. A two-factor edgeR analysis revealed that the dietary patterns resulted in three differentially expressed genes related to lipid metabolism (SCD, FADS1, and SQLE). The expression of these genes was associated with cardiometabolic risk factors and atherosclerotic lesion severity. Subsequent gene enrichment analysis indicated the WD, compared to the HHD, resulted in higher interferon signaling and inflammation, with some of these genes being significantly associated with serum TNF-α and/or hsCRP concentrations, but not atherosclerotic lesion severity. No significant effect of atorvastatin therapy on gene expression, nor its interaction with dietary patterns, was identified. In conclusion, Western and heart healthy-type dietary patterns differentially affect the expression of genes associated with lipid metabolism, interferon signaling, and inflammation in the jejunum of Ossabaw pigs.