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BACKGROUND: Plasma apolipoprotein B (apo B) and VLDL and LDL with apolipoprotein C-III (apo C-III) are independent risk factors for cardiovascular disease (CVD). Dietary intake affects lipoprotein concentration and composition related to those apolipoproteins. OBJECTIVE: We studied differences in apo B lipoproteins with and without apo C-III after 3 healthy diets based on the Dietary Approaches to Stop Hypertension Trial diet. DESIGN: Healthy participants (n = 162) were fed each of 3 healthy diets for 6 wk in a crossover design. Diets differed by emphasis of either carbohydrate (Carb), unsaturated fat (Unsat), or protein (Prot). Blood was collected at baseline and after diets for analysis. RESULTS: Compared with the Carb diet, the Prot diet reduced plasma apo B and triglycerides in VLDL with apo C-III (16%, P = 0.07; 11%, P = 0.05, respectively) and apo B in LDL with apo C-III (16%, P = 0.04). Compared with the Unsat diet, the Prot diet reduced triglycerides in VLDL with apo C-III (16%, P = 0.02). Compared with baseline (subjects' usual diet was higher in saturated fat), the Prot diet reduced apo B in LDL with apo C-III (11%, P = 0.05), and all 3 diets reduced plasma total apo B (6-10%, P < 0.05) and apo B in the major type of LDL, LDL without apo C-III (8-10%, P < 0.01). All 3 diets reduced the ratio of apo C-III to apo E in VLDL. CONCLUSIONS: Substituting protein for carbohydrate in the context of a healthy dietary pattern reduced atherogenic apo C-III-containing LDL and its precursor, apo C-III-containing VLDL, resulting in the most favorable profile of apo B lipoproteins. In addition, compared with a typical high-saturated fat diet, healthy diets that emphasize carbohydrate, protein, or unsaturated fat reduce plasma total and LDL apo B and produce a lower more metabolically favorable ratio of apo C-III to apo E. Copyright © 2008 American Society for Nutrition [ABSTRACT FROM AUTHOR]

Aims/hypothesis: A type 2 diabetes-risk-increasing variant, MTNR1B (melatonin receptor 1B) rs10830963, regulates the circadian function and may influence the variability in metabolic responses to dietary carbohydrates. We investigated whether the effects of carbohydrate quantity and dietary glycaemic index (GI) on glycaemic response during OGTTs varied by the risk G allele of MTNR1B-rs10830963., Methods: This study included participants (n=150) of a randomised crossover-controlled feeding trial of four diets with high/low GI levels and high/low carbohydrate content for 5 weeks. The MTNR1B-rs10830963 (C/G) variant was genotyped. Glucose response during 2 h OGTT was measured at baseline and the end of each diet intervention., Results: Among the four study diets, carrying the risk G allele (CG/GG vs CC genotype) of MTNR1B-rs10830963 was associated with the largest AUC of glucose during 2 h OGTT after consuming a high-carbohydrate/high-GI diet (β 134.32 [SE 45.69] mmol/l × min; p=0.004). The risk G-allele carriers showed greater increment of glucose during 0-60 min (β 1.26 [0.47] mmol/l; p=0.008) or 0-90 min (β 1.10 [0.50] mmol/l; p=0.028) after the high-carbohydrate/high-GI diet intervention, but not after consuming the other three diets. At high carbohydrate content, reducing GI levels decreased 60 min post-OGTT glucose (mean -0.67 [95% CI: -1.18, -0.17] mmol/l) and the increment of glucose during 0-60 min (mean -1.00 [95% CI: -1.67, -0.33] mmol/l) and 0-90 min, particularly in the risk G-allele carriers (p interaction <0.05 for all)., Conclusions/interpretation: Our study shows that carrying the risk G allele of MTNR1B-rs10830963 is associated with greater glycaemic responses after consuming a diet with high carbohydrates and high GI levels. Reducing GI in a high-carbohydrate diet may decrease post-OGTT glucose concentrations among the risk G-allele carriers., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Humans spend much of the day in the postprandial state. However, most research and clinical guidelines on plasma lipids pertain to blood drawn after a 12-hour fast. We aimed to study the metabolic differences of apoB lipoproteins between the fasting and postprandial states., Methods: We investigated plasma apoB metabolism using stable isotope tracers in 12 adult volunteers under fasting and continuous postprandial conditions in a randomized crossover study. We determined the metabolism of apoB in multiple lipoprotein subfractions, including light and dense VLDLs (very-low-density lipoproteins), IDLs (intermediate-density lipoproteins), and light and dense LDLs (low-density lipoproteins) that do or do not contain apoE or apoC3., Results: A major feature of the postprandial state is 50% lower secretion rate of triglyceride-rich lipoproteins and concurrent slowdown of their catabolism in circulation, as shown by 34% to 55% lower rate constants for the metabolic pathways of conversion by lipolysis from larger to smaller lipoproteins and direct clearance of lipoproteins from the circulation. In addition, the secretion pattern of apoB lipoprotein phenotypes was shifted from particles containing apoE and apoC3 in the fasting state to those without either protein in the postprandial state., Conclusions: Overall, during the fasting state, hepatic apoB lipoprotein metabolism is activated, characterized by increased production, transport, and clearance. After food intake, endogenous apoB lipoprotein metabolism is globally reduced as appropriate to balance dietary input to maintain the supply of energy to peripheral tissues., Competing Interests: Disclosures J.D. Furtado is currently an employee of and holds stock/stock options in Biogen. Additionally, the studies performed in the current article are not related to C. Zheng’s current affiliation at National Resilience, Inc, or C. Khoo’s current affiliation at Ocean Spray Cranberries, Inc. The other authors report no conflicts.

High-density lipoproteins (HDLs) are promising targets for predicting and treating atherosclerotic cardiovascular disease (ASCVD), as they mediate removal of excess cholesterol from lipid-laden macrophages that accumulate in the vasculature. This functional property of HDLs, termed cholesterol efflux capacity (CEC), is inversely associated with ASCVD. HDLs are compositionally diverse, associating with >250 different proteins, but their relative contribution to CEC remains poorly understood. Our goal was to identify and define key HDL-associated proteins that modulate CEC in humans. The proteomic signature of plasma HDL was quantified in 36 individuals in the multi-ethnic population-based Dallas Heart Study (DHS) cohort that exhibited persistent extremely high (>=90th%) or extremely low CEC (<=10th%) over 15 years. Levels of apolipoprotein (Apo)A-I associated ApoC-II, ApoC-III, and ApoA-IV were differentially correlated with CEC in high (r = 0.49, 0.41, and -0.21 respectively) and low (r = -0.46, -0.41, and 0.66 respectively) CEC groups (p for heterogeneity (pHet) = 0.03, 0.04, and 0.003 respectively). Further, we observed that levels of ApoA-I with ApoC-III, complement C3 (CO3), ApoE, and plasminogen (PLMG) were inversely associated with CEC in individuals within the low CEC group (r = -0.11 to -0.25 for subspecies with these proteins vs. r = 0.58 to 0.65 for subspecies lacking these proteins; p < 0.05 for heterogeneity). These findings suggest that enrichment of specific proteins on HDLs and, thus, different subspecies of HDLs, differentially modulate the removal of cholesterol from the vasculature.

Background and Objectives: Polyunsaturated fatty acids (PUFAs) have neuroprotective and anti-inflammatory effects and could be beneficial in amyotrophic lateral sclerosis (ALS). Higher dietary intake and plasma levels of PUFAs, in particular alpha-linolenic acid (ALA), have been associated with a lower risk of ALS in large epidemiologic cohort studies, but data on disease progression in patients with ALS are sparse. We examined whether plasma levels of ALA and other PUFAs contributed to predicting survival time and functional decline in patients with ALS., Methods: We conducted a study among participants in the EMPOWER clinical trial who had plasma samples collected at the time of randomization that were available for fatty acid analyses. Plasma fatty acids were measured using gas chromatography. We used Cox proportional hazards models and linear regression to evaluate the association of individual fatty acids with risk of death and joint rank test score of functional decline and survival., Results: Fatty acid analyses were conducted in 449 participants. The mean (SD) age of these participants at baseline was 57.5 (10.7) years, and 293 (65.3%) were men; 126 (28.1%) died during follow-up. Higher ALA levels were associated with lower risk of death (age-adjusted and sex-adjusted hazard ratio comparing highest vs lowest quartile 0.50, 95% CI 0.29-0.86, p -trend = 0.041) and higher joint rank test score (difference in score according to 1 SD increase 10.7, 95% CI 0.2-21.1, p = 0.045), consistent with a slower functional decline. The estimates remained similar in analyses adjusted for body mass index, race/ethnicity, symptom duration, site of onset, riluzole use, family history of ALS, predicted upright slow vital capacity, and treatment group. Higher levels of the n-3 fatty acid eicosapentaenoic acid and the n-6 fatty acid linoleic acid were associated with a lower risk of death during follow-up., Discussion: Higher levels of ALA were associated with longer survival and slower functional decline in patients with ALS. These results suggest that ALA may have a favorable effect on disease progression in patients with ALS., (© 2023 American Academy of Neurology.)

Background: Nonesterified fatty acids (NEFAs) play key roles in the pathophysiology of diabetes and cardiovascular disease., Objectives: We sought to determine whether macronutrient content differences affect NEFA concentrations in a randomized crossover trial., Methods: Total NEFAs were measured from postintervention specimens of participants in the OMNI Heart trial (Optimal Macronutrient Intake Trial to Prevent Heart Disease). OMNI Heart compared 3 healthful diets to evaluate their effect on systolic blood pressure and serum LDL cholesterol: carbohydrate-rich diet (58% carbohydrate); protein-rich diet (25% protein), about half from plant sources; and a diet rich in unsaturated fatty acids (21% unsaturated fat), predominantly monounsaturated. The trial included 164 participants who consumed the 3 diets, each for 6 wk. Data were analyzed from the 156 participants with unthawed serum available from the week 6 visit for all diet periods. We used ANCOVA and generalized estimating equations (GEEs) to compare serum NEFA concentrations across the 3 diet periods., Results: The mean ± SD age of study participants was 52.9 ± 10.6 y and mean BMI was 30.3 ± 6.1 kg/m2. Fifty-five percent of participants were women and 55% were African American. Comparisons of adjusted mean serum NEFA concentrations after each diet intervention identified no statistically significant differences (58% carbohydrate: 0.144 ± 0.083 mEq/L; 25% protein: 0.143 ± 0.076 mEq/L; 21% unsaturated fat: 0.143 ± 0.084 mEq/L; ANCOVA, P = 0.99). Likewise, we observed no significant serum NEFA concentration difference by diet in adjusted GEE models. In adjusted models, serum NEFA concentrations were positively associated, as anticipated, with female sex and higher BMI., Conclusions: In this randomized crossover trial, we observed nearly identical serum NEFA concentrations after each of 3 healthful diets, regardless of macronutrient content., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Alcohol consumption increases circulating high-density lipoprotein cholesterol (HDL-C), but HDL protein cargo may better reflect HDL function. This study examined the associations between alcohol intake and HDL subspecies containing or lacking apoC3, apoE, and apoJ in a well-phenotyped cohort. We performed a cross-sectional analysis of 2092 Cardiovascular Health Study participants aged 70 or older with HDL subspecies measured in stored specimens from 1998 to 1999. Associations between alcohol intake and apoA1 defined HDL subspecies lacking or containing apoC3, apoE, and apoJ, and circulating levels of total apoA1, apoC3, apoE, and apoJ were examined. HDL subspecies lacking and containing apoC3, apoE, and apoJ were all positively associated with alcohol intake, with ∼1% per additional drink per week or ∼7% per additional drink per day (subspecies without the apolipoproteins, P ≤ 2 × 10 -9 , subspecies with the apolipoproteins, P ≤ 3 × 10 -5 ). Total apoA1 was also directly associated with alcohol consumption, with a 1% increase per additional drink per week (P = 1 × 10 -14 ). Total apoC3 blood levels were 0.5% higher per additional drink per week (P = 0.01), but the association was driven by a few heavily drinking men. Alcohol intake was positively associated with HDL subspecies lacking and containing apoC3, apoE, or apoJ, and with total plasma apoA1. ApoC3 was directly, albeit not as robustly associated with alcohol intake. HDL protein cargo is crucial for its anti-atherosclerotic functions, but it remains to be determined whether HDL subspecies play a role in the putative association between limited alcohol intake and lower risk of coronary heart disease., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

HDL-cholesterol is associated with reduced risk of cardiovascular disease, and is used in clinical practice for risk stratification. HDL is composed of many protein-defined subspecies that each comprises just a few percent of the total, some associated with lower and some with higher risk of CVD. HDL that contains apoC3 or apoE are subspecies that have opposing actions on HDL reverse cholesterol transport and opposing associations with risk of future CVD, apoC3 adverse and apoE beneficial. In addition to coronary heart disease, HDL that contains apoC3 is associated with risk of future type 2 diabetes and insulin resistance; ischemic stroke and cerebral infarction; dementia and the deposition of beta-amyloid in the brain. HDL that contains apoE and apoE itself are associated with lower risk of dementia. Other HDL subspecies that contain complement C3, alpha-2 macroglobulin, plasminogen, or haptoglobin are associated with higher future risk of coronary heart disease, whereas others such as HDL that contains apoC1 are associated with lower risk. At this time, these findings provide improved understanding of the multifaceted HDL system to better determine risk and targeting of therapy for the most prevalent chronic lifestyle diseases in our society., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Context: Selective androgen receptor modulators (SARMs), because of their preferential muscle vs prostate selectivity, are being developed for muscle-wasting conditions. Oral SARMs suppress high-density lipoprotein cholesterol (HDL-C) but their effects on functional capacity and atherogenic potential of HDL particles are unknown., Objective: To determine the effects of an oral SARM (OPK-88004) on cholesterol efflux capacity, HDL particle number and size, apolipoprotein particle number and size and HDL subspecies., Methods: We measured cholesterol efflux capacity (CEC); HDL particle number and size; APOB; APOA1; and protein-defined HDL subspecies associated with coronary heart disease (CHD) risk in men, who had undergone prostatectomy for low-grade prostate cancer during 12-week treatment with placebo or 1, 5, or 15 mg of an oral SARM (OPK-88004)., Results: SARM significantly suppressed HDL-C ( P  < .001) but HDL particle size did not change significantly. SARM had minimal effect on CEC of HDL particles (change + 0.016, -0.036, +0.070, and -0.048%/µmol-HDL/L -1 at 0, 1, 5, and 15 mg SARM, P  = .045). SARM treatment suppressed APOAI ( P  < .001) but not APOB ( P  = .077), and reduced APOA1 in HDL subspecies associated with increased (subspecies containing α2-macroglobulin, complement C3, or plasminogen) as well as decreased (subspecies containing APOC1 or APOE) CHD risk; relative proportions of APOA1 in these HDL subspecies did not change. SARM increased hepatic triacylglycerol lipase (HTGL) ( P  < .001)., Conclusion: SARM treatment suppressed HDL-C but had minimal effect on its size or cholesterol efflux function. SARM reduced APOA1 in HDL subspecies associated with increased as well as decreased CHD risk. SARM-induced increase in HTGL could contribute to HDL-C suppression. These data do not support the simplistic notion that SARM-associated suppression of HDL-C is necessarily proatherogenic; randomized trials are needed to determine SARM's effects on cardiovascular events., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: Whether HDL (high-density lipoprotein) is associated with risk of vascular brain injury is unclear. HDL is comprised of many apo (apolipoprotein) species, creating distinct subtypes of HDL., Methods: We utilized sandwich ELISA to determine HDL subspecies from plasma collected in 1998/1999 from 2001 CHS (Cardiovascular Health Study) participants (mean age, 80 years)., Results: In cross-sectional analyses, participants with higher apoA1 in plasma and lower apoE in HDL were less likely to have prevalent covert magnetic resonance imaging-defined infarcts: odds ratio for apoA1 Q4 versus Q1, 0.68 (95% CI, 0.50-0.93), and odds ratio for apoE Q4 versus Q1, 1.36 (95% CI, 1.01-1.84). Similarly, apoA1 in the subspecies of HDL that lacked apoC3, apoJ, or apoE was inversely related to covert infarcts, and apoE in the subspecies of HDL that lacked apoC3 or apoJ was directly related to covert infarcts in prospective analyses. In contrast, the concentrations of apoA1 and apoE in the complementary subspecies of HDL that contained these apos were unrelated to covert infarcts. Patterns of associations between incident overt ischemic stroke and apoA1, apoE, and apoA1 and apoE in subspecies of HDL were similar to those observed for covert infarcts but less pronounced., Conclusions: This study highlights HDL subspecies defined by apo content as relevant biomarkers of covert and overt vascular brain injury.

Rationale: The relationship between many fatty acids and respiratory outcomes remains unclear, especially with regard to mechanistic actions. Altered regulation of the process of lung repair is a key feature of chronic lung disease and may impact the potential for pulmonary rehabilitation, but underlying mechanisms of lung repair following injury or inflammation are not well-studied. The epidermal growth factor receptor agonist amphiregulin (AREG) has been demonstrated to promote lung repair following occupational dust exposure in animals. Studies suggest the polyunsaturated fatty acid (PUFA) docosahexaenoic acid (DHA) may enhance the production of AREG. The objective of this study was to determine the relationship between fatty acids and lung function in a population of veterans and determine if fatty acid status is associated with concentrations of AREG., Materials and Methods: Data were collected from a cross-sectional study of veterans within the Nebraska-Western Iowa Health Care System. Whole blood assays were performed to quantify AREG concentrations via a commercially available ELISA kit. Fatty acids from plasma samples from the same patients were measured using gas-liquid chromatography. Intakes of fatty acids were quantified with a validated food frequency questionnaire. Linear regression models were used to determine whether plasma fatty acids or intakes of fatty acids predicted lung function or AREG concentrations. A p < 0.05 was considered statistically significant., Results: Ninety participants were included in this analysis. In fully adjusted models, plasma fatty acids were associated with AREG production, including the PUFA eicosapentaenoic acid (EPA) (β = 0.33, p = 0.03) and the monounsaturated fatty acid octadecenoic acid: (β = -0.56, p = 0.02). The omega-3 PUFA docosapentaenoic acid (DPA) was positively associated with lung function (β = 0.28, p = 0.01; β = 26.5, p = 0.05 for FEV 1 /FVC ratio and FEV 1 % predicted, respectively), as were the omega-6 PUFAs eicosadienoic acid (β = 1.13, p < 0.001; β = 91.2, p = 0.005 for FEV 1 /FVC ratio and FEV 1 % predicted, respectively) and docosadienoic acid (β = 0.29, p = 0.01 for FEV 1 /FVC ratio). Plasma monounsaturated and saturated fatty acids were inversely associated with lung function., Conclusion: Opposing anti- and pro-inflammatory properties of different fatty acids may be associated with lung function in this population, in part by regulating AREG induction., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hanson, Ponce, Isaak, Heires, Nordgren, Wichman, Furtado, LeVan and Romberger.)

Objective: Plasma total HDL (high-density lipoprotein) is a heterogeneous mix of many protein-based subspecies whose functions and associations with coronary heart disease vary. We hypothesize that increasing HDL by CETP (cholesteryl ester transfer protein) inhibition failed to reduce cardiovascular disease risk, in part, because it increased dysfunctional subspecies associated with higher risk such as HDL that contains apoC3. Approach and Results: We studied participants in 2 randomized, double-blind, placebo-controlled trials of a CETP inhibitor on a background of atorvastatin treatment: ACCENTUATE (The Addition of Evacetrapib to Atorvastatin Compared to Placebo, High Intensity Atorvastatin, and Atorvastatin With Ezetimibe to Evaluate LDL-C Lowering in Patients With Primary Hyperlipidemia; 130 mg evacetrapib; n=126) and ILLUMINATE (Phase 3 Multi Center, Double Blind, Randomized, Parallel Group Evaluation of the Fixed Combination Torcetrapib/Atorvastatin, Administered Orally, Once Daily [Qd], Compared With Atorvastatin Alone, on the Occurrence of Major Cardiovascular Events in Subjects With Coronary Heart Disease or Risk Equivalents; 60 mg torcetrapib; n=80). We measured the concentration of apoA1 in total plasma and 17 protein-based HDL subspecies at baseline and 3 months. Both CETP inhibitors increased apoA1 in HDL that contains apoC3 the most of all HDL subspecies (median placebo-adjusted percent increase: evacetrapib 99% and torcetrapib 50%). They also increased apoA1 in other HDL subspecies associated with higher coronary heart disease risk such as those involved in inflammation (α-2-macroglobulin and complement C3) or hemostasis (plasminogen), and in HDL that contains both apoE and apoC3, a complex subspecies associated with higher coronary heart disease risk. ApoA1 in HDL that contains apoC1, associated with lower risk, increased 71% and 40%, respectively. Only HDL that contains apoL1 showed no response to either drug., Conclusions: CETP inhibitors evacetrapib and torcetrapib increase apoA1 in HDL subspecies that contain apoC3 and other HDL subspecies associated with higher risk of coronary heart disease. Subspecies-specific effects shift HDL subspecies concentrations toward a profile associated with higher risk, which may contribute to lack of clinical benefit from raising HDL by pharmaceutical CETP inhibition.

Introduction: Plant-based diets rich in fruits and vegetables have been associated with lower risk of dementia, but the specific role of antioxidants, a key class of bioactive phytochemicals, has not been well ascertained., Methods: We measured antioxidants in a case-cohort study nested within the Ginkgo Evaluation of Memory Study. We included 996 randomly selected participants and 521 participants who developed dementia, of which 351 were diagnosed with Alzheimer's disease (AD) during a median of 5.9 years of follow-up. We measured baseline plasma levels of retinol, α-, and γ-tocopherol; zeaxanthin and lutein (combined); beta-cryptoxanthin; cis-lycopene; trans-lycopene; α-carotene; and trans-β-carotene by organic phase extraction followed by chromatographic analysis and related these to neurologist-adjudicated risks of all-cause dementia and AD., Results: Plasma retinol, α-, and γ-tocopherol, and carotenoids were not significantly related to risk of dementia or AD. Associations were not significant upon Bonferroni correction for multiple testing and were consistent within strata of sex, age, apolipoprotein E ε4 genotype, mild cognitive impairment at baseline, and intake of multivitamin, vitamin A or β-carotene, or vitamin E supplements. Higher trans-β-carotene tended to be related to a higher risk of dementia (adjusted hazard ratio [HR] per 1 standard deviation [SD] higher trans-β-carotene: 1.10; 95% confidence interval [CI]: 1.00, 1.20) and α-carotene tended to be associated with higher risk of AD only (adjusted HR per 1 SD higher α-carotene: 1.15; 95% CI: 1.02, 1.29)., Discussion: Plasma antioxidants were not significantly associated with risk of dementia or AD among older adults. Similar studies in younger populations are required to better understand the association between plasma antioxidants and dementia risk., Competing Interests: Dr. DeKosky acknowledges payments as a dementia editor for UpToDate and payments from Acumen, Chair Medical Advisory Board (MAB); Biogen, Chair, DSMB; Cognition Therapeutics, Chair, MAB; Prevail Pharma, Chair, DSMB; Vaccinex, Inc, Chair, DSMB; and payments for his role as associate editor at Neurotherapeutics. Dr. Fitzpatrick acknowledges payments from Bloodm Hurst & O'Reardon, LLP; payments for Pulmonary Specialist‐Health Coach Consultation (PuSHCon) funded by NIH (UCSF); and honoraria as NIA‐S Study Section member. Dr. Lopez acknowledges payments from Biogen and Grifols. Dr. Kuller acknowledges payments from UpToDate for articles on Alzheimer ’s disease. Dr. Mukamal acknowledges grant support unrelated to this project from the US Highbush Blueberry Council, consulting fees from the University of Washington and Wolters Kluwer, payments from The Journal of Internal Medicine, and an advisory role for the University of Pittsburgh (no payments)., (© 2021 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Carotenoids are antioxidant nutrients with the potential to provide protection against oxidative stress. Plasma carotenoid concentrations are lower in newborn infants compared to their mothers; however, limited information is available regarding how concentrations differ by gestational age. The objective of this research is to assess maternal and umbilical cord plasma carotenoid concentrations and maternal-umbilical cord plasma ratios across five groups of birth gestational age. Mother-infant dyads were enrolled at delivery for collection of maternal and umbilical cord blood. Plasma carotenoids were analyzed by HPLC and LC-MS/MS. Birth gestational age was categorized into five groups, and the Kruskal-Wallis test compared carotenoid concentrations and maternal-umbilical cord plasma ratios between these groups. A p -value of < 0.05 was considered statistically significant. 370 mother-infant dyads were included, with most infants delivered at early term (20.3%) or term (64.6%). Though maternal plasma concentrations increased with birth gestational age, we observed less variability in umbilical cord plasma concentrations, thus the maternal-umbilical cord plasma ratio also increased with birth CGA groups for lutein + zeaxanthin ( p = 0.008), β-cryptoxanthin ( p = 0.027), α-carotene ( p = 0.030); β-carotene approached significance ( p = 0.056). Additional research is needed to determine if carotenoid concentrations were physiologic to varying gestational ages or if they were impacted by factors associated with preterm birth.

There is emerging evidence linking fruit and vegetable consumption and cognitive function. However, studies focusing on the nutrients underlying this relationship are lacking. We aim to examine the association between plasma nutrients and cognition in a population at risk for cognitive decline with a suboptimal diet. The Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) trial is a randomized controlled intervention that examines the effects of the MIND diet to prevent cognitive decline. The primary outcome is global cognition. A multivariate linear model was used to investigate the association between blood nutrients and global and/or domain-specific cognition. The model was adjusted for age, sex, education, study site, smoking status, cognitive activities and physical activities. High plasma α-carotene was associated with better global cognition. Participants in the highest tertile of plasma α-carotene had a higher global cognition z score of 0⋅17 when compared with individuals in the lowest tertile ( P 0⋅002). Circulating α-carotene levels were also associated with higher semantic memory scores ( P for trend 0⋅007). Lutein and zeaxanthin (combined) was positively associated with higher semantic memory scores ( P for trend 0⋅009). Our study demonstrated that higher α-carotene levels in blood were associated with higher global cognition scores in a US population at risk for cognitive decline. The higher α-carotene levels in blood reflected greater intakes of fruits, other types of vegetables and lesser intakes of butter and margarine and meat. The higher circulating levels of lutein plus zeaxanthin reflected a dietary pattern with high intakes of fruits, green leafy, other vegetables and cheese, and low consumption of fried foods. Objective nutrient markers in the blood can better characterize dietary intake, which may facilitate the implementation of a tailored dietary intervention for the prevention of cognitive decline., (© The Author(s) 2021.)

Background: Perinatal inflammation adversely affects health. Therefore, aims of this IRB-approved study are: (1) compare inflammatory compounds within and between maternal and umbilical cord blood samples at the time of delivery, (2) assess relationships between inflammatory compounds in maternal and cord blood with birth characteristics/outcomes, and (3) assess relationships between blood and placental fat-soluble nutrients with blood levels of individual inflammatory compounds., Methods: Mother-infant dyads were enrolled (n = 152) for collection of birth data and biological samples of maternal blood, umbilical cord blood, and placental tissue. Nutrient levels included: lutein + zeaxanthin; lycopene; α-, β-carotene; β-cryptoxanthin; retinol; α-, γ-, δ-tocopherol. Inflammatory compounds included: tumor necrosis factor-α, superoxide dismutase, interleukins (IL) 1β, 2, 6, 8, 10., Results: Median inflammatory compound levels were 1.2-2.3 times higher in cord vs. maternal blood, except IL2 (1.3 times lower). Multiple significant correlations existed between maternal vs. infant inflammatory compounds (range of r = 0.22-0.48). While relationships existed with blood nutrient levels, the most significant were identified in placenta where all nutrients (except δ-tocopherol) exhibited relationships with inflammatory compounds. Relationships between anti-inflammatory nutrients and proinflammatory compounds were primarily inverse., Conclusion: Inflammation is strongly correlated between mother-infant dyads. Fat-soluble nutrients have relationships with inflammatory compounds, suggesting nutrition is a modifiable factor., Impact: Mother and newborn inflammation status are strongly interrelated. Levels of fat-soluble nutrients in blood, but especially placenta, are associated with blood levels of proinflammatory and anti-inflammatory compounds in both mother and newborn infant. As fat-soluble nutrient levels are associated with blood inflammatory compounds, nutrition is a modifiable factor to modulate inflammation and improve perinatal outcomes., (© 2020. International Pediatric Research Foundation, Inc.)

Context: High density lipoprotein (HDL) in humans is composed of a heterogeneous group of particles varying in protein composition as well as biological effects., Objective: We investigated the prospective associations between HDL subspecies containing and lacking apolipoprotein (apo) C-III at baseline and insulin sensitivity at year 3., Design, Setting, and Participants: A prospective cohort study of 864 healthy volunteers drawn from the relationship between insulin sensitivity and cardiovascular disease (RISC) study, a multicenter European clinical investigation, whose recruitment initiated in 2002, with a follow-up of 3 years., Main Measures: Insulin sensitivity was estimated from an oral glucose tolerance test at baseline and year 3, and by euglycemic-hyperinsulinemic clamp at baseline only. The apolipoprotein concentrations were measured at baseline by a sandwich enzyme-linked immunosorbent assay (ELISA)-based method., Results: The 2 HDL subspecies demonstrated significantly opposite associations with insulin sensitivity at year 3 (P-heterogeneity = 0.004). The highest quintile of HDL containing apoC-III was associated with a 1.2% reduction in insulin sensitivity (P-trend = 0.02), while the highest quintile of HDL lacking apoC-III was associated with a 1.3% increase (P-trend = 0.01), compared to the lowest quintile. No significant association was observed for total HDL, and very low density lipoprotein (VLDL) and low density lipoprotein (LDL) containing apoC-III. ApoC-III contained in HDL was associated with a decrease in insulin sensitivity even more strongly than plasma total apoC-III., Conclusion: Both HDL containing apoC-III and apoC-III in HDL adversely affect the beneficial properties of HDL on insulin response to glucose. Our results support the potential of HDL-associated apoC-III as a promising target for diabetes prevention and treatment., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Phospholipids are biomarkers of dietary fat intake and metabolism, linked to several cardiometabolic disorders. Few prospective studies have assessed plasma phospholipids in relation to dementia risk and cognitive function., Objectives: We aimed to evaluate the association between a decrease in linoleic acid accompanied with an increase in other fatty acids and cognitive function and dementia risk., Methods: We conducted a case-cohort study nested within the Ginkgo Evaluation of Memory Study. We included 1252 participants, 498 of whom who developed dementia during a mean of 5 y of follow-up. We measured 45 individual plasma phospholipids (as a percentage of total plasma phospholipid fatty acids) by GC and related these to Modified Mini-Mental State Examination (3MSE) scores at baseline and neurologist-adjudicated incidence of all-cause dementia and Alzheimer disease (AD), adjusting for sociodemographic and clinical characteristics., Results: Substitution of 1% of SFAs for 1% of linoleic acid, the predominant polyunsaturated n-6 (ɷ-6) fatty acid, was associated with higher risk of dementia (HR per 1% of SFAs instead of linoleic acid = 1.03; 95% CI: 1.00, 1.07) and a 0.08 point lower 3MSE score at baseline (95% CI: -0.12, -0.03), signifying worse cognitive function. When compared with linoleic acid, we found no associations of total monounsaturated, n-3 polyunsaturated, or trans fatty acids with risk of dementia or AD. However, the substitution of 1% of the marine n-3 PUFA DHA for linoleic acid was associated with lower risk of dementia (HR = 0.86 per 1% of DHA instead of linoleic acid; 95% CI: 0.76, 0.96). These associations were not modified by apolipoprotein E genotype, mild cognitive impairment at baseline, age, or sex., Conclusions: Specific elements of diet may be associated with late-life dementia, a hypothesis that requires formal testing in randomized controlled trials and that represents a possible preventive intervention., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background Plasma omega-3 polyunsaturated fatty acids (ω3-PUFAs) have been shown to be inversely correlated with the risk of cardiovascular death in primary prevention. The risk relationship in the setting of an acute coronary syndrome is less well established. Methods and Results Baseline plasma ω3-PUFA composition (α-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid) was assessed through gas chromatography with flame ionization detection in a case-cohort study involving 203 patients with cardiovascular death, 325 with myocardial infarction, 271 with ventricular tachycardia, and 161 with atrial fibrillation, and a random sample of 1612 event-free subjects as controls from MERLIN-TIMI 36 (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST-Elevation-Acute Coronary Syndrome-Thrombolysis in Myocardial Infarction 36), a trial of patients hospitalized with non-ST-segment-elevation -acute coronary syndrome. After inverse-probability-weighted multivariable adjustment including all traditional risk factors, a higher relative proportion of long-chain ω3-PUFAs (eicosapentaenoic acid, docosapentaenoic acid, docosahexaenoic acid) were associated with 18% lower odds of cardiovascular death (adjusted [adj] odds ratio [OR] per 1 SD, 0.82; 95% CI, 0.68-0.98) that was primarily driven by 27% lower odds of sudden cardiac death (adj OR per 1 SD, 0.73; 95% CI, 0.55-0.97). Long-chain ω3-PUFA levels in the top quartile were associated with 51% lower odds of cardiovascular death (adj OR 0.49; 95% CI, 0.27-0.86) and 63% lower odds of sudden cardiac death (adj OR, 0.37; 95% CI, 0.16-0.56). An attenuated relationship was seen for α-linolenic acid and subsequent odds of cardiovascular (adj OR, 0.92; 95% CI, 0.74-1.14) and sudden cardiac death (adj OR, 0.91; 95% CI, 0.67-1.25). No significant relationship was observed between any ω3-PUFAs and the odds of cardiovascular death unrelated to sudden cardiac death, myocardial infarction, atrial fibrillation, or early post-acute coronary syndrome ventricular tachycardia. Conclusions In patients after non-ST-segment-elevation-acute coronary syndrome, plasma long-chain ω3-PUFAs are inversely associated with lower odds of sudden cardiac death, independent of traditional risk factors and lipids. Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT00099788.

Alzheimer's dementia (AD) is the sixth leading cause of death in the U.S., with an estimated $305 billion cost of care in 2020. Currently there are no cures or therapies to ameliorate the disease progression and symptoms. Growing evidence links a diet characterized by high antioxidant components with benefits to cognitive function, which is indicative of the preventative potential of dietary inteventions. The Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) study is a 3-year, multicenter, randomized controlled trial to test the effects of the MIND diet on cognitive function in 604 individuals at risk for AD. Men and women ages 65 to 84 years were recruited. Eligible participants were randomized to either the MIND diet with mild caloric restriction or their usual diet with mild caloric restriction. Cognitive assessments, medical history, blood pressure, anthropometric measurements, and blood and urine sample collections will be taken at baseline and follow-up visits. MRI scans will be completed on approximately half of the enrolled participants at the start and end of the study. Unique features of the MIND study include: 1) a dietary pattern, rather than single nutrient or food, tested in an at-risk population; 2) foods featured as key components of the MIND diet (i.e. extra-virgin olive oil, blueberries, and nuts) provided for participants; and 3) MRI scans of brain structure and volume that may provide potential mechanistic evidence on the effects of the diet. Results from the study will be crucial to the development of dietary guidelines for the prevention of AD., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: To assess whether pre-diagnostic lipid levels are associated with Amyotrophic lateral sclerosis (ALS) risk. Methods: We conducted a matched case-control study nested in five large prospective US cohorts (the Nurses' Health Study, the Health Professionals Follow-up Study, the Cancer Prevention Study II Nutrition Cohort, the Multiethnic Cohort Study, and the Women's Health Initiative), and identified 275 individuals who developed ALS during follow-up and had provided blood samples before disease diagnosis. For each ALS case, we randomly selected two controls who were alive at the time of the case diagnosis and matched on cohort, birth year (±1 year), sex, race/ethnicity, fasting status, and time of blood draw. We measured total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG) levels in the plasma samples, and used conditional logistic regression to estimate associations between lipid levels and ALS risk. Results: Higher levels of HDL-C were associated with higher ALS risk in an analysis adjusted for the matching factors (risk ratio [RR] Q4 vs. Q1: 1.78, 95% confidence interval [CI]: 1.18-2.69, p trend: 0.007). The estimate remained similar in a multivariable analysis additionally adjusted for body mass index, physical activity, smoking, alcohol intake, plasma urate levels, and use of cholesterol-lowering drugs (RR Q4 vs. Q1: 1.71, 95% CI: 1.07-2.73, p trend: 0.02). Plasma levels of TC, LDL-C, and TG were not associated with ALS risk. Conclusions: Higher pre-diagnostic HDL-C levels, but not levels of other lipids, were associated with a higher risk of ALS.

Objective: HDL (high-density lipoprotein) contains functional proteins that define single subspecies, each comprising 1% to 12% of the total HDL. We studied the differential association with coronary heart disease (CHD) of 15 such subspecies. Approach and Results: We measured plasma apoA1 (apolipoprotein A1) concentrations of 15 protein-defined HDL subspecies in 4 US-based prospective studies. Among participants without CVD at baseline, 932 developed CHD during 10 to 25 years. They were matched 1:1 to controls who did not experience CHD. In each cohort, hazard ratios for each subspecies were computed by conditional logistic regression and combined by meta-analysis. Higher levels of HDL subspecies containing alpha-2 macroglobulin, CoC3 (complement C3), HP (haptoglobin), or PLMG (plasminogen) were associated with higher relative risk compared with the HDL counterpart lacking the defining protein (hazard ratio range, 0.96-1.11 per 1 SD increase versus 0.73-0.81, respectively; P for heterogeneity <0.05). In contrast, HDL containing apoC1 or apoE were associated with lower relative risk compared with the counterpart (hazard ratio, 0.74; P =0.002 and 0.77, P =0.001, respectively)., Conclusions: Several subspecies of HDL defined by single proteins that are involved in thrombosis, inflammation, immunity, and lipid metabolism are found in small fractions of total HDL and are associated with higher relative risk of CHD compared with HDL that lacks the defining protein. In contrast, HDL containing apoC1 or apoE are robustly associated with lower risk. The balance between beneficial and harmful subspecies in a person's HDL sample may determine the risk of CHD pertaining to HDL and paths to treatment.

Importance: The ε4 allele of the apolipoprotein E (APOE) gene and lower apolipoprotein E (apoE) protein levels in plasma are risk factors for Alzheimer disease, but the underlying biological mechanisms are not fully understood. Half of plasma apoE circulates on high-density lipoproteins (HDLs). Higher apoE levels in plasma HDL were previously found to be associated with lower coronary heart disease risk, but the coexistence of another apolipoprotein, apoC3, modified this lower risk., Objective: To investigate associations between the presence of apoE in different lipoproteins with cognitive function, particularly the risk of dementia., Design, Setting, and Participants: This prospective case-cohort study embedded in the Ginkgo Evaluation of Memory Study (2000-2008) analyzed data from 1351 community-dwelling participants 74 years and older. Of this group, 995 participants were free of dementia at baseline (recruited from September 2000 to June 2002) and 521 participants were diagnosed with incident dementia during follow-up until 2008. Data analysis was performed from January 2018 to December 2019., Exposures: Enzyme-linked immunosorbent assay-measured concentration of apoE in whole plasma, HDL-depleted plasma (non-HDL), HDL, and HDL subspecies that contain or lack apoC3 or apoJ., Main Outcomes and Measures: Adjusted hazard ratios for risk of dementia and Alzheimer disease during follow-up and adjusted differences (β coefficients) in Alzheimer Disease Assessment-Cognitive Subscale (ADAS-cog) and Modified Mini-Mental State Examination scores at baseline., Results: Among 1351 participants, the median (interquartile range) age was 78 (76-81) years; 639 (47.3%) were women. The median (interquartile range) follow-up time was 5.9 (3.7-6.5) years. Higher whole plasma apoE levels and higher apoE levels in HDL were associated with better cognitive function assessed by ADAS-cog (whole plasma, β coefficient, -0.15; 95% CI, -0.24 to -0.06; HDL, β coefficient, -0.20; 95% CI, -0.30 to -0.10) but were unassociated with dementia or Alzheimer disease risk. When separated by apoC3, a higher apoE level in HDL that lacks apoC3 was associated with better cognitive function (ADAS-cog per SD: β coefficient, 0.17; 95% CI, -0.27 to -0.07; Modified Mini-Mental State Examination score per SD: β coefficient, 0.25; 95% CI, 0.07 to 0.42) and lower risk of dementia (hazard ratio per SD, 0.86; 95% CI, 0.76 to 0.99). In contrast, apoE levels in HDL that contains apoC3 were unassociated with any of these outcomes., Conclusions and Relevance: In a prospective cohort of older adults with rigorous follow-up of dementia, the apoE level in HDL that lacked apoC3 was associated with better cognitive function and lower dementia risk. This finding suggests that the cardioprotective associations of this novel lipoprotein extend to dementia.

Whether HDL is associated with dementia risk is unclear. In addition to apoA1, other apolipoproteins are found in HDL, creating subspecies of HDL that may have distinct metabolic properties. We measured apoA1, apoC3, and apoJ levels in plasma and apoA1 levels in HDL that contains or lacks apoE, apoJ, or apoC3 using a modified sandwich ELISA in a case-cohort study nested within the Ginkgo Evaluation of Memory Study. We included 995 randomly selected participants and 521 participants who developed dementia during a mean of 5.1 years of follow-up. The level of total apoA1 was not significantly related to dementia risk, regardless of the coexistence of apoC3, apoJ, or apoE. Higher levels of total plasma apoC3 were associated with better cognitive function at baseline (difference in Modified Mini-Mental State Examination scores tertile 3 vs. tertile 1: 0.60; 95% CI: 0.23, 0.98) and a lower dementia risk (adjusted hazard ratio tertile 3 vs. tertile 1: 0.73; 95% CI: 0.55, 0.96). Plasma concentrations of apoA1 in HDL and its apolipoprotein-defined subspecies were not associated with cognitive function at baseline or with the risk of dementia during follow-up. Similar studies in other populations are required to better understand the association between apoC3 and Alzheimer's disease pathology., (Copyright © 2020 Koch et al.)

Objective: To examine the association between prediagnostic plasma polyunsaturated fatty acids levels (PUFA) and amyotrophic lateral sclerosis (ALS)., Methods: We identified 275 individuals who developed ALS while enrolled in 5 US prospective cohorts, and randomly selected 2 controls, alive at the time of the case diagnosis, matched on cohort, birth year, sex, ethnicity, fasting status, and time of blood draw. We measured PUFA, expressed as percentages of total fatty acids, using gas liquid chromatography and used conditional logistic regression to estimate risk ratios (RR) and 95% confidence intervals (CI) for the association between PUFA and ALS., Results: There was no association between total, n-3, and n-6 PUFA, eicosapentaenoic acid, or docosapentaenoic acid levels and ALS. Higher plasma α-linolenic acid (ALA) in men was associated with lower risk of ALS in age- and matching factor-adjusted analyses (top vs bottom quartile: RR = 0.21 [95% CI 0.07, 0.58], p for trend = 0.004). In women, higher plasma arachidonic acid was associated with higher risk (top vs bottom quartile: RR = 1.65 [95% CI 0.99, 2.76], p for trend = 0.052). Multivariable adjustment, including correlated PUFA, did not change the findings for ALA and arachidonic acid. In men and women combined, higher plasma docosahexaenoic acid (DHA) was associated with higher risk of ALS (top vs bottom quartile: RR = 1.56 [95% CI 1.01, 2.41], p for trend = 0.054), but in multivariable models the association was only evident in men., Conclusions: The majority of individual PUFAs were not associated with ALS. In men, ALA was inversely and DHA was positively related to risk of ALS, while in women arachidonic acid was positively related. These findings warrant confirmation in future studies., (© 2019 American Academy of Neurology.)

Background: Very-long-chain SFAs (VLCSFAs), such as arachidic acid (20:0), behenic acid (22:0), and lignoceric acid (24:0), have demonstrated inverse associations with cardiometabolic conditions, although more evidence is needed to characterize their relation with risk of type 2 diabetes (T2D). In addition, little is known regarding their potential dietary and lifestyle predictors., Objective: We aimed to examine the association of plasma and erythrocyte concentrations of VLCSFAs with incident T2D risk., Methods: We used existing measurements of fatty acid concentrations in plasma and erythrocytes among 2854 and 2831 participants in the Nurses' Health Study (NHS) and Health Professionals Follow-Up Study (HPFS), respectively. VLCSFAs were measured using GLC, and individual fatty acid concentrations were expressed as a percentage of total fatty acids. Incident T2D cases were identified by self-reports and confirmed by a validated supplementary questionnaire. Cox proportional hazards regression was used to evaluate the association between VLCSFAs and T2D, adjusting for demographic, lifestyle, and dietary variables., Results: During 39,941 person-years of follow-up, we documented 243 cases of T2D. Intakes of peanuts, peanut butter, vegetable fat, dairy fat, and palmitic/stearic (16:0-18:0) fatty acids were significantly, albeit weakly, correlated with plasma and erythrocyte VLCSFA concentrations (|rs| ≤ 0.19). Comparing the highest with the lowest quartiles of plasma concentrations, pooled HRs (95% CIs) were 0.51 (0.35, 0.75) for arachidic acid, 0.43 (0.28, 0.64) for behenic acid, 0.40 (0.27, 0.61) for lignoceric acid, and 0.41 (0.27, 0.61) for the sum of VLCSFAs, after multivariate adjustments for demographic, lifestyle, and dietary factors. For erythrocyte VLCSFAs, only arachidic acid and behenic acid concentrations were inversely associated with T2D risk., Conclusions: Our findings suggest that, in US men and women, higher plasma concentrations of VLCSFAs are associated with lower risk of T2D. More research is needed to understand the mechanistic pathways underlying these associations., (Copyright © The Author(s) 2019.)

Background: The associations of perfluoroalkyl substance (PFAS) exposure with blood lipids and lipoproteins are inconsistent, and existing studies did not account for metabolic heterogeneity of lipoprotein subspecies. This study aimed to examine the associations between plasma PFAS concentrations and lipoprotein and apolipoprotein subspecies., Methods: The study included 326 men and women from the 2-year Prevention of Obesity Using Novel Dietary Strategies (POUNDS) Lost randomized trial. Five PFASs, including perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorohexanesulfonic acid (PFHxS), perfluorononanoic acid (PFNA), and perfluorodecanoic acid (PFDA), were measured in plasma at baseline. For lipoprotein and apolipoprotein subspecies, total plasma was fractionated first by apolipoprotein (apo) C-III content and then by density. Each subfraction was then measured for apoB, apoC-III, and apoE concentrations, as well as triglyceride and cholesterol contents, both at baseline and at 2 years., Results: For lipids and apolipoproteins in total plasma at baseline, elevated plasma PFAS concentrations were significantly associated with higher apoB and apoC-III concentrations, but not with total cholesterol or triglycerides. After multivariate adjustment of lifestyle factors, lipid-lowering medication use, and dietary intervention groups, PFAS concentrations were primarily associated with lipids or apolipoprotein concentrations in intermediate-to-low density lipoprotein (IDL + LDL) and high-density lipoprotein (HDL) that contain apoC-III. Comparing the highest and lowest tertiles of PFOA, the least-square means (SE) (mg/dl) were 4.16 (0.4) vs 3.47 (0.4) for apoB (P trend = 0.04), 2.03 (0.2) vs 1.66 (0.2) for apoC-III (P trend = 0.04), and 8.4 (0.8) vs 6.8 (0.8) for triglycerides (P trend = 0.03) in IDL + LDL fraction that contains apoC-III. For HDL that contains apoC-III, comparing the highest and lowest tertiles of PFOA, the least-square means (SE) (mg/dl) of apoC-III were 11.9 (0.7) vs 10.4 (0.7) (P trend = 0.01). In addition, elevated PFNA and PFDA concentrations were also significantly associated with higher concentrations of apoE in HDL that contains apoC-III (P trend< 0.01). Similar patterns of associations were demonstrated between baseline PFAS concentrations and lipoprotein subspecies measured at 2 years. Baseline PFAS levels were not associated with changes in lipoprotein subspecies during the intervention., Conclusions: Our results suggest that plasma PFAS concentrations are primarily associated with blood lipids and apolipoproteins in subspecies of IDL, LDL, and HDL that contain apoC-III, which are associated with elevated cardiovascular risk in epidemiological studies. Future studies of PFAS-associated cardiovascular risk should focus on lipid subfractions.

Background: Recent studies suggested an inverse association between exposures to perfluoroalkyl substances (PFASs) and bone mineral density (BMD). Whether exposures to PFASs are also associated with changes in BMD has not been examined., Methods: Five major PFASs (perfluorooctanesulfonic acid, PFOS; perfluorooctanoic acid, PFOA; perfluorohexanesulfonic acid, PFHxS; perfluorononanoic acid, PFNA; perfluorodecanoic acid, PFDA) and BMD (g/cm 2 ) at six bone sites (spine, total hip, femoral neck, hip intertrochanteric area, hip trochanter, and hip Ward's triangle area) were measured at baseline among 294 participants in the POUNDS-LOST study, a weight-loss trial, of whom a total of 175 participants had BMD measured at both baseline and year 2. Linear regression was used to model the differences or changes in BMD for each SD increment of PFAS concentrations. In a secondary analysis, interactions between PFASs and baseline body mass index (BMI), as well as a BMI-related genetic risk score (GRS) derived from 97 BMI-predicting SNPs were examined in relation to changes in BMD., Results: At baseline, both PFOS and PFOA were significantly associated with lower BMD at several sites. For each SD increase of PFOS, the βs (95% CIs) for BMD were -0.020(-0.037, -0.003) for spine, -0.013(-0.026, 0.001) for total hip, -0.014(-0.028, 0.000) for femoral neck, and -0.013(-0.026, 0.000) for hip trochanter. For PFOA, the corresponding figures were -0.021(-0.038, -0.004) for spine, -0.015(-0.029, -0.001) for total hip, and -0.015(-0.029, -0.002) for femoral neck. After adjusting for baseline covariates and 2-year weight change, higher baseline plasma concentrations of PFOS, PFNA, and PFDA were associated with greater reduction in BMD in the hip; the βs (95% CIs) were -0.005(-0.009, -0.001), -0.006(-0.010, -0.001), and -0.005(-0.009, -0.001), respectively. Similar associations were found in hip intertrochanteric area for all PFASs except PFHxS, with βs ranging from -0.006 for PFOA to -0.008 for PFOS and PFNA. Participants with a higher GRS tended to have less PFAS-related BMD decline in total hip (P interaction  = 0.005) and the hip intertrochanteric area (P interaction  = 0.021). There were similar PFAS-related BMD changes by baseline BMI levels, although the interactions did not achieve statistical significance., Conclusions: This study demonstrated that higher plasma PFAS concentrations were not only associated with a lower BMD at baseline, but also a faster BMD loss in a weight-loss trial setting. Genetic predisposition to larger body size may somewhat attenuate the deleterious effects of PFASs on BMD. Further exploration of the possible impact of PFAS exposures on bone density is warranted., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Collecting dietary intake data is associated with challenges due to the subjective nature of self-administered instruments. Biomarkers may objectively estimate the consumption of specific dietary items or help assess compliance in dietary intervention studies. Our aim was to use a panel of plasma and urine biomarkers to assess the validity of self-reported dietary intake using a modified Mediterranean Diet Scale (mMDS) among firefighters participating in Feeding America's Bravest (FAB), an MD cluster-randomized controlled trial. In our nested biomarker pilot study, participants were randomly selected from both the MD intervention group ( n = 24) and the control group ( n = 24) after 12-months of dietary intervention. At baseline data collection for the pilot study (t = 12-months of FAB), participants in the control group crossed-over to receive the MD intervention (active intervention) for 6-months. Participants in the intervention group continued in a self-sustained continuation phase (SSP) of the intervention. Food frequency questionnaires (FFQ), 13-item-mMDS questionnaires, 40 plasma fatty acids, inflammatory biomarkers and urinary hydroxytyrosol and tyrosol were analyzed at both time points. Spearman's correlation, t -tests and linear regression coefficients were calculated using SAS software. Overall, the mMDS derived from the FFQ was highly correlated with the specific 13-domain-mMDS (r = 0.74). The concordance between the two questionnaires for low and high adherence to MD was high for all the participants in the parent trial (κ = 0.76). After 6 months of intervention in the pilot study, plasma saturated fatty acid decreased in both groups (active intervention: -1.3 ± 1.7; p = 0.002; SSP: -1.12 ± 1.90; p = 0.014) and oleic acid improved in the SSP ( p = 0.013). Intake of olive oil was positively associated with plasma omega-3 ( p = 0.004) and negatively with TNF-α ( p < 0.001) at baseline. Choosing olive oil as a type of fat was also associated with higher levels of plasma omega-3 ( p = 0.019) at baseline and lower TNF-α ( p = 0.023) at follow up. Intake of red and processed meats were associated with lower serum omega-3 ( p = 0.04) and fish consumption was associated with lower IL-6 at baseline ( p = 0.022). The overall mMDS was associated with an increase in plasma omega-3 ( p = 0.021). Good correlation was found between nutrient intake from the FFQ and the corresponding plasma biomarkers (omega-3, EPA and DHA). In this MD randomized controlled trial, some key plasma biomarkers were significantly associated with key MD diet components and the overall mMDS supporting the validity of the mMDS questionnaire as well as compliance with the intervention.

Total plasma fatty acids or those in cholesteryl ester and phospholipids are often used to reflect fatty acid intake in epidemiological studies, but their relative performance as biomarkers of intake has not been clearly evaluated within a single population. The assessment of fatty acids in plasma fractions is more labor intensive. Thus, their use as biomarkers of dietary intake needs to be justified. Dietary intake was assessed in 200 population-based controls from a case-control study of diet and heart disease in Costa Rica by a validated food frequency questionnaire (FFQ). Fatty acids in fasting whole plasma and plasma fractions (cholesteryl ester, phospholipid, and triglyceride + free fatty acid) were measured in the 200 controls by the same laboratory using gas chromatography with flame ionization detection (GC-FID). We compared the plasma and plasma fractions data with the FFQ and adipose fatty acid profile using partial Spearman correlations to assess utility as biomarkers of intake and exposure. We found that whole plasma was equally or more strongly correlated with the FFQ and adipose fatty acid profile than either cholesteryl ester or phospholipid in most of the established markers of dietary intake, including dairy (15:0 and 17:0) and seafood (eicosapentaenoic acid and docosahexaenoic acid). Of the three plasma fractions, only fatty acids in the plasma triglyceride + free fatty acid fraction had stronger correlations with dietary intake than whole plasma. In our study population, fatty acids measured in fasting whole plasma perform as good as or better than those measured in plasma fractions as biomarkers for dietary fatty acid intake. Thus, the fractionation of plasma to evaluate long-term fatty acid intake may not be warranted., Competing Interests: The authors declare no conflict of interest.

Aims/hypothesis: Apolipoprotein C-III (apoC-III) is a small proinflammatory protein that may play a key role in diabetes pathophysiology. However, prior observational studies have been limited to predominantly white populations, and the biological links between apoC-III and diabetes, particularly the role of apoC-III on specific lipoprotein particles, are not yet well understood. We therefore investigated associations of total apoC-III and apoC-III-defined lipoprotein subspecies with incident diabetes and glucose metabolism measures in a multi-ethnic cohort., Methods: For the current analyses, baseline (2000-2002) plasma total apoC-III and apolipoprotein A-I concentrations of HDL containing or lacking apoC-III were newly measured via sandwich ELISA in 4579 participants from the Multi-Ethnic Study of Atherosclerosis. Multivariable Cox regression was used to examine associations of apolipoproteins with incident diabetes until early 2012 (567 cases), and linear mixed models were used to estimate associations with longitudinally assessed continuous measures of glucose metabolism. Similar exploratory analyses of plasma apolipoprotein B concentrations of LDL and VLDL containing or lacking apoC-III were performed in a subset of participants (LDL, n = 1545; VLDL, n = 1526)., Results: In the overall population, elevated total apoC-III concentrations were associated with a higher rate of diabetes (top vs bottom quintile, HR 1.88; 95% CI 1.42, 2.47; p trend  = 0.0002). ApoC-III-defined HDL subspecies displayed opposing associations with incidence of diabetes (p for heterogeneity = 0.02). While HDL lacking apoC-III was inversely associated with incidence of diabetes (top vs bottom quintile, HR 0.66; 95% CI 0.46, 0.93; p trend  = 0.002), HDL containing apoC-III was not associated (HR 1.11; 95% CI 0.78, 1.58; p trend  = 0.61). Similarly, only HDL lacking apoC-III was beneficially associated with plasma glucose (p trend  = 0.003), HbA 1c (p trend  = 0.04) and insulin sensitivity (p trend  < 0.0001), and higher HDL containing apoC-III was associated with lower insulin sensitivity (p trend  = 0.04). Neither of the apoC-III-defined LDL subspecies was associated with incident diabetes, while VLDL was more strongly associated with the incidence of diabetes when it lacked apoC-III. Further adjustment for plasma triacylglycerols as a potential intermediate attenuated the associations of total apoC-III and apoC-III-defined lipoprotein subspecies. No statistically significant differences were observed across racial/ethnic groups., Conclusions/interpretation: Our findings in a multi-ethnic population support the involvement of apoC-III in the development of diabetes, potentially through its association with circulating triacylglycerols. The presence of apoC-III on HDL also diminished the protective association of HDL with incident diabetes. Further investigation of apoC-III and apoC-III-defined HDL subspecies may inform the development of novel diabetes treatment and prevention strategies.

Background: HDL that contains apolipoprotein E (apoE) is a subspecies especially active in steps in reverse cholesterol transport, a process that brings cholesterol from peripheral cells to the liver. Here, we studied the effect of dietary unsaturated fat compared with carbohydrate on the metabolism of HDL containing apoE., Methods: We enrolled 9 adults who were overweight or obese and had below-average HDL-cholesterol in a crossover study of a high-fat diet, primarily unsaturated, and a low-fat, high-carbohydrate diet. A metabolic tracer study was performed after each diet period., Results: Dietary fat increased the secretion, metabolism, and clearance of HDL subspecies containing apoE. Dietary fat increased the rate of clearance of large cholesterol-rich HDL containing apoE and increased their conversion to small HDL containing apoE, indicating selective cholesterol ester delivery to the liver. The high-unsaturated-fat diet did not affect the metabolism of HDL lacking apoE., Conclusion: HDL containing apoE is a diet-responsive metabolic pathway that renders HDL more biologically active in reverse cholesterol transport. This may be a mechanism by which unsaturated fat protects against coronary heart disease. Protein-based HDL subspecies such as HDL containing apoE may be used to identify additional atheroprotective treatment targets not evident in the total HDL-cholesterol measurement., Trial Registration: ClinicalTrials.gov NCT01399632., Funding: NIH and the National Center for Advancing Translational Science.

The growing interest in potential health effects of long-chain polyunsaturated fatty acids (PUFAs) makes it important to evaluate the method used to assess the fatty acid intake in nutrition research studies. We aimed to validate the questionnaire-based dietary intake of selected PUFAs: eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), α-linolenic acid (ALA), linoleic acid (LA), and arachidonic acid (AA) within the Danish National Birth Cohort (DNBC), by comparing 345 women's reported intake with concentration of plasma biomarkers. The applied questionnaire- and biomarker data reflect dietary intake from around the same time point in mid-pregnancy and relationships were investigated by use of Pearson and Spearman correlation and linear regression statistics. We demonstrated moderate but consistent adjusted correlations between dietary intake estimates and the corresponding plasma biomarker concentrations (differences in plasma concentration per 100 mg/day greater intake of 0.05 (95% CI: 0.02; 0.08)) and 0.05 (95% CI: 0.01; 0.08) percentage of total plasma fatty acids for EPA and DHA, respectively). The associations strengthened when restricting the analyses to women with ALA intake below the median intake. We found a weak correlation between the dietary intake of ALA and its plasma biomarker with a difference in plasma concentration of 0.07 (95% CI: 0.03; 0.10) percent of total plasma fatty acids per 1 g/day greater intake, while the dietary intake of LA and AA did not correlate with their corresponding biomarkers., Competing Interests: The authors declare no conflict of interest. The funding agencies did not have any role in design and conduct of the study; collection, management, and interpretation of the data; or preparation, review, or approval of the manuscript.

Objective- HDL (high-density lipoprotein) in plasma is a heterogeneous group of lipoproteins typically containing apo AI as the principal protein. Most HDLs contain additional proteins from a palate of nearly 100 HDL-associated polypeptides. We hypothesized that some of these proteins define distinct and stable apo AI HDL subspecies with unique proteomes that drive function and associations with disease. Approach and Results- We produced 17 plasma pools from 80 normolipidemic human participants (32 men, 48 women; aged 21-66 years). Using immunoaffinity isolation techniques, we isolated apo AI containing species from plasma and then used antibodies to 16 additional HDL protein components to isolate compositional subspecies. We characterized previously described HDL subspecies containing apo AII, apo CIII, and apo E; and 13 novel HDL subspecies defined by presence of apo AIV, apo CI, apo CII, apo J, α-1-antitrypsin, α-2-macroglobulin, plasminogen, fibrinogen, ceruloplasmin, haptoglobin, paraoxonase-1, apo LI, or complement C3. The novel species ranged in abundance from 1% to 18% of total plasma apo AI. Their concentrations were stable over time as demonstrated by intraclass correlations in repeated sampling from the same participants over 3 to 24 months (0.33-0.86; mean 0.62). Some proteomes of the subspecies relative to total HDL were strongly correlated, often among subspecies defined by similar functions: lipid metabolism, hemostasis, antioxidant, or anti-inflammatory. Permutation analysis showed that the proteomes of 12 of the 16 subspecies differed significantly from that of total HDL. Conclusions- Taken together, correlation and permutation analyses support speciation of HDL. Functional studies of these novel subspecies and determination of their relation to diseases may provide new avenues to understand the HDL system of lipoproteins.

Background: Fish oil supplementation has been shown to delay spontaneous delivery, but the levels and clinical significance remain uncertain. We examined the association between plasma fatty acids quantified in pregnancy and subsequent risk of early preterm birth., Methods: In a case-control design nested in the Danish National Birth Cohort, we identified 376 early preterm cases (<34 gestational weeks, excluding preeclampsia cases) and 348 random controls. Plasma eicosapentaenoic acid plus docosahexaenoic acid (EPA+DHA% of total fatty acids), were measured twice in pregnancy, at gestation weeks 9 and 25 (medians). Odds ratios and 95% confidence intervals (CI's) for associations between EPA+DHA and early preterm risk were estimated by logistic regression, adjusted for the woman's age, height, pre-pregnancy BMI, parity, smoking, and socioeconomic factors. Hypotheses and analytical plan were defined and archived a priori., Findings: Analysis using restricted cubic splines of the mean of 1st and 2nd sample measurements showed a strong and significant non-linear association (p < 0.0001) in which the risk of early preterm birth steeply increased when EPA+DHA concentrations were lower than 2% and flattened out at higher levels. Women in the lowest quintile (EPA+DHA < 1.6%) had 10.27 times (95% confidence interval 6.80-15.79, p < 0.0001) increased risk, and women in the second lowest quintile had 2.86 (95% CI 1.79-4.59, p < 0.0001) times increased risk, when compared to women in the three aggregated highest quintiles (EPA+DHA ≥ 1.8%)., Interpretation: Low plasma concentration of EPA and DHA during pregnancy is a strong risk factor for subsequent early preterm birth in Danish women., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Apolipoproteins of demonstrated importance to brain cholesterol and ß-amyloid metabolism may serve as novel risk markers for Alzheimer's pathology., Methods: We measured apolipoproteins (apoE, apoJ, apoA-I, and apoC-III and their uniquely defined subspecies) by enzyme-linked immunosorbent assay in plasma collected in 2000 and 2008 from 176 dementia-free participants of the Ginkgo Evaluation of Memory Study and related these to ß-amyloid on positron emission tomography scans, hippocampal volume, and white matter lesion volume in 2009., Results: Higher apoE was associated with lower ß-amyloid deposition. Despite apoA-I being unrelated to hippocampal volume, subspecies of apoA-I containing or lacking apoJ or apoC-III showed opposite associations with hippocampal volume. Higher apoJ and apoE lacking apoJ were associated with higher hippocampal volume and higher white matter lesion volume, respectively. Associations were similar in participants without cognitive impairment or APOE ε4 noncarrier and when analyzing apolipoproteins in 2000-2002., Discussion: Apolipoproteins may be important minimally invasive biomarkers indicative of Alzheimer's pathology.

Background: The causal role of high-density lipoprotein (HDL) cholesterol in cardioprotection has been questioned by genetic and randomized studies. Novel measures that relate to HDL function may contribute new information to the prediction of cardiovascular risk. Apolipoprotein C-III (apoC-III) is a key regulator of lipoprotein metabolism. We investigated whether subspecies of HDL defined by apoC-III are associated with coronary heart disease (CHD)., Methods: We used immunoaffinity chromatography to measure the apoA-I concentrations of HDL that contains and lacks apoC-III in 2 prospective studies of adults free of CHD. In MESA (Multi-Ethnic Study of Atherosclerosis), 5657 participants (52% women, 52-72 years of age) were followed for risk of CHD from 2000 to 2002 through 2013. In a case-cohort study nested within the DCH study (Danish Diet, Cancer, and Health), 3642 participants (47% women, 51-64 years of age) were followed from 1994 to 1997 through 2010. Subsequently, we conducted a meta-analysis that combined these results with the previously published findings from 2 cohort studies that used similar laboratory methodology to measure lipoproteins, totaling 2997 incident cases., Results: ApoC-III was found on 6% to 8% of apoA-I. The 2 HDL subspecies showed opposing associations, with risk of CHD in each of the individual cohorts and in the meta-analysis ( P heterogeneity between the 2 subspecies <0.01). HDL that contains apoC-III was associated with a higher risk of CHD (pooled relative risk per standard deviation, 1.09; 95% confidence interval, 1.01-1.18), whereas HDL that lacks apoC-III was associated with lower risk (relative risk, 0.76; 95% confidence interval, 0.70-0.83). The relative risk for HDL lacking apoC-III was even more negative than the relative risk for total HDL (relative risk, 0.80; 95% confidence interval, 0.74-0.87)., Conclusions: Our findings from 4 prospective studies support the hypothesis that apoC-III may mark a subfraction of HDL that is associated with higher risk of CHD. New measures reflecting HDL structure and function may provide novel insights for cardiovascular risk that extend beyond traditional plasma HDL cholesterol concentrations., (© 2017 American Heart Association, Inc.)

Background: Apolipoprotein C-III (apoC-III), a small proinflammatory protein present on 6% to 7% of high-density lipoprotein (HDL) particles, defines a subspecies of HDL adversely associated with coronary heart disease in primarily white cohorts. In a multi-ethnic population free of clinical cardiovascular disease, we evaluated the relationship between apoC-III-defined HDL subspecies and subclinical markers of atherosclerotic pathology., Methods and Results: We investigated cross-sectional associations between apolipoprotein A-I concentrations of apoC-III-defined HDL subspecies, measured via ELISA and imaging measures of subclinical atherosclerosis, among 4659 participants in the MESA (The Multi-Ethnic Study of Atherosclerosis) at baseline (2000-2002). HDL particles containing and lacking apoC-III were divergently associated with coronary artery calcification in women ( P -heterogeneity=0.002) but not in men ( P -heterogeneity=0.31) and with carotid plaque score ( P -heterogeneity=0.02) and intima-media thickness ( P -heterogeneity=0.06) in the overall study population. HDL lacking apoC-III was inversely associated with all outcome measures (coronary artery calcification, women: odds ratio per SD=0.81 [95% confidence interval [CI], 0.73-0.90]; carotid plaque, overall: odds ratio per SD=0.92 [95% CI, 0.84-1.00]; intima-media thickness, overall: mean difference per SD=-14.0 µm [95% CI, -21.1 to -6.7 μm]), whereas HDL containing apoC-III was positively associated (coronary artery calcification, women: odds ratio=1.10 [95% CI, 0.99-1.22]; plaque, overall: odds ratio=1.10 [95% CI, 1.01-1.19]) or unassociated. Neither total HDL nor HDL subspecies was associated with changes in subclinical atherosclerosis measures up to 10 years later., Conclusions: The presence of apoC-III defined a subspecies of HDL not inversely associated with baseline measures of subclinical atherosclerosis, supporting a role of apoC-III in the pathophysiology of cardiovascular disease., (© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Background: Subspecies of HDL contain apolipoprotein E (apoE) and/or apoCIII. Both proteins have properties that could affect HDL metabolism. The relation between HDL metabolism and risk of coronary heart disease (CHD) is not well understood., Methods: Eighteen participants were given a bolus infusion of [D3]L-leucine to label endogenous proteins on HDL. HDL was separated into subspecies containing apoE and/or apoCIII and then into 4 sizes. Metabolic rates for apoA-I in HDL subspecies and sizes were determined by interactive modeling. The concentrations of apoE in HDL that contain or lack apoCIII were measured in a prospective study in Denmark including 1,949 incident CHD cases during 9 years., Results: HDL containing apoE but not apoCIII is disproportionately secreted into the circulation, actively expands while circulating, and is quickly cleared. These are key metabolic steps in reverse cholesterol transport, which may protect against atherosclerosis. ApoCIII on HDL strongly attenuates these metabolic actions of HDL apoE. In the epidemiological study, the relation between HDL apoE concentration and CHD significantly differed depending on whether apoCIII was present. HDL apoE was associated significantly with lower risk of CHD only in the HDL subspecies lacking apoCIII., Conclusions: ApoE and apoCIII on HDL interact to affect metabolism and CHD. ApoE promotes metabolic steps in reverse cholesterol transport and is associated with lower risk of CHD. ApoCIII, when coexisting with apoE on HDL, abolishes these benefits. Therefore, differences in metabolism of HDL subspecies pertaining to reverse cholesterol transport are reflected in differences in association with CHD., Trial Registration: Clinicaltrials.gov NCT01399632., Funding: This work was supported by NIH grant R01HL095964 to FMS and by a grant to the Harvard Clinical and Translational Science Center (8UL1TR0001750) from the National Center for Advancing Translational Science.

Background: The potential endocrine-disrupting effects of perfluoroalkyl substances (PFASs) have been demonstrated in animal studies, but whether PFASs may interfere with body weight regulation in humans is largely unknown. This study aimed to examine the associations of PFAS exposure with changes in body weight and resting metabolic rate (RMR) in a diet-induced weight-loss setting., Methods and Findings: In the 2-year POUNDS Lost randomized clinical trial based in Boston, Massachusetts, and Baton Rouge, Louisiana, that examined the effects of energy-restricted diets on weight changes, baseline plasma concentrations of major PFASs were measured among 621 overweight and obese participants aged 30-70 years. Body weight was measured at baseline and 6, 12, 18, and 24 months. RMR and other metabolic parameters, including glucose, lipids, thyroid hormones, and leptin, were measured at baseline and 6 and 24 months. Participants lost an average of 6.4 kg of body weight during the first 6 months (weight-loss period) and subsequently regained an average of 2.7 kg of body weight during the period of 6-24 months (weight regain period). After multivariate adjustment, baseline PFAS concentrations were not significantly associated with concurrent body weight or weight loss during the first 6 months. In contrast, higher baseline levels of PFASs were significantly associated with a greater weight regain, primarily in women. In women, comparing the highest to the lowest tertiles of PFAS concentrations, the multivariate-adjusted mean weight regain (SE) was 4.0 (0.8) versus 2.1 (0.9) kg for perfluorooctanesulfonic acid (PFOS) (Ptrend = 0.01); 4.3 (0.9) versus 2.2 (0.8) kg for perfluorooctanoic acid (PFOA) (Ptrend = 0.007); 4.7 (0.9) versus 2.5 (0.9) kg for perfluorononanoic acid (PFNA) (Ptrend = 0.006); 4.9 (0.9) versus 2.7 (0.8) kg for perfluorohexanesulfonic acid (PFHxS) (Ptrend = 0.009); and 4.2 (0.8) versus 2.5 (0.9) kg for perfluorodecanoic acid (PFDA) (Ptrend = 0.03). When further adjusted for changes in body weight or thyroid hormones during the first 6 months, results remained similar. Moreover, higher baseline plasma PFAS concentrations, especially for PFOS and PFNA, were significantly associated with greater decline in RMR during the weight-loss period and less increase in RMR during the weight regain period in both men and women. Limitations of the study include the possibility of unmeasured or residual confounding by socioeconomic and psychosocial factors, as well as possible relapse to the usual diet prior to randomization, which could have been rich in foods contaminated by PFASs through food packaging and also dense in energy., Conclusions: In this diet-induced weight-loss trial, higher baseline plasma PFAS concentrations were associated with a greater weight regain, especially in women, possibly explained by a slower regression of RMR levels. These data illustrate a potential novel pathway through which PFASs interfere with human body weight regulation and metabolism. The possible impact of environmental chemicals on the obesity epidemic therefore deserves attention., Trial Registration: ClinicalTrials.gov NCT00072995.

Background and Aims: About 6-7% of high density lipoprotein (HDL) has a protein called apolipoprotein (apo) C-III that regulates lipoprotein metabolism and can provoke an inflammatory response. HDL without apoC-III is inversely associated with coronary heart disease (CHD), whereas HDL with apoC-III is directly associated with CHD. We investigated how the presence of apoC-III affects the association between HDL and early stages of atherosclerosis measured as carotid intima-media thickness (cIMT)., Methods: We examined the cross-sectional associations between the apoA-I concentrations of HDL subspecies with and without apoC-III and cIMT measured by high resolution B-mode carotid ultrasonography among 847 participants from the European multi-center Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) study., Results: HDL with and without apoC-III demonstrated significantly opposite associations with both cIMT indexes (p-heterogeneity of associations comparing the two subspecies was 0.002 for cIMT at common carotid artery (cIMT at CCA) and 0.006 for the maximum cIMT in any carotid segment (cIMT max)). Compared to the lowest quintile, the highest quintile of apoA-I in HDL without apoC-III was associated with 3.7% lower cIMT at CCA (p-trend = 0.01) or 7.3% lower cIMT max (p-trend = 0.003), while the highest quintile of apoA-I in HDL with apoC-III was associated with 4.4% higher cIMT at CCA (p-trend = 0.001) or 7.9% higher cIMT max (p-trend = 0.002). Total apoA-I as well as total HDL cholesterol was not associated with cIMT whereas higher levels of total apoC-III and apoC-III contained in HDL were significantly associated with higher cIMT (p-trend<0.01)., Conclusions: HDL apoC-III is a promising target for atherosclerosis prevention and treatment., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Apolipoprotein C-III (apoC-III) is a potentially novel biomarker that may play an important role in the pathogenesis of diabetes, particularly when present on the surface of high-density lipoprotein (HDL). In a case-cohort study carried out among 434 incident diabetes cases occurring before 2007 and 3,101 noncases in the Danish Diet, Cancer, and Health Study, we examined associations of baseline (1993-1997) plasma concentrations of apoC-III and subspecies of HDL defined by the presence or absence of apoC-III with risk of diabetes using Cox regression. ApoC-III was strongly associated with risk of diabetes (for top quintile vs. bottom quintile, hazard ratio (HR) = 3.43, 95% confidence interval (CI): 1.75, 6.70; P-trend < 0.001). The cholesterol concentration of HDL (HDL cholesterol (HDL-C)) without apoC-III was inversely associated with risk of diabetes (HR = 0.48, 95% CI: 0.27, 0.85; P-trend = 0.002), more so than total HDL-C (HR = 0.60, 95% CI: 0.35, 1.03; P-trend = 0.04), whereas HDL-C with apoC-III was not associated (HR = 1.05, 95% CI: 0.50, 2.21; P-trend = 0.44) (for HDL-C with apoC-III vs. HDL-C without apoC-III, P-heterogeneity = 0.002). ApoC-III itself is a strong risk marker for diabetes, and its presence on HDL may impair the antidiabetogenic properties of HDL. ApoC-III has potential to be a therapeutic target for the prevention of diabetes., (© The Author(s) 2017. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

HDLs are a family of heterogeneous particles that vary in size, composition, and function. The structure of most HDLs is maintained by two scaffold proteins, apoA-I and apoA-II, but up to 95 other "accessory" proteins have been found associated with the particles. Recent evidence suggests that these accessory proteins are distributed across various subspecies and drive specific biological functions. Unfortunately, our understanding of the molecular composition of such subspecies is limited. To begin to address this issue, we separated human plasma and HDL isolated by ultracentrifugation (UC-HDL) into particles with apoA-I and no apoA-II (LpA-I) and those with both apoA-I and apoA-II (LpA-I/A-II). MS studies revealed distinct differences between the subfractions. LpA-I exhibited significantly more protein diversity than LpA-I/A-II when isolated directly from plasma. However, this difference was lost in UC-HDL. Most LpA-I/A-II accessory proteins were associated with lipid transport pathways, whereas those in LpA-I were associated with inflammatory response, hemostasis, immune response, metal ion binding, and protease inhibition. We found that the presence of apoA-II enhanced ABCA1-mediated efflux compared with LpA-I particles. This effect was independent of the accessory protein signature suggesting that apoA-II induces a structural change in apoA-I in HDLs., (Copyright © 2017 by the American Society for Biochemistry and Molecular Biology, Inc.)

The presence of apoC-III on HDL impairs HDL's inverse association with coronary heart disease (CHD). Little is known about modifiable factors explaining variation in HDL subspecies defined according to apoC-III. The aim was to investigate cross-sectional associations of anthropometry and lifestyle with HDL subspecies in 3,631 participants from the Diet, Cancer, and Health study originally selected for a case-cohort study (36% women; age 50-65 years) who were all free of CHD. Greater adiposity and less activity were associated with higher HDL containing apoC-III and lower HDL lacking apoC-III. Per each 15 cm higher waist circumference, the level of HDL containing apoC-III was 2.8% higher (95% CI: 0.4, 5.3; P = 0.024) and the level of HDL not containing apoC-III was 4.7% lower (95% CI: -6.0, -3.4; P = <0.0001). Associations for physical activity were most robust to multivariable modeling. Each 20 metabolic equivalent task hours per week reported higher physical activity was associated with 0.9% (95% CI: -1.7, -0.1; P = 0.031) lower HDL containing apoC-III and 0.5% higher (95% CI: 0.1, 1.0; P = 0.029) HDL lacking apoC-III. Lower alcohol consumption was associated with lower HDL lacking apoC-III (percent difference per 15 g/day: 1.58 (95% CI: 0.84, 2.32; P = <0.0001). Adiposity and sedentary lifestyle were associated with a less favorable HDL subspecies profile., (Copyright © 2017 by the American Society for Biochemistry and Molecular Biology, Inc.)

Introduction: Subspecies of apolipoproteins can be defined by fractionating apolipoproteins based on the presence and absence of coexisting apolipoproteins., Methods: We determined age- and sex-adjusted correlations of enzyme-linked immunosorbent assay-measured plasma and cerebrospinal fluid (CSF) apolipoproteins (apoA-I, apoC-III, apoE, and apoJ) or apolipoprotein subspecies (apoA-I with and without apoC-III, ApoE, or apoJ; apoE with and without apoC-III or apoJ) in 22 dementia-free participants., Results: CSF apoE did not correlate with plasma apolipoproteins or their subspecies. CSF apoJ correlated most strongly with plasma apoA-I without apoJ ( r  = 0.7). CSF apoA-I correlated similarly strong with plasma total apoA-I and all apoA-I subspecies ( r  ≥ 0.4) except for apoA-I with apoE ( r  = 0.3) or apoA-I with apoJ ( r  = 0.3). CSF apoC-III was most strongly correlated with plasma apoA-I with apoC-III ( r  = 0.7)., Discussion: CSF levels of some apolipoproteins implicated in the pathophysiology of dementia might be better approximated by specific plasma apolipoprotein subspecies than total plasma concentrations.

Background: Lipoprotein subspecies containing apoCIII adversely affect cardiovascular disease (CVD) risk; for example, low density lipoprotein (LDL) with apoCIII is a stronger CVD predictor than LDL without apoCIII. The Epanova for Lowering Very High Triglycerides (EVOLVE) trial showed that Epanova (omega-3 carboxylic acids [OM3-CA]) significantly lowered TG and apoCIII but raised LDL-C. However, it is unknown what subspecies of LDL were affected by treatment., Objective: To determine how lipoprotein subspecies are affected by omega-3 fatty acid treatment, we studied the effect of OM3-CA on apoCIII concentrations in high density lipoprotein (HDL), LDL, and very low density lipoprotein (VLDL) and on the concentrations of subspecies of HDL, LDL, and VLDL that contain or do not contain apoCIII., Methods: We analyzed plasma from a subset of subjects from the EVOLVE trial, a 12-week double-blind study of 399 subjects with fasting TG of 500 to 2000 mg/dL who were randomized to OM3-CA 2, 3, or 4 g/d or olive oil (placebo)., Results: OM3-CA significantly reduced plasma apoCIII relative to placebo, as well as apoCIII in HDL, and apoCIII in LDL. Treatment did not significantly affect the concentration of LDL with apoCIII, a subspecies highly associated with CVD risk. OM3-CA increased selectively the concentration of LDL that does not contain apoCIII, a subspecies with a weak relation to coronary heart disease. The reduction in apoCIII was associated with plasma increases in eicosapentaenoic acid, docosahexaenoic acid, and arachidonic acid and decreases in linoleic, palmitic, and oleic acids., Conclusion: Reduction in apoCIII may be a mechanism for the TG-lowering effects of OM3-CA. The increase in LDL-C seen in the EVOLVE trial may not be associated with increased risk of CVD., (Copyright © 2016 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Purpose: Several circulating carotenoids have been inversely associated with postmenopausal breast cancer risk in large cohort studies and a pooled analysis. Whether associations differ by tumor or participant characteristics remains unclear. We investigated the associations of plasma carotenoids with postmenopausal breast cancer risk overall and by estrogen receptor (ER) status, tumor stage, smoking status, and body mass index, in a case-control study nested in the Cancer Prevention Study II Nutrition Cohort., Methods: A total of 496 invasive breast cancer cases diagnosed between blood draw in 1998-2001 and June 30, 2007 and matched 1:1 with controls on race, birth date, and blood draw date were included. Multivariable-adjusted conditional and unconditional logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs)., Results: Plasma α-carotene above the lowest quartile was associated with significant 40-43% lower risk of invasive breast cancer risk (fourth vs. first quartile OR 0.60, 95% CI 0.41-0.87, P-trend = 0.037) after adjustment for multiple covariates. This inverse association was strengthened after further adjustment for other plasma carotenoids and total fruit and vegetable intake (fourth vs. first quartile OR 0.50, 95% CI 0.29-0.85, P-trend = 0.041). Other plasma carotenoids or total carotenoids were not associated with breast cancer risk. The inverse association of α-carotene with breast cancer remained for ER+, but not for ER- tumors, although test for heterogeneity was not statistically significant (P-heterogeneity = 0.49)., Conclusions: These results suggest that higher plasma α-carotene is associated with lower risk of invasive breast cancer.

Background: African-Americans have higher HDL, less visceral adipose tissue (VAT) and lower triglyceride (TG) and apoCIII concentrations than whites, despite being more insulin-resistant. We studied in African-American and white women the influences of insulin resistance and VAT on the apoAI concentrations of two HDL subspecies, one that contains apoCIII that is associated with increased risk of coronary heart disease (CHD) and one that does not have apoCIII that is associated with decreased CHD; and on the apoCIII concentrations of HDL and of the apoB lipoproteins., Methods: The participants were 32 women (14 African-Americans, 18 white) of similar age (39 ± 12 vs. 42 ± 11y). Mean BMI was 34 kg/m(2) in the African-Americans compared to 30 in the whites. A standard diet (33% fat, 52% carbohydrate, 15% protein) was provided for 7 days followed by a test meal (40% fat, 40% carbohydrate, 20% protein) on Day 8. Insulin sensitivity index (SI) was calculated from the minimal model., Results: After controlling for SI, African-Americans have a higher mean apoAI level in HDL with apoCIII compared with whites (12.9 ± 2.8 and 10.9 ± 2.9 mg/dL, respectively, P = 0.05). SI was associated with higher apoAI in HDL with apoCIII, whereas VAT was not associated with this HDL subspecies. This pattern of results was reversed for apoCIII concentrations in apoB lipoproteins. After adjusting for SI, African-Americans had lower apoCIII in apoB lipoproteins. SI was associated with lower apoCIII in total apoB lipoproteins, whereas VAT was associated with higher apoCIII in all the apoB lipoproteins. Additional adjustment for VAT tended to reduce the difference in apoCIII between the groups., Conclusions: African-American women have a higher HDL with apoCIII level than whites when controlled for insulin sensitivity. African-Americans have lower insulin sensitivity. Insulin sensitivity is associated with higher levels of HDL with apoCIII. ApoCIII levels in VLDL are lower in African-American women than whites, also affected by insulin sensitivity which is associated with low apoCIII in VLDL. VAT has a strong association with apoCIII in apoB lipoproteins but not with apoAI in HDL with apoCIII., Trial Registration: ClinicalTrials.gov Identifier: NCT00484861.

Background: African-Americans are more insulin-resistant than whites but have lower triglyceride (TG) concentrations. The metabolic basis for this is unknown. Our goal was to determine in a cross-sectional study the effect of insulin resistance, visceral adipose tissue (VAT) and the apolipoproteins, B, C-III and E, on race differences in TG content of very low density lipoproteins (VLDL)., Methods: The participants were 31 women (16 African-American, 15 white) of similar age (37 ± 9 vs. 38 ± 11y (mean ± SD), P = 0.72) and BMI (32.4 ± 7.2 vs. 29.3 ± 6.0 kg/m2, P = 0.21). A standard diet (33% fat, 52% carbohydrate, 15% protein) was given for 7 days followed by a test meal (40% fat, 40% carbohydrate, 20% protein) on Day 8. Insulin sensitivity index (SI) was calculated from the minimal model. VAT was measured at L2-3. The influence of race, SI, VAT and apolipoproteins on the TG content of VLDL was determined by random effects models (REM)., Results: African-Americans were more insulin-resistant (SI: 3.6 ± 1.3 vs. 5.6 ± 2.6 mU/L-1.min-1, P < 0.01) with less VAT (75 ± 59 vs. 102 ± 71 cm2, P < 0.01). TG, apoB and apoC-III content of light and dense VLDL were lower in African-Americans (all P < 0.05 except for apoC-III in light VLDL, P = 0.11). ApoE content did not vary by race. In REM, VAT but not SI influenced the TG concentration of VLDL. In models with race, SI, VAT and all apolipoproteins entered, race was not significant but apoC-III and VAT remained significant determinants of TG concentration in light and dense VLDL., Conclusions: Low concentrations of apoC-III and VAT in African-Americans contribute to race differences in TG concentrations., Trial Registration: ClinicalTrials.gov Identifier: NCT00484861.