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Association of the gut microbiota and fecal short-chain fatty acids with skeletal muscle mass and strength in children.
Chen, F, Li, Q, Chen, Y, Wei, Y, Liang, J, Song, Y, Shi, L, Wang, J, Mao, L, Zhang, B, et al
FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2022;(1):e22109
Abstract
We aimed to investigate whether the gut microbiota and fecal short-chain fatty acids (SCFAs) are associated with skeletal muscle mass and strength in healthy Chinese children aged 6-9 years. In this study, 412 children were enrolled. 16S rRNA gene sequencing was used to characterize the gut microbiota compositions. Fecal SCFAs were quantified using high-performance liquid chromatography. Dual X-ray absorptiometry was used to measure the total body lean soft tissue mass (TSM), total body fat mass (TBF), appendicular skeletal muscle mass (ASM), and appendicular fat mass (AFM). TSM/height2 (TSMI), ASM/height2 (ASMI), TSM/weight (TSMR), ASM/weight (ASMR), and the ratio of TSM/TBF and ASM/AFM were calculated. Handgrip strength (HGS) was measured using the Jamar® Plus+ Hand Dynamometer. A multiple regression analysis after adjustment for covariates and multiple test correction showed some operational taxonomic units in partial least squares models identified by Multivariate methods with Unbiased Variable selection analysis such as genera of Faecalibacterium, Lachnospira, Lachnospiraceae_ND3007_group, and Lachnospiraceae_UCG-004 were positively correlated with at least one measure of TSM, TSMI, ASM, ASMI, and ASMI Z-score (β: 0.103-0.143, pFDR : .008-.032) but negatively correlated with at least one measure of TSMR, TSM/TBF, ASMR, ASM/AFM, and ASMR Z-score (β: -0.185 to 0.124, pFDR = .008-.045). Children with higher fecal butyric acid, acetic acid, and total SCFA levels exhibited higher TSM, ASM, TSMI, ASMI, and ASMI Z-score and lower TSM/TBF, ASM/AFM, TSMR, ASMR, and ASMR Z-score. However, after additional adjustment for TBF or body mass index, only the associations for Faecalitalea and Pyramidobacter still existed. Mediation analysis suggested that total body fat significantly mediated 66.3%-95.3% of the estimated association of microbiota and SCFAs with TSM, ASM, and ASMI Z-score. Our results suggest that the associations of gut microbiota and SCFAs with skeletal muscle quality in children may largely depend upon on total body fat content.
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Single nucleotide polymorphism of fatty acid desaturase gene and breast cancer risk in estrogen receptor subtype.
Preethika, A, Sonkusare, S, Suchetha Kumari, N
Gene. 2022;:146330
Abstract
BACKGROUND Breast cancer (BC) is the most common cancer of women and the second most common cancer overall globally. Data suggest that the plasma concentration of omega fatty acids (n-3 and n-6) and the impact of the genetic variant are associated with diet-related inflammatory disease, BC. This study was aimed to find an association between genetic variant rs174537 of fatty acid desaturase gene 1(FADS 1) and breast cancer estrogen receptor subtype. METHODOLOGY Hundred and two blood samples from women were quantified for fatty acids by gas chromatography. SNP rs 174537(G > T) showed maximum variability and the strongest genetic determinant in the Genome-wide association study were genotyped using Sanger sequencing. RESULTS The highest tertile of ALA showed a significantly reduced risk of BC compared to the lowest tertile (OR = 0.2, 95 %CL = 0.1-1.14, P = 0.03). Median values of ALA were higher in GT/TT genotype in ER +ve molecular subtype (P = 0.03) and DPA was higher in GG genotype of ER-ve molecular subtype (P = 0.037). When both the groups were put together the highest tertile of GG tertile showed significantly reduced risk of BC compared with the other lowest tertiles of GG and GT/TT genotypes (OR, 95% CL = 0.45(0.2-0.9). CONCLUSION The high levels of arachidonic acid and low levels of n-3 fatty acids result in a pro-inflammatory milieu and that these pro-inflammatory effects might contribute to BC. We conclude that the individuals with genetically determined lower activity of FADS1(minor allele T) will derive greater advantage from n-3 FAs than those with higher FADS1 activity (G allele) and reduce the BC risk.
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Increased serum cholesterol and long-chain fatty acid levels are associated with the efficacy of nivolumab in patients with non-small cell lung cancer.
Karayama, M, Inui, N, Inoue, Y, Yoshimura, K, Mori, K, Hozumi, H, Suzuki, Y, Furuhashi, K, Fujisawa, T, Enomoto, N, et al
Cancer immunology, immunotherapy : CII. 2022;(1):203-217
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Abstract
BACKGROUND Lipids have immunomodulatory functions and the potential to affect cancer immunity. METHODS The associations of pretreatment serum cholesterol and long-chain fatty acids with the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were evaluated in 148 patients with non-small cell lung cancer who received nivolumab. RESULTS When each lipid was separately evaluated, increased low-density lipoprotein (LDL)-cholesterol (P < 0.001), high-density lipoprotein (HDL)-cholesterol (P = 0.014), total cholesterol (P = 0.007), lauric acid (P = 0.015), myristic acid (P = 0.022), myristoleic acid (P = 0.035), stearic acid (P = 0.028), linoleic acid (P = 0.005), arachidic acid (P = 0.027), eicosadienoic acid (P = 0.017), dihomo-γ-linolenic acid (P = 0.036), and behenic acid levels (P = 0.032) were associated with longer PFS independent of programmed death ligand 1 (PD-L1) expression. Meanwhile, increased LDL-cholesterol (P < 0.001), HDL-cholesterol (P = 0.009), total cholesterol (P = 0.036), linoleic acid (P = 0.014), and lignoceric acid levels (P = 0.028) were associated with longer OS independent of PD-L1 expression. When multiple lipids were evaluated simultaneously, LDL-cholesterol (P = 0.003), HDL-cholesterol (P = 0.036), and lauric acid (P = 0.036) were independently predictive of PFS, and LDL-cholesterol (P = 0.008) and HDL-cholesterol (P = 0.031) were predictive of OS. ORR was not associated with any serum lipid. CONCLUSIONS Based on the association of prolonged survival in patients with increased serum cholesterol and long-chain fatty acid levels, serum lipid levels may be useful for predicting the efficacy of immune checkpoint inhibitor therapy.
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Role of Bempedoic Acid in Clinical Practice.
Ballantyne, CM, Bays, H, Catapano, AL, Goldberg, A, Ray, KK, Saseen, JJ
Cardiovascular drugs and therapy. 2021;(4):853-864
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Abstract
Many patients do not achieve optimal low-density lipoprotein cholesterol (LDL-C) levels with statins alone; others are unable to tolerate statin therapy. Additional non-statin treatment options including ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors, and bile acid sequestrants are often necessary to further reduce the risk of atherosclerotic cardiovascular disease. This review provides practical guidance as to the use of bempedoic acid to lower LDL-C and includes direction as to which patients may benefit and advice for safety monitoring during treatment. Bempedoic acid, a new class of agent, is a prodrug converted to bempedoyl-CoA by very long-chain acyl-CoA synthetase 1, an enzyme with high expression in the liver but that is undetectable in the skeletal muscle. Bempedoic acid inhibits the enzyme adenosine triphosphate (ATP)-citrate lyase, which lies two steps upstream from β-hydroxy β-methylglutaryl-CoA reductase in the cholesterol biosynthesis pathway. In clinical trials conducted in patients with or at risk for atherosclerotic cardiovascular disease or familial heterozygous hypercholesterolemia, bempedoic acid in combination with statins and/or ezetimibe significantly reduced LDL-C, apolipoprotein B, and high-sensitivity C-reactive protein compared with placebo. Bempedoic acid is generally well tolerated with no clinically meaningful increase in muscle-related symptoms relative to placebo, even in patients taking maximally tolerated statins. A small increase in serum uric acid (mean increase 0.8 mg/dL) is the most noteworthy adverse effect. Bempedoic acid provides an effective and generally well-tolerated medication to further reduce LDL-C in patients taking maximally tolerated statins or manage LDL-C levels in those who are unable to take statins. The potential for a reduced incidence of major cardiovascular events with bempedoic acid is being investigated in the CLEAR Outcomes trial, with results expected in 2023.
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Effects of gut microbiota and fatty acid metabolism on dyslipidemia following weight-loss diets in women: Results from a randomized controlled trial.
Ma, Y, Sun, Y, Sun, L, Liu, X, Zeng, R, Lin, X, Li, Y
Clinical nutrition (Edinburgh, Scotland). 2021;(11):5511-5520
Abstract
BACKGROUND & AIMS In our early feeding trial among overweight and obese Chinese women, both low-carbohydrate (LC) and calorie-restricted (CR) diets reduced weight and fat mass, but only the LC diet significantly improved dyslipidemia. We aimed to investigate the impacts of altered gut microbiota, fatty acid (FAs), and acylcarnitines, markers of mitochondrial function on blood lipids. METHODS Fecal and blood samples from 48 participants at baseline and the end of a 12-week trial were used to perform metagenomics and targeted-metabolomics including erythrocyte FAs and plasma acylcarnitines, respectively. RESULTS The two diets altered microbial structure and co-abundance gene clusters (CAGs) at different magnitudes. After a 12-week intervention, the Bacteroidetes/Firmicutes ratio increased significantly in the LC diet (P = 0.015) but not in the CR diet, which only showed an increased trend (P = 0.28). At the microbial function level, the LC group showed lower branched-chain amino acid biosynthesis and higher serine biosynthesis than the CR group. Moreover, the LC diet reduced levels of 14:0 and 16:1n-7 FAs in the de novo lipogenesis pathway, but increased 20:5n-3 compared with the CR diet. Both groups had increased plasma acylcarnitines except that the LC group had larger elevated short-chain acylcarnitines. After backward stepwise selection, a cluster of changed CAGs, FAs and acylcarnitines were found to be associated with improved lipid profile. However, changed CAGs showed higher contribution rates in elevating HDL-cholesterol (81.6%) and reducing triglycerides (89.3%) than changed FAs and acylcarnitines. CONCLUSIONS The two weight-loss diets induced different changes of gut microbiota, plasma acylcarnitines, and erythrocyte FAs. Changes in gut microbiota rather than FA or acylcarnitine profiles showed greater contribution to improved lipid profile in these overweight and obese Chinese women. TRIAL REGISTRATION The trial was registered at http://clinicaltrials.gov/show/NCT01358890.
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Dietary fatty acids as nutritional modulators of sirtuins: a systematic review.
Caldas, APS, Rocha, DMUP, Bressan, J, Hermsdorff, HHM
Nutrition reviews. 2021;(2):235-246
Abstract
CONTEXT The sirtuins (SIRT1 to SIRT7) constitute a family of highly conserved nicotinamide adenine dinucleotide-dependent proteins. When activated, sirtuins control essential cellular processes to maintain metabolic homeostasis, while lack of expression of sirtuins has been related to chronic disease. OBJECTIVE The aim of this systematic review is to analyze the role of fat consumption as a modulator of human sirtuins. DATA SOURCES This review was conducted according to PRISMA guidelines. Studies were identified by searches of the electronic databases PubMed/MEDLINE, Scopus, and Web of Science. STUDY SELECTION Randomized clinical trials assessing the effect of fatty acid consumption on sirtuin mRNA expression, sirtuin protein expression, or sirtuin protein activity were eligible for inclusion. DATA EXTRACTION Two authors screened and determined the quality of the studies; disagreements were resolved by the third author. All authors compared the compiled data. RESULTS Seven clinical studies with 3 different types of interventions involving healthy and nonhealthy participants were selected. Only SIRT1 and SIRT3 were evaluated. Overall, the evidence from clinical studies to date is insufficient to understand how lipid consumption modulates sirtuins in humans. The best-characterized mechanism highlights oleic acid as a natural activator of SIRT1. CONCLUSION These results draw attention to a new field of interest in nutrition science. The possible activation of sirtuins by dietary fat manipulation may represent an important nutritional strategy for management of chronic and metabolic disease. SYSTEMATIC REVIEW REGISTRATION PROSPERO registration number CRD42018114456.
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Rationale and design of the CLEAR-outcomes trial: Evaluating the effect of bempedoic acid on cardiovascular events in patients with statin intolerance.
Nicholls, S, Lincoff, AM, Bays, HE, Cho, L, Grobbee, DE, Kastelein, JJ, Libby, P, Moriarty, PM, Plutzky, J, Ray, KK, et al
American heart journal. 2021;:104-112
Abstract
Although statins play a pivotal role in the prevention of atherosclerotic cardiovascular disease, many patients fail to achieve recommended lipid levels due to statin-associated muscle symptoms. Bempedoic acid is an oral pro-drug that is activated in the liver and inhibits cholesterol synthesis in hepatocytes, but is not activated in skeletal muscle which has the potential to avoid muscle-related adverse events. Accordingly, this agent effectively lowers atherogenic lipoproteins in patients who experience statin-associated muscle symptoms. However, the effects of bempedoic acid on cardiovascular morbidity and mortality have not been studied. STUDY DESIGN Cholesterol Lowering via Bempedoic acid, an ACL-Inhibiting Regimen (CLEAR) Outcomes is a randomized, double-blind, placebo-controlled clinical trial. Included patients must have all of the following: (i) established atherosclerotic cardiovascular disease or have a high risk of developing atherosclerotic cardiovascular disease, (ii) documented statin intolerance, and (iii) an LDL-C ≥100 mg/dL on maximally-tolerated lipid-lowering therapy. The study randomized 14,014 patients to treatment with bempedoic acid 180 mg daily or matching placebo on a background of guideline-directed medical therapy. The primary outcome is a composite of the time to first cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization. The trial will continue until 1620 patients experience a primary endpoint, with a minimum of 810 hard ischemic events (cardiovascular death, nonfatal myocardial infarction or nonfatal stroke) and minimum treatment duration of 36 months and a projected median treatment exposure of 42 months. CONCLUSIONS CLEAR Outcomes will determine whether bempedoic acid 180 mg daily reduces the incidence of adverse cardiovascular events in high vascular risk patients with documented statin intolerance and elevated LDL-C levels.
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The Pharmacokinetics of Triheptanoin and Its Metabolites in Healthy Subjects and Patients With Long-Chain Fatty Acid Oxidation Disorders.
Lee, SK, Gupta, M, Shi, J, McKeever, K
Clinical pharmacology in drug development. 2021;(11):1325-1334
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Long-chain fatty acid oxidation disorders (LC-FAODs) are a group of life-threatening autosomal recessive disorders caused by defects in nuclear genes encoding mitochondrial enzymes involved in the conversion of dietary long-chain fatty acids into energy. Triheptanoin is an odd-carbon, medium-chain triglyceride consisting of 3 fatty acids with 7 carbons each on a glycerol backbone developed to treat adult and pediatric patients with LC-FAODs. The pharmacokinetics of triheptanoin and circulating metabolites were explored in healthy subjects and patients with LC-FAODs using noncompartmental analyses. Systemic exposure to triheptanoin following an oral administration was negligible, as triheptanoin is extensively hydrolyzed to glycerol and heptanoate in the gastrointestinal tract. Multiple peaks for triheptanoin metabolites were observed in the plasma following oral administration of triheptanoin, generally coinciding with the time that meals were served. Heptanoate, the pharmacologically active metabolite of triheptanoin supplementing energy sources in patients with LC-FAODs, showed the greatest exposure among the metabolites of triheptanoin in human plasma following oral administration of triheptanoin. The exposure of heptanoate was approximately 10-fold greater than that of beta-hydroxypentoate, a downstream metabolite of heptanoate. Exposure to triheptanoin metabolites appeared to increase following multiple doses as compared with the single dose, and with the increase in triheptanoin dose levels.
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A combination of single nucleotide polymorphisms is associated with the interindividual variability in the blood lipid response to dietary fatty acid consumption in a randomized clinical trial.
Rajendiran, E, Lamarche, B, She, Y, Ramprasath, V, Eck, P, Brassard, D, Gigleux, I, Levy, E, Tremblay, A, Couture, P, et al
The American journal of clinical nutrition. 2021;(2):564-577
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BACKGROUND Blood lipid concentrations display high interindividual variability in response to dietary interventions, partly due to genetic factors. Existing studies have focused on single nucleotide polymorphisms (SNPs) analyzed individually, which only explain a limited fraction of the variability of these complex phenotypes. OBJECTIVE We aimed to identify combinations of SNPs associated with the variability in LDL cholesterol and triglyceride (TG) concentration changes following 5 dietary interventions. DESIGN In a multicenter randomized crossover trial, 92 participants with elevated waist circumference and low HDL cholesterol concentrations consumed 5 isoenergetic diets for 4 wk: a diet rich in saturated fatty acids (SFAs) from cheese, SFA from butter, monounsaturated fatty acids (MUFAs), n-6 polyunsaturated fatty acids (PUFAs), and a diet higher in carbohydrates (CHO). The association between 22 candidate SNPs in genes involved in lipid and bile acid metabolism and transport and changes in LDL cholesterol and TG concentrations was assessed with univariate statistics followed by partial least squares regression. RESULTS Endpoint LDL cholesterol concentrations were significantly different (cheese: 3.18 ± 0.04, butter: 3.31 ± 0.04, MUFA 3.00 ± 0.04, PUFA 2.81 ± 0.04, CHO: 3.11 ± 0.04 mmol/L; P < 0.001) while endpoint TG concentrations were not (P = 0.117). Both displayed consistently elevated interindividual variability following the dietary interventions (CVs of 34.5 ± 2.2% and 55.8 ± 1.8%, respectively). Among the 22 candidate SNPs, only ABCA1-rs2066714 and apolipoprotein E (APOE) isoforms exhibited consistent significant effects, namely on LDL cholesterol concentrations. However, several SNPs were significantly associated with changes in LDL cholesterol and TG concentrations in a diet-specific fashion. Generated multivariate models explained from 16.0 to 33.6% of the interindividual variability in LDL cholesterol concentration changes and from 17.5 to 32.0% of that in TG concentration changes. CONCLUSIONS We report combinations of SNPs associated with a significant part of the variability in LDL cholesterol and TG concentrations following dietary interventions differing in their fatty acid profiles.
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Egg and saturated fat containing breakfasts have no acute effect on acute glycemic control in healthy adults: a randomized partial crossover trial.
Dhanasekara, CS, Dawson, JA, Binks, M, Childress, A, Dhurandhar, NV
Nutrition & diabetes. 2021;(1):34
Abstract
BACKGROUND/OBJECTIVES High egg consumption is associated with poor glycemic control. Considering the widespread consumption of eggs, it is crucial to determine causality in this association. We tested if egg consumption acutely alters glucose disposal in the absence or presence of saturated fat, which is frequently consumed with eggs. SUBJECTS/METHODS In a randomized partial crossover clinical trial, 48 subjects (consuming ≥ 1 egg/week) received two of four isocaloric, macronutrient-matched breakfasts. The groups were defined based on the main ingredient of the breakfasts offered: eggs (EB); saturated fat (SB); eggs and saturated fat (ES); and control, which included a cereal based breakfast (CB). The breakfasts were offered in two testing sessions spaced seven days apart. Six blood samples (pre breakfast (fasting); 30, 60, 90, 120, and 180 minutes post breakfast) were collected to measure glucose and insulin levels. Area under the curves (AUC) were analyzed controlling for the baseline concentrations using mixed-effects models accounting for within-subject dependencies to compare these across breakfast assignments. RESULTS Forty-eight patients (46% males, age 25.8 ± 7.7 years, BMI 25.7 ± 4.6 kg/m2) were included. Neither EB, SB nor ES was associated with a significant difference in AUC of glucose or insulin compared to CB (p > 0.1). CONCLUSIONS Acutely, consumption of egg breakfast with or without accompanying saturated fat does not adversely affect glucose disposal in healthy adults. While this is reassuring for continued egg consumption, a long-term evaluation of egg intake with or without saturated fat would be the next step.