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Nature Apr 2024Genome-wide association analyses using high-throughput metabolomics platforms have led to novel insights into the biology of human metabolism. This detailed knowledge of...
Genome-wide association analyses using high-throughput metabolomics platforms have led to novel insights into the biology of human metabolism. This detailed knowledge of the genetic determinants of systemic metabolism has been pivotal for uncovering how genetic pathways influence biological mechanisms and complex diseases. Here we present a genome-wide association study for 233 circulating metabolic traits quantified by nuclear magnetic resonance spectroscopy in up to 136,016 participants from 33 cohorts. We identify more than 400 independent loci and assign probable causal genes at two-thirds of these using manual curation of plausible biological candidates. We highlight the importance of sample and participant characteristics that can have significant effects on genetic associations. We use detailed metabolic profiling of lipoprotein- and lipid-associated variants to better characterize how known lipid loci and novel loci affect lipoprotein metabolism at a granular level. We demonstrate the translational utility of comprehensively phenotyped molecular data, characterizing the metabolic associations of intrahepatic cholestasis of pregnancy. Finally, we observe substantial genetic pleiotropy for multiple metabolic pathways and illustrate the importance of careful instrument selection in Mendelian randomization analysis, revealing a putative causal relationship between acetone and hypertension. Our publicly available results provide a foundational resource for the community to examine the role of metabolism across diverse diseases.
Topics: Female; Humans; Pregnancy; Acetone; Biomarkers; Cholestasis, Intrahepatic; Cohort Studies; Genome-Wide Association Study; Hypertension; Lipoproteins; Magnetic Resonance Spectroscopy; Mendelian Randomization Analysis; Metabolic Networks and Pathways; Metabolomics; Phenotype; Polymorphism, Single Nucleotide; Pregnancy Complications
PubMed: 38448586
DOI: 10.1038/s41586-024-07148-y -
Nutrients Aug 2023The ketogenic diet (KD) restricts carbohydrate consumption, leading to an increase in ketone bodies, such as acetoacetate, β-hydroxybutyrate, and acetone, which are... (Review)
Review
The ketogenic diet (KD) restricts carbohydrate consumption, leading to an increase in ketone bodies, such as acetoacetate, β-hydroxybutyrate, and acetone, which are utilized as energy substrates. This dietary approach impacts several biochemical processes, resulting in improved clinical management of various disorders, particularly in childhood. However, the exact mechanisms underlying the efficacy of KD remain unclear. Interestingly, KD may also impact the gut microbiota, which plays a pivotal role in metabolism, nutrition, and the development of the immune and nervous systems. KD has gained popularity for its potential benefits in weight loss, blood sugar control, and certain neurological conditions. This narrative review sums up KD-related studies published over 30 years. While short-term studies have provided valuable insights into the effects of KD on the gut microbiota, persistent uncertainties surround its long-term efficacy and potential for inducing dysbiosis. The significant influence of KD on epigenetic mechanisms, intracellular pathways, and gut microbial composition underscores its potential as a therapeutic choice. However, a judicious consideration of the potential risks associated with the strict adherence to a low-carbohydrate, high-fat, and high-protein regimen over prolonged periods is imperative. As KDs gain popularity among the adolescent and young adult demographic for weight management, it becomes imperative to undertake additional research to comprehensively assess their impact on nutritional status and gut microbiota, ensuring a holistic and sustainable approach to medical nutrition.
Topics: Adolescent; Young Adult; Humans; Diet, Ketogenic; Gastrointestinal Microbiome; 3-Hydroxybutyric Acid; Acetone; Carbohydrates
PubMed: 37686712
DOI: 10.3390/nu15173680 -
International Journal of Environmental... Nov 2021Fluctuating crude oil price and global environmental problems such as global warming and climate change lead to growing demand for the production of renewable chemicals... (Review)
Review
Fluctuating crude oil price and global environmental problems such as global warming and climate change lead to growing demand for the production of renewable chemicals as petrochemical substitutes. Butanol is a nonpolar alcohol that is used in a large variety of consumer products and as an important industrial intermediate. Thus, the production of butanol from renewable resources (e.g., biomass and organic waste) has gained a great deal of attention from researchers. Although typical renewable butanol is produced via a fermentative route (i.e., acetone-butanol-ethanol (ABE) fermentation of biomass-derived sugars), the fermentative butanol production has disadvantages such as a low yield of butanol and the formation of byproducts, such as acetone and ethanol. To avoid the drawbacks, the production of renewable butanol via non-fermentative catalytic routes has been recently proposed. This review is aimed at providing an overview on three different emerging and promising catalytic routes from biomass/organic waste-derived chemicals to butanol. The first route involves the conversion of ethanol into butanol over metal and oxide catalysts. Volatile fatty acid can be a raw chemical for the production of butanol using porous materials and metal catalysts. In addition, biomass-derived syngas can be transformed to butanol on non-noble metal catalysts promoted by alkali metals. The prospect of catalytic renewable butanol production is also discussed.
Topics: Acetone; Biomass; Butanols; Ethanol; Fermentation
PubMed: 34831504
DOI: 10.3390/ijerph182211749 -
Chemical Communications (Cambridge,... Dec 2022We present our design of a cross-catalytic system based on organocatalysis. The system features two organic reactions, namely a deprotection reaction of Fmoc protected...
We present our design of a cross-catalytic system based on organocatalysis. The system features two organic reactions, namely a deprotection reaction of Fmoc protected proline and a Mannich reaction between acetone and dihydroisoquinoline. The products of these two reactions, proline and a tetrahydroisoquinoline, respectively, are capable of reciprocal reaction rate enhancement. Detailed kinetic studies of the system and seeding experiments support the cross-catalytic relationship in the reaction network.
Topics: Kinetics; Catalysis; Proline; Acetone
PubMed: 36448644
DOI: 10.1039/d2cc05610k -
Applied Microbiology and Biotechnology Mar 2017Clostridial acetone-butanol-ethanol (ABE) fermentation features a remarkable shift in the cellular metabolic activity from acid formation, acidogenesis, to the... (Review)
Review
Clostridial acetone-butanol-ethanol (ABE) fermentation features a remarkable shift in the cellular metabolic activity from acid formation, acidogenesis, to the production of industrial-relevant solvents, solventogensis. In recent decades, mathematical models have been employed to elucidate the complex interlinked regulation and conditions that determine these two distinct metabolic states and govern the transition between them. In this review, we discuss these models with a focus on the mechanisms controlling intra- and extracellular changes between acidogenesis and solventogenesis. In particular, we critically evaluate underlying model assumptions and predictions in the light of current experimental knowledge. Towards this end, we briefly introduce key ideas and assumptions applied in the discussed modelling approaches, but waive a comprehensive mathematical presentation. We distinguish between structural and dynamical models, which will be discussed in their chronological order to illustrate how new biological information facilitates the 'evolution' of mathematical models. Mathematical models and their analysis have significantly contributed to our knowledge of ABE fermentation and the underlying regulatory network which spans all levels of biological organization. However, the ties between the different levels of cellular regulation are not well understood. Furthermore, contradictory experimental and theoretical results challenge our current notion of ABE metabolic network structure. Thus, clostridial ABE fermentation still poses theoretical as well as experimental challenges which are best approached in close collaboration between modellers and experimentalists.
Topics: 1-Butanol; Acetic Acid; Acetone; Batch Cell Culture Techniques; Butyric Acid; Clostridium acetobutylicum; Computer Simulation; Ethanol; Fermentation; Hydrogen-Ion Concentration; Lactic Acid; Metabolic Networks and Pathways; Models, Theoretical; Solvents
PubMed: 28210797
DOI: 10.1007/s00253-017-8137-4 -
Obesity (Silver Spring, Md.) Dec 2015Endogenous acetone production is a by-product of the fat metabolism process. Because of its small size, acetone appears in exhaled breath. Historically, endogenous... (Review)
Review
OBJECTIVE
Endogenous acetone production is a by-product of the fat metabolism process. Because of its small size, acetone appears in exhaled breath. Historically, endogenous acetone has been measured in exhaled breath to monitor ketosis in healthy and diabetic subjects. Recently, breath acetone concentration (BrAce) has been shown to correlate with the rate of fat loss in healthy individuals. In this review, the measurement of breath acetone in healthy subjects is evaluated for its utility in predicting fat loss and its sensitivity to changes in physiologic parameters.
RESULTS
BrAce can range from 1 ppm in healthy non-dieting subjects to 1,250 ppm in diabetic ketoacidosis. A strong correlation exists between increased BrAce and the rate of fat loss. Multiple metabolic and respiratory factors affect the measurement of BrAce. BrAce is most affected by changes in the following factors (in descending order): dietary macronutrient composition, caloric restriction, exercise, pulmonary factors, and other assorted factors that increase fat metabolism or inhibit acetone metabolism. Pulmonary factors affecting acetone exchange in the lung should be controlled to optimize the breath sample for measurement.
CONCLUSIONS
When biologic factors are controlled, BrAce measurement provides a non-invasive tool for monitoring the rate of fat loss in healthy subjects.
Topics: Acetone; Adipose Tissue; Breath Tests; Caloric Restriction; Diabetes Mellitus; Diabetic Ketoacidosis; Exhalation; Fasting; Humans; Lipid Metabolism; Monitoring, Physiologic; Weight Loss
PubMed: 26524104
DOI: 10.1002/oby.21242 -
Biosensors Jan 2021The ketogenic diet, while originally thought to treat epilepsy in children, is now used for weight loss due to increasing evidence indicating that fat is burned more... (Review)
Review
The ketogenic diet, while originally thought to treat epilepsy in children, is now used for weight loss due to increasing evidence indicating that fat is burned more rapidly when there is a low carbohydrate intake. This low carbohydrate intake can lead to elevated ketone levels in the blood and breath. Breath and blood ketones can be measured to gauge the level of ketosis and allow for adjustment of the diet to meet the user's needs. Blood ketone levels have been historically used, but now breath acetone sensors are becoming more common due to less invasiveness and convenience. New technologies are being researched in the area of acetone sensors to capitalize on the rising popularity of the diet. Current breath acetone sensors come in the form of handheld breathalyzer devices. Technologies in development mostly consist of semiconductor metal oxides in different physio-chemical formations. These current devices and future technologies are investigated here with regard to utility and efficacy. Technologies currently in development do not have extensive testing of the selectivity of the sensors including the many compounds present in human breath. While some sensors have undergone human testing, the sample sizes are very small, and the testing was not extensive. Data regarding current devices is lacking and more research needs to be done to effectively evaluate current devices if they are to have a place as medical devices. Future technologies are very promising but are still in early development stages.
Topics: Acetone; Biosensing Techniques; Breath Tests; Diet, Ketogenic; Humans; Ketosis; Weight Reduction Programs
PubMed: 33478049
DOI: 10.3390/bios11010026 -
Scientific Reports Jun 2022This paper presents the use of cyclic voltammetry to measure acetone concentration in liquid and vapor forms at disposable screen-printed electrodes of platinum working...
This paper presents the use of cyclic voltammetry to measure acetone concentration in liquid and vapor forms at disposable screen-printed electrodes of platinum working electrode, platinum counter electrode, and silver/silver chloride reference electrode. The main characteristics of the acetone sensor including its linearity, sensitivity, reproducibility, and limit of detection (LOD) were studied by doing different experiments to test both liquid and vapor samples in the physiological range of 1 µM to 10 mM. The change in acetone concentration was monitored by comparing the lineshape of butterfly region before and after injecting the acetone sample in the baseline solution that contains 0.5 M HSO. The sensor was shown to have a good sensitivity, reproducibility, and a linear response with respect to the acetone concentration in both liquid and gas phases over a range of 1 µM to 10 mM with R > 0.97 and LOD of 0.1 µM. The system stability was improved by building a closed glass system to reduce the exchange of acetone with the surrounding air in an open environment. The closed system was tested using vapor samples and the error bars in the calibration curve were reduced to more than half of their values before using the closed system. The new system will be used extensively in future for an enzyme-based acetone sensor that will be used for diabetes monitoring.
Topics: Acetone; Electrodes; Gases; Limit of Detection; Platinum; Reproducibility of Results
PubMed: 35773395
DOI: 10.1038/s41598-022-15135-4 -
Journal of Dairy Science Nov 2020Ketosis is a metabolic disorder of increasing importance in high-yielding dairy cows, but accurate population-wide binary health trait recording is difficult to...
Ketosis is a metabolic disorder of increasing importance in high-yielding dairy cows, but accurate population-wide binary health trait recording is difficult to implement. Against this background, proper Gaussian indicator traits, which can be routinely measured in milk, are needed. Consequently, we focused on the ketone bodies acetone and β-hydroxybutyrate (BHB), measured via Fourier-transform infrared spectroscopy (FTIR) in milk. In the present study, 62,568 Holstein cows from large-scale German co-operator herds were phenotyped for clinical ketosis (KET) according to a veterinarian diagnosis key. A sub-sample of 16,861 cows additionally had first test-day observations for FTIR acetone and BHB. Associations between FTIR acetone and BHB with KET and with test-day traits were studied phenotypically and quantitative genetically. Furthermore, we estimated SNP marker effects for acetone and BHB (application of genome-wide association studies) based on 40,828 SNP markers from 4,384 genotyped cows, and studied potential candidate genes influencing body fat mobilization. Generalized linear mixed models were applied to infer the influence of binary KET on Gaussian-distributed acetone and BHB (definition of an identity link function), and vice versa, such as the influence of acetone and BHB on KET (definition of a logit link function). Additionally, linear models were applied to study associations between BHB, acetone and test-day traits (milk yield, fat percentage, protein percentage, fat-to-protein ratio and somatic cell score) from the first test-day after calving. An increasing KET incidence was statistically significant associated with increasing FTIR acetone and BHB milk concentrations. Acetone and BHB concentrations were positively associated with fat percentage, fat-to-protein ratio and somatic cell score. Bivariate linear animal models were applied to estimate genetic (co)variance components for KET, acetone, BHB and test-day traits within parities 1 to 3, and considering all parities simultaneously in repeatability models. Pedigree-based heritabilities were quite small (i.e., in the range from 0.01 in parity 3 to 0.07 in parity 1 for acetone, and from 0.03-0.04 for BHB). Heritabilites from repeatability models were 0.05 for acetone, and 0.03 for BHB. Genetic correlations between acetone and BHB were moderate to large within parities and considering all parities simultaneously (0.69-0.98). Genetic correlations between acetone and BHB with KET from different parities ranged from 0.71 to 0.99. Genetic correlations between acetone across parities, and between BHB across parities, ranged from 0.55 to 0.66. Genetic correlations between KET, acetone, and BHB with fat-to-protein ratio and with fat percentage were large and positive, but negative with milk yield. In genome-wide association studies, we identified SNP on BTA 4, 10, 11, and 29 significantly influencing acetone, and on BTA 1 and 16 significantly influencing BHB. The identified potential candidate genes NRXN3, ACOXL, BCL2L11, HIBADH, KCNJ1, and PRG4 are involved in lipid and glucose metabolism pathways.
Topics: 3-Hydroxybutyric Acid; Acetone; Animals; Cattle; Cattle Diseases; Female; Genome-Wide Association Study; Genotype; Glucose; Ketone Bodies; Ketosis; Lactation; Lipid Metabolism; Milk; Parity; Pedigree; Phenotype; Pregnancy
PubMed: 32952022
DOI: 10.3168/jds.2020-18339 -
International Journal of Molecular... Sep 2022Metabolomics is a fundamental approach to discovering novel biomarkers and their potential use for precision medicine. When applied for population screening, NMR-based... (Review)
Review
Metabolomics is a fundamental approach to discovering novel biomarkers and their potential use for precision medicine. When applied for population screening, NMR-based metabolomics can become a powerful clinical tool in precision oncology. Urine tests can be more widely accepted due to their intrinsic non-invasiveness. Our review provides the first exhaustive evaluation of NMR metabolomics for the determination of colorectal cancer (CRC) in urine. A specific search in PubMed, Web of Science, and Scopus was performed, and 10 studies met the required criteria. There were no restrictions on the query for study type, leading to not only colorectal cancer samples versus control comparisons, but also prospective studies of surgical effects. With this review, all compounds in the included studies were merged into a database. In doing so, we identified up to 100 compounds in urine samples, and 11 were found in at least three articles. Results were analyzed in three groups: case (CRC and adenomas)/control, pre-/post-surgery, and combining both groups. When combining the case-control and the pre-/post-surgery groups, up to twelve compounds were found to be relevant. Seven down-regulated metabolites in CRC were identified, creatinine, 4-hydroxybenzoic acid, acetone, carnitine, d-glucose, hippuric acid, l-lysine, l-threonine, and pyruvic acid, and three up-regulated compounds in CRC were identified, acetic acid, phenylacetylglutamine, and urea. The pathways and enrichment analysis returned only two pathways significantly expressed: the pyruvate metabolism and the glycolysis/gluconeogenesis pathway. In both cases, only the pyruvic acid (down-regulated in urine of CRC patients, with cancer cell proliferation effect in the tissue) and acetic acid (up-regulated in urine of CRC patients, with chemoprotective effect) were present.
Topics: Acetates; Acetone; Biomarkers; Carnitine; Colorectal Neoplasms; Creatinine; Glucose; Humans; Lysine; Metabolomics; Precision Medicine; Prospective Studies; Pyruvic Acid; Threonine; Urea
PubMed: 36232473
DOI: 10.3390/ijms231911171