Details of a Researcher - Tomita, Masaru

Papers - Tomita, Masaru

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A serum metabolomics-based profile in low bone mineral density postmenopausal women

Miyamoto T., Hirayama A., Sato Y., Koboyashi T., Katsuyama E., Kanagawa H., Miyamoto H., Mori T., Yoshida S., Fujie A., Morita M., Watanabe R., Tando T., Miyamoto K., Tsuji T., Funayama A., Nakamura M., Matsumoto M., Soga T., Tomita M., Toyama Y.

Bone (Bone) 95 1 - 4 2017

Joint Work, Accepted, ISSN 87563282

Osteoporosis is characterized as a metabolic disorder of bone tissue, and various metabolic markers are now available to support its diagnosis and evaluate treatment effects. Substances produced as end products of metabolomic activities are the correlated factors to the biological or metabolic status, and thus, metabolites are considered highly sensitive markers of particular pathological states, including osteoporosis. Here we undertook comprehensive serum metabolomics analysis in postmenopausal women with or without low bone mineral density (low BMD vs controls) for the first time using capillary electrophoresis/mass spectrometry. Among the metabolites tested, 57 were detected in sera. Levels of hydroxyproline, Gly-Gly and cystine, differed significantly between groups, with Gly-Gly and cystine significantly lower in the low BMD group and hydroxyproline, a reported marker of osteoporosis, significantly higher. Levels of TRACP5b, a bone resorption marker, were significantly higher in the low BMD group, supporting the study's validity. Taken together, our findings represent novel metabolomic profiling in low BMD in postmenopausal women.

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Metabolomic Profiling as a Possible Reverse Engineering Tool for Estimating Processing Conditions of Dry-Cured Hams.

Sugimoto M, Obiya S, Kaneko M, Enomoto A, Honma M, Wakayama M, Soga T, Tomita M.

Journal of Agricultural and Food Chemistry (Journal of Agricultural and Food Chemistry) 65 ( 2 ) 402 - 410 2017

Joint Work, Accepted, ISSN 00218561

Dry-cured hams are popular among consumers. To increase the attractiveness of the product, objective analytical methods and algorithms to evaluate the relationship between observable properties and consumer acceptability are required. In this study, metabolomics, which is used for quantitative profiling of hundreds of small molecules, was applied to 12 kinds of drycured hams from Japan and Europe. In total, 203 charged metabolites, including amino acids, organic acids, nucleotides, and peptides, were successfully identified and quantified. Metabolite profiles were compared for the samples with different countries of origin and processing methods (e.g., smoking or use of a starter culture). Principal component analysis of the metabolite profiles with sensory properties revealed significant correlations for redness, homogeneity, and fat whiteness. This approach could be used to design new ham products by objective evaluation of various features.

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Rearing and observation of immature stages of the hoverfly Microdon katsurai (Diptera, Syrphidae)

Iwai,H., Horikawa, D., Arakawa, K., Tomita, M., Komatsu, T. and Maruyama, M.

Biodiversity Data Journal (Biodiversity Data Journal) 4 ( 1 ) e10185 2017

Joint Work, Accepted, ISSN 1314-2828

Background The hoverfly Microdon (Chymophila) katsurai Maruyama et Hironaga 2004 was speculated to be a myrmecophilous species associated with the ant Polyrhachis lamellidens based on observations of adults near the ant nest. However, there have been no reports regarding the observation of immature stages of this species in association with P. lamellidens. New information For the first time, we found three M. katsurai larvae inside a P. lamellidens nest and conducted rearing experiments on the larval M. katsurai. P. lamellidens workers did not show any inspection or attack behavior against the M. katsurai larvae under rearing conditions, suggesting that M. katsurai larvae can survive inside a P. lamellidens nest. Although no predatory behavior by the M. katsurai larvae was observed, all the M. katsurai larvae pupated and emerged in a rearing environment. The dorsal surface of the larval M. katsurai has a distinct pale green color with a uniform reticular structure. The puparium of M. katsurai shows several morphological features that are characteristic of the subgenus Chymophila. We conclude that M. katsurai is likely a myrmecophilous species that utilizes P. lamellidens as a specific host and that classification of M. katsurai based on puparium morphology is concordant with that based on adult morphology.

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Alteration of fatty acid chain length of Chlamydomonas reinhardtii by simultaneous expression of medium-chain-specific thioesterase and acyl carrier protein

*Inaba, Y., Nakahigashi, K., Ito, T. and Tomita, M.

Phycological Research 65 ( 1 ) 94 - 99 2017

Joint Work, Accepted, ISSN 13220829

Biofuel from fatty acids with chain lengths of 8–15 (C8–C15) have properties similar to those of conventional diesel and jet fuels, thus, can save time and reduce costs for the refurbishment of engines and maintenance of oiling facilities. Most oil-producing algae yield C16–C18 fatty acids; however, the manipulation of algae using genetic engineering is a promising approach to obtain C8–C15 fatty acids. The introduction of a medium-chain-specific thioesterase (TE) is expected to effectively alter algae to produce medium-chain fatty acids (MCFAs). TE is the main determinant of fatty acid chain length as it releases fatty acids from the acyl carrier protein (ACP) in the fatty acid elongation cycle. In a previous study, the introduction of heterologous C8–C12-specific TEs into Chlamydomonas reinhardtii did not increase the yield of MCFAs. This effect was attributed to a low affinity of the heterologous TEs to C. reinhardtii ACP. Therefore, we introduced both the C10–C14-specific TE gene and the ACP gene from the land plant Cuphea lanceolata into C. reinhardtii. We measured free fatty acids (FFAs) and triacylglycerols (TAGs) in the transformants using liquid chromatography–mass spectrometry. The production of C12:0 and C14:0, chain length 12 and 14 without unsaturation, FFAs was not significantly increased in any of the tested strains. However, we found a slight but significant increase in TAG-containing MCFAs in both TE only and TE–ACP transformants. The increased production rate of C14:0-containing TAGs ranged from 1.25- to 1.58-fold, indicating the ability of medium-chain-specific TE to increase MCFAs. These results suggest that the selection of specific TEs is important when modifying eukaryotic algae to produce MCFAs.

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Differential binding of three major human ADAR isoforms to coding and long non-coding transcripts.

Galipon, J., Ishii, R., Suzuki, Y., Tomita, M., and * Ui-Tei, K.

Genes (Genes) 8 ( 2 ) 68 2017

Joint Work, Accepted, ISSN 2073-4425

RNA editing by deamination of adenosine to inosine is an evolutionarily conserved process involved in many cellular pathways, from alternative splicing to miRNA targeting. In humans, it is carried out by no less than three major adenosine deaminases acting on RNA (ADARs): ADAR1-p150, ADAR1-p110, and ADAR2. However, the first two derive from alternative splicing, so that it is currently impossible to delete ADAR1-p110 without also knocking out ADAR1-p150 expression. Furthermore, the expression levels of ADARs varies wildly among cell types, and no study has systematically explored the effect of each of these isoforms on the cell transcriptome. In this study, RNA immunoprecipitation (RIP)-sequencing on overexpressed ADAR isoforms tagged with green fluorescent protein (GFP) shows that each ADAR is associated with a specific set of differentially expressed genes, and that they each bind to distinct set of RNA targets. Our results show a good overlap with known edited transcripts, establishing RIP-seq as a valid method for the investigation of RNA editing biology.

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Developmental changes in the balance of glycolytic ATP production and oxidative phosphorylation in ventricular cells: A simulation study

Sano HI, Toki T, Naito Y, Tomita M.

Journal of Theoretical Biology (Journal of Theoretical Biology) 419 269 - 277 2017

Joint Work, Accepted, ISSN 00225193

The developmental program of the heart requires accurate regulation to ensure continuous circulation and simultaneous cardiac morphogenesis, because any functional abnormalities may progress to congenital heart malformation. Notably, energy metabolism in fetal ventricular cells is regulated in a manner that differs from adult ventricular cells: fetal cardiomyocytes generally have immature mitochondria and fetal ventricular cells show greater dependence on glycolytic ATP production. However, although various characteristics of energy metabolism in fetal ventricular cells have been reported, to our knowledge, a quantitative description of the contributions of these factors to fetal ventricular cell functions has not yet been established. Here, we constructed a mathematical model to integrate various characteristics of fetal ventricular cells and predicted the contribution of each characteristic to the maintenance of intracellular ATP concentration and sarcomere contraction under anoxic conditions. Our simulation results demonstrated that higher glycogen content, higher hexokinase activity, and lower creatine concentration helped prolong the time for which ventricular cell contraction was maintained under anoxic conditions. The integrated model also enabled us to quantitatively assess the contributions of factors related to energy metabolism in ventricular cells. Because fetal cardiomyocytes exhibit similar energy metabolic profiles to stem cell-derived cardiomyocytes and those in the failing heart, an improved understanding of these fetal ventricular cells will contribute to a better comprehension of the processes in stem cell-derived cardiomyocytes or under pathological conditions.

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Evolutionary Analysis of HIV-1 Pol Proteins Reveals Representative Residues for Viral Subtype Differentiation

Nagata S, Imai J, Makino G, Tomita M, Kanai A.

Frontiers in Microbiology (Frontiers in Microbiology) 8 ( NOV ) 2151 2017

ISSN 1664-302X

RNA viruses have been used as model systems to understand the patterns and processes of molecular evolution because they have high mutation rates and are genetically diverse. Human immunodeficiency virus 1 (HIV-1), the etiological agent of acquired immune deficiency syndrome, is highly genetically diverse, and is classified into several groups and subtypes. However, it has been difficult to use its diverse sequences to establish the overall phylogenetic relationships of different strains or the trends in sequence conservation with the construction of phylogenetic trees. Our aims were to systematically characterize HIV-1 subtype evolution and to identify the regions responsible for HIV-1 subtype differentiation at the amino acid level in the Pol protein, which is often used to classify the HIV-1 subtypes. In this study, we systematically characterized the mutation sites in 2,052 Pol proteins from HIV-1 group M (144 subtype A; 1,528 subtype B; 380 subtype C), using sequence similarity networks. We also used spectral clustering to group the sequences based on the network graph structures. A stepwise analysis of the cluster hierarchies allowed us to estimate a possible evolutionary pathway for the Pol proteins. The subtype A sequences also clustered according to when and where the viruses were isolated, whereas both the subtype B and C sequences remained as single clusters. Because the Pol protein has several functional domains, we identified the regions that are discriminative by comparing the structures of the domain-based networks. Our results suggest that sequence changes in the RNase H domain and the reverse transcriptase (RT) connection domain are responsible for the subtype classification. By analyzing the different amino acid compositions at each site in both domain sequences, we found that a few specific amino acid residues (i.e., M357 in the RT connection domain and Q480, Y483, and L491 in the RNase H domain) represent the differences among the subtypes. These residues were located on the surface of the RT structure and in the vicinity of the amino acid sites responsible for RT enzymatic activity or function.

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Thymidine Catabolism as a Metabolic Strategy for Cancer Survival

Tabata S, Yamamoto M, Goto H, Hirayama A, Ohishi M, Kuramoto T, Mitsuhashi A, Ikeda R, Haraguchi M, Kawahara K, Shinsato Y, Minami K, Saijo A, Hanibuchi M, Nishioka Y, Sone S, Esumi H, Tomita M, Soga T, Furukawa T, Akiyama SI.

Cell Reports (Cell Reports) 19 ( 7 ) 1313-1321 - 1321 2017

Thymidine phosphorylase (TP), a rate-limiting enzyme in thymidine catabolism, plays a pivotal role in tumor progression; however, the mechanisms underlying this role are not fully understood. Here, we found that TP-mediated thymidine catabolism could supply the carbon source in the glycolytic pathway and thus contribute to cell survival under conditions of nutrient deprivation. In TP-expressing cells, thymidine was converted to metabolites, including glucose 6-phosphate, lactate, 5-phospho-α-D-ribose 1-diphosphate, and serine, via the glycolytic pathway both in vitro and in vivo. These thymidine-derived metabolites were required for the survival of cells under low-glucose conditions. Furthermore, activation of thymidine catabolism was observed in human gastric cancer. These findings demonstrate that thymidine can serve as a glycolytic pathway substrate in human cancer cells.

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Dynamic Organization of Chromatin Domains Revealed by Super-Resolution Live-Cell Imaging

Nozaki T, Imai R, Tanbo M, Nagashima R, Tamura S, Tani T, Joti Y, Tomita M, Hibino K, Kanemaki MT, Wendt KS, Okada Y, Nagai T, Maeshima K.

Molecular Cell (Molecular Cell) 67 ( 2 ) 282-293 - 293.e7 2017

ISSN 10972765

The eukaryotic genome is organized within cells as chromatin. For proper information output, higher-order chromatin structures can be regulated dynamically. How such structures form and behave in various cellular processes remains unclear. Here, by combining super-resolution imaging (photoactivated localization microscopy [PALM]) and single-nucleosome tracking, we developed a nuclear imaging system to visualize the higher-order structures along with their dynamics in live mammalian cells. We demonstrated that nucleosomes form compact domains with a peak diameter of ∼160 nm and move coherently in live cells. The heterochromatin-rich regions showed more domains and less movement. With cell differentiation, the domains became more apparent, with reduced dynamics. Furthermore, various perturbation experiments indicated that they are organized by a combination of factors, including cohesin and nucleosome-nucleosome interactions. Notably, we observed the domains during mitosis, suggesting that they act as building blocks of chromosomes and may serve as information units throughout the cell cycle.

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Draft Genome Sequence of Roseovarius sp. A-2, an Iodide-Oxidizing Bacterium Isolated from Natural Gas Brine Water, Chiba, Japan.

Yuliana T, Nakajima N, Yamamura S, Tomita M, Suzuki H, Amachi S

Journal of genomics 5 51 - 53 2017

ISSN 1839-9940

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18S Ribosomal RNA Gene Phylogeny of a Colonial Volvocalean Lineage (Tetrabaenaceae-Goniaceae-Volvocaceae, Volvocales, Chlorophyceae) and Its Close Relatives

Takashi Nakada, Takuro Ito, Masaru Tomita

The Journal of Japanese Botany 345 - 354 2016.12

Serum metabolome profiles characterized by patients with hepatocellular carcinoma associated with hepatitis B and C

Saito T, Sugimoto M, Okumoto K, Haga H, Katsumi T, Mizuno K, Nishina T, Sato S, Igarashi K, Maki H, Tomita M, Ueno Y, Soga T.

World Journal of Gastroenterology (World Journal of Gastroenterology) 22 ( 27 ) 6224 - 6234 2016.07

ISSN 10079327

AIM: To clarify the characteristics of metabolite profiles in virus-related hepatocellular carcinoma (HCC) patients using serum metabolome analysis. METHODS: The serum levels of low-molecular-weight metabolites in 68 patients with HCC were quantified using capillary electrophoresis chromatography and mass spectrometry. Thirty and 38 of the patients suffered from hepatitis B virus-related HCC (HCC-B) and hepatitis C virus-related HCC (HCC-C), respectively. RESULTS: The main metabolites characteristic of HCC were those associated with glutathione metabolism, notably 13 γ-glutamyl peptides, which are by-products of glutathione induction. Two major profiles, i.e. , concentration patterns, of metabolites were identified in HCC patients, and these were classified into two groups: an HCC-B group and an HCC-C group including some of the HCC-B cases. The receiver operating characteristic curve for the multiple logistic regression model discriminating HCC-B from HCC-C incorporating the concentrations of glutamic acid, methionine and γ-glutamyl-glycine-glycine showed a highly significant area under the curve value of 0.94 (95%CI: 0.89-1.0, P < 0.0001). CONCLUSION: The serum levels of γ-glutamyl peptides, as well as their concentration patterns, contribute to the development of potential biomarkers for virus-related HCC. The difference in metabolite profiles between HCC-B and HCC-C may reflect the respective metabolic reactions that underlie the different pathogeneses of these two types of HCC.

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Erratum to: Metabolomic profiling reveals novel biomarkers of alcohol intake and alcohol-induced liver injury in community-dwelling men.

Harada S, Takebayashi T, Kurihara A, Akiyama M, Suzuki A, Hatakeyama Y, Sugiyama D, Kuwabara K, Takeuchi A, Okamura T, Nishiwaki Y, Tanaka T, Hirayama A, Sugimoto M, Soga T, Tomita M

Environmental health and preventive medicine 21 ( 4 ) 283 - 284 2016.07

ISSN 1342-078X

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Smad2/3 proteins are required for immobilization-induced skeletal muscle atrophy

Tando T, Hirayama A, Furukawa M, Sato Y, Kobayashi T, Funayama A, Kanaji A, Hao W, Watanabe R, Morita M, Oike T, Miyamoto K, Soga T, Nomura M, Yoshimura A, Tomita M, Matsumoto M, Nakamura M, Toyama Y, Miyamoto T.

Journal of Biological Chemistry (Journal of Biological Chemistry) 291 ( 23 ) 12184 - 12194 2016.06

ISSN 00219258

Skeletal muscle atrophy promotes muscle weakness, limiting activities of daily living. However, mechanisms underlying atrophy remain unclear. Here, we show that skeletal muscle immobilization elevates Smad2/3 protein but not mRNA levels in muscle, promoting atrophy. Furthermore, we demonstrate that myostatin, which negatively regulates muscle hypertrophy, is dispensable for denervation-induced muscle atrophy and Smad2/3 protein accumulation. Moreover, muscle-specific Smad2/3-deficient mice exhibited significant resistance to denervation-induced muscle atrophy. In addition, expression of the atrogenes Atrogin-1 and MuRF1, which underlie muscle atrophy, did not increase in muscles of Smad2/3-deficient mice following denervation. We also demonstrate that serum starvation promotes Smad2/3 protein accumulation in C2C12 myogenic cells, an in vitro muscle atrophy model, an effect inhibited by IGF1 treatment. In vivo, we observed IGF1 receptor deactivation in immobilized muscle, even in the presence of normal levels of circulating IGF1. Denervation-induced muscle atrophy was accompanied by reduced glucose intake and elevated levels of branched-chain amino acids, effects that were Smad2/3-dependent. Thus, muscle immobilization attenuates IGF1 signals at the receptor rather than the ligand level, leading to Smad2/3 protein accumulation, muscle atrophy, and accompanying metabolic changes.

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Phylogenetic Position and Molecular Chronology of a Colonial Green Flagellate, Stephanosphaera pluvialis (Volvocales, Chlorophyceae), among Unicellular Algae

Munakata H., Nakada T., Nakahigashi K., Nozaki H., Tomita M.

Journal of Eukaryotic Microbiology (Journal of Eukaryotic Microbiology) 63 ( 3 ) 340 - 348 2016.05

ISSN 10665234

The genus Balticola comprises a group of unicellular green flagellate algae and is composed of four species formerly classified in the genus Haematococcus. Balticola is closely related to a colonial green flagellate, Stephanosphaera pluvialis. Although the phylogeny among these genera was previously investigated based on two nuclear gene sequences, the phylogenetic sister of S. pluvialis has yet to be determined. In the present study, the species diversity of Balticola and Stephanosphaera was investigated using 18S rRNA gene sequences, and phylogenetic analyses of combined nuclear and chloroplast gene sequences were performed to understand the evolutionary origin of coloniality in Stephanosphaera. The divergence times of four colonial volvocalean flagellates from their respective unicellular sisters were also estimated. Six Balticola genotypes and a single Stephanosphaera genotype were recognized, and one Balticola genotype was resolved as the sister of S. pluvialis, showing that Balticola is a nonmonophyletic genus. The divergence time of Stephanosphaera from its nearest Balticola relative was estimated to be 4-63 million years ago, and these genera represent the most recently diverged pair of unicellular and colonial flagellates among the Volvocales.

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Combination of quantitative changes in ionic components to enhance the contractile force during T-tubule development

Wakita M., Sano H.I., Naito Y., Tomita M.

Computing in Cardiology 43 1093 - 1096 2016.03

ISSN 23258861

During rodent ventricular cell development, the sarcoplasmic reticulum (SR) is scarce and poorly organized. A Ca2+ transient in embryonic ventricular cells depends mostly on Ca2+ influx through L-type Ca2+ channels. In rat ventricular cells, transverse tubules (t-tubules) begin to form postnatally. As such, Ca2+-induced Ca2+ release (CICR), in which ryanodine receptor channels on the SR are activated via Ca2+ influx through L-type Ca2+ channels on the t-tubules, is not established in embryonic ventricular cells. Here, we modeled developmental changes in Guinea pig ventricular cells and identified the factors that enhance contraction of the cells with an increase in CICR.

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Simulation study on the balance of glycolytic ATP production and oxidative phosphorylation in embryonic and adult ventricular cells

Sano H.I., Naito Y., Tomita M.

Computing in Cardiology 43 249 - 252 2016.03

ISSN 23258861

Here, we integrated various characteristics of fetal ventricular cells based on a mathematical model and predicted the contribution of each characteristic to maintenance of intracellular ATP concentration and sarcomere contraction under anoxic conditions. Our simulation results showed that higher glycogen content, higher hexokinase activity, and lower creatine concentration helped to prolong the time that contraction of ventricular cells was maintained under anoxic conditions. The integrated model enabled us to quantitatively assess the contributions of factors related to energy metabolism in ventricular cells.

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Metabolomic profiling reveals novel biomarkers of alcohol intake and alcohol-induced liver injury in community-dwelling men

Harada S., Takebayashi T., Kurihara A., Akiyama M., Suzuki A., Hatakeyama Y., Sugiyama D., Kuwabara K., Takeuchi A., Okamura T., Nishiwaki Y., Tanaka T., Hirayama A., Sugimoto M., Soga T., Tomita M.

Environmental Health and Preventive Medicine (Environmental Health and Preventive Medicine) 21 ( 1 ) 18 - 26 2016.01

ISSN 1342078X

Objective: Metabolomics is a promising approach to the identification of biomarkers in plasma. Here, we performed a population-based, cross-sectional study to identify potential biomarkers of alcohol intake and alcohol-induced liver injury by metabolomic profiling using capillary electrophoresis-mass spectrometry (CE-MS). Methods: Fasting plasma samples were collected from 896 Japanese men who participated in the baseline survey of the Tsuruoka Metabolomics Cohort Study, and 115 polar metabolites were identified and absolutely quantified by CE-MS. Information on daily ethanol intake was collected through a standardized, self-administered questionnaire. The associations between ethanol intake and plasma concentration of metabolites were examined. Relationships between metabolite concentrations or their ratios and serum liver enzyme levels in the highest ethanol intake group (>46.0 g/day) were then examined by linear regression analysis. Replication analysis was conducted in 193 samples collected from independent population of this cohort. Results: Nineteen metabolites were identified to have an association with daily alcohol consumption both in the original and replication population. Three of these metabolites (threonine, glutamine, and guanidinosuccinate) were found to associate well with elevated levels of serum liver enzymes in the highest ethanol intake group, but not in the non-drinker group. We also found that the glutamate/glutamine ratio had a much stronger relation to serum γ-glutamyltransferase, aspartate transaminase, and alanine transaminase than glutamate or glutamine alone (standardized beta = 0.678, 0.558, 0.498, respectively). Conclusions: We found 19 metabolites associated with alcohol intake, and three biomarker candidates (threonine, guanidinosuccinate and glutamine) of alcohol-induced liver injury. Glutamate/glutamine ratio might also be good biomarker.

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Conversion of graded phosphorylation into switch-like nuclear translocation via autoregulatory mechanisms in ERK signalling

Shindo Y, Iwamoto K, Mouri K, Hibino K, Tomita M, Kosako H, Sako Y, Takahashi K.

Nature Communications (Nature Communications) 7 10485 2016.01

The phosphorylation cascade in the extracellular signal-regulated kinase (ERK) pathway is a versatile reaction network motif that can potentially act as a switch, oscillator or memory. Nevertheless, there is accumulating evidence that the phosphorylation response is mostly linear to extracellular signals in mammalian cells. Here we find that subsequent nuclear translocation gives rise to a switch-like increase in nuclear ERK concentration in response to signal input. The switch-like response disappears in the presence of ERK inhibitor, suggesting the existence of autoregulatory mechanisms for ERK nuclear translocation involved in conversion from a graded to a switch-like response. In vitro reconstruction of ERK nuclear translocation indicates that ERK-mediated phosphorylation of nucleoporins regulates ERK translocation. A mathematical model and knockdown experiments suggest a contribution of nucleoporins to regulation of the ERK nuclear translocation response. Taken together, this study provides evidence that nuclear translocation with autoregulatory mechanisms acts as a switch in ERK signalling.

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Profiling of plasma metabolites in postmenopausal women with metabolic syndrome

Iida M., Harada S., Kurihara A., Fukai K., Kuwabara K., Sugiyama D., Takeuchi A., Okamura T., Akiyama M., Nishiwaki Y., Suzuki A., Hirayama A., Sugimoto M., Soga T., Tomita M., Banno K., Aoki D., Takebayashi T.

Menopause (Menopause) 23 ( 7 ) 749 - 758 2016

Joint Work, ISSN 10723714

Objective:The aim of the study was to investigate the associations of amino acids and other polar metabolites with metabolic syndrome (MetS) in postmenopausal women in a lean Asian population. Methods:The participants were 1,422 female residents enrolled in a cohort study from April to August 2012. MetS was defined according to the National Cholesterol Education Program Adult Treatment Panel III modified for Japanese women. Associations were examined between MetS and 78 metabolites assayed in fasting plasma samples using capillary electrophoresis-mass spectrometry. Replication analysis was performed to confirm the robustness of the results in a separate population created by random allocation. Results:Analysis was performed for 877 naturally postmenopausal women, including 594 in the original population and 283 in the replication population. The average age, body mass index, and levels of high- and low-density lipoprotein cholesterol of the entire population were 64.6 years, 23.0kg/m2, 72.1mg/dL, and 126.1mg/dL, respectively. There was no significant difference in low-density lipoprotein cholesterol levels between women with and without MetS. Thirteen metabolites were significantly related to MetS: multiple plasma amino acids were elevated in women with MetS, including branched-chain amino acids, alanine, glutamate, and proline; and alpha-aminoadipate, which is generated by lysine degradation, was also significantly increased. Conclusions:Our large-scale metabolomic profiling indicates that Japanese postmenopausal women with MetS have abnormal polar metabolites, suggesting altered catabolic pathways. These results may help to understand metabolic disturbance, including in persons with normal body mass index and relatively high levels of high-density lipoprotein cholesterol, and may have clinical utility based on further studies.

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