Publications (12)47.66 Total impact
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Article: Cord Serum Lipidome in Prediction of Islet Autoimmunity and Type 1 Diabetes.
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ABSTRACT: Earlier studies show that children who later progress to type 1 diabetes (T1D) have decreased pre-autoimmune concentrations of multiple phospholipids as compared to non-progressors. It is still unclear whether these changes associate with development of β-cell autoimmunity or specifically with clinical T1D. Here we studied umbilical cord serum lipidome in newborn infants who later developed T1D (N=33), infants who developed three or four (N=31), two (N=31), or one (N=48) islet autoantibody during the follow-up, and controls (N=143) matched for gender, HLA-DQB1 genotype, city and period of birth. The analyses of serum molecular lipids were performed using the established lipidomics platform based on Ultra Performance Liquid Chromatography(TM) coupled to mass spectrometry (UPLC-MS). We found that T1D progressors are characterized by a distinct cord blood lipidomic profile which includes reduced major choline-containing phospholipids including sphingomyelins and phosphatidylcholines. A molecular signature was developed comprising seven lipids which predicted high risk for progression to T1D, with an odds ratio of 5.94 (95% CI, 1.07 - 17.50). Reduction in choline-containing phospholipids in cord blood is therefore specifically associated with progression to T1D but not with development of β-cell autoimmunity in general.Diabetes 04/2013; · 8.29 Impact Factor -
Article: Characterization of microbial metabolism of Syrah grape products in an in vitro colon model using targeted and non-targeted analytical approaches.
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ABSTRACT: PURPOSE: Syrah red grapes are used in the production of tannin-rich red wines. Tannins are high molecular weight molecules, proanthocyanidins (PAs), and poorly absorbed in the upper intestine. In this study, gut microbial metabolism of Syrah grape phenolic compounds was investigated. METHODS: Syrah grape pericarp was subjected to an enzymatic in vitro digestion model, and red wine and grape skin PA fraction were prepared. Microbial conversion was screened using an in vitro colon model with faecal microbiota, by measurement of short-chain fatty acids by gas chromatography (GC) and microbial phenolic metabolites using GC with mass detection (GC-MS). Red wine metabolites were further profiled using two-dimensional GC mass spectrometry (GCxGC-TOFMS). In addition, the effect of PA structure and dose on conversion efficiency was investigated by GC-MS. RESULTS: Red wine exhibited a higher degree of C1-C3 phenolic acid formation than PA fraction or grape pericarp powders. Hydroxyphenyl valeric acid (flavanols and PAs as precursors) and 3,5-dimethoxy-4-hydroxybenzoic acid (anthocyanin as a precursor) were identified from the red wine metabolite profile. In the absence of native grape pericarp or red wine matrix, the isolated PAs were found to be effective in the dose-dependent inhibition of microbial conversions and short-chain fatty acid formation. CONCLUSIONS: Metabolite profiling was complementary to targeted analysis. The identified metabolites had biological relevance, because the structures of the metabolites resembled fragments of their grape phenolic precursors or were in agreement with literature data.European Journal of Nutrition 06/2012; · 2.75 Impact Factor -
Article: Insulin signaling regulates fatty acid catabolism at the level of CoA activation.
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ABSTRACT: The insulin/IGF signaling pathway is a highly conserved regulator of metabolism in flies and mammals, regulating multiple physiological functions including lipid metabolism. Although insulin signaling is known to regulate the activity of a number of enzymes in metabolic pathways, a comprehensive understanding of how the insulin signaling pathway regulates metabolic pathways is still lacking. Accepted knowledge suggests the key regulated step in triglyceride (TAG) catabolism is the release of fatty acids from TAG via the action of lipases. We show here that an additional, important regulated step is the activation of fatty acids for beta-oxidation via Acyl Co-A synthetases (ACS). We identify pudgy as an ACS that is transcriptionally regulated by direct FOXO action in Drosophila. Increasing or reducing pudgy expression in vivo causes a decrease or increase in organismal TAG levels respectively, indicating that pudgy expression levels are important for proper lipid homeostasis. We show that multiple ACSs are also transcriptionally regulated by insulin signaling in mammalian cells. In sum, we identify fatty acid activation onto CoA as an important, regulated step in triglyceride catabolism, and we identify a mechanistic link through which insulin regulates lipid homeostasis.PLoS Genetics 01/2012; 8(1):e1002478. · 8.69 Impact Factor -
Article: MPEA--metabolite pathway enrichment analysis.
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ABSTRACT: We present metabolite pathway enrichment analysis (MPEA) for the visualization and biological interpretation of metabolite data at the system level. Our tool follows the concept of gene set enrichment analysis (GSEA) and tests whether metabolites involved in some predefined pathway occur towards the top (or bottom) of a ranked query compound list. In particular, MPEA is designed to handle many-to-many relationships that may occur between the query compounds and metabolite annotations. For a demonstration, we analysed metabolite profiles of 14 twin pairs with differing body weights. MPEA found significant pathways from data that had no significant individual query compounds, its results were congruent with those discovered from transcriptomics data and it detected more pathways than the competing metabolic pathway method did. AVAILABILITY: The web server and source code of MPEA are available at http://ekhidna.biocenter.helsinki.fi/poxo/mpea/.Bioinformatics 07/2011; 27(13):1878-9. · 5.47 Impact Factor -
Article: Association of lipidome remodeling in the adipocyte membrane with acquired obesity in humans.
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ABSTRACT: Identification of early mechanisms that may lead from obesity towards complications such as metabolic syndrome is of great interest. Here we performed lipidomic analyses of adipose tissue in twin pairs discordant for obesity but still metabolically compensated. In parallel we studied more evolved states of obesity by investigating a separated set of individuals considered to be morbidly obese. Despite lower dietary polyunsaturated fatty acid intake, the obese twin individuals had increased proportions of palmitoleic and arachidonic acids in their adipose tissue, including increased levels of ethanolamine plasmalogens containing arachidonic acid. Information gathered from these experimental groups was used for molecular dynamics simulations of lipid bilayers combined with dependency network analysis of combined clinical, lipidomics, and gene expression data. The simulations suggested that the observed lipid remodeling maintains the biophysical properties of lipid membranes, at the price, however, of increasing their vulnerability to inflammation. Conversely, in morbidly obese subjects, the proportion of plasmalogens containing arachidonic acid in the adipose tissue was markedly decreased. We also show by in vitro Elovl6 knockdown that the lipid network regulating the observed remodeling may be amenable to genetic modulation. Together, our novel approach suggests a physiological mechanism by which adaptation of adipocyte membranes to adipose tissue expansion associates with positive energy balance, potentially leading to higher vulnerability to inflammation in acquired obesity. Further studies will be needed to determine the cause of this effect.PLoS Biology 06/2011; 9(6):e1000623. · 11.45 Impact Factor -
Article: Drug metabolome of the simvastatin formed by human intestinal microbiota in vitro.
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ABSTRACT: The human colon contains a diverse microbial population which contributes to degradation and metabolism of food components. Drug metabolism in the colon is generally poorly understood. Metabolomics techniques and in vitro colon models are now available which afford detailed characterization of drug metabolites in the context of colon metabolism. The aim of this work was to identify novel drug metabolites of Simvastatin (SV) by using an anaerobic human in vitro colon model at body temperature coupled with systems biology platform, excluding the metabolism of the host liver and intestinal epithelia. Comprehensive two-dimensional gas chromatography with a time-of-flight mass spectrometry (GC×GC-TOFMS) was used for the metabolomic analysis. Metabolites showing the most significant differences in the active faecal suspension were elucidated in reference with SV fragmentation and compared with controls: inactive suspension or buffer with SV, or with active suspension alone. Finally, time courses of selected metabolites were investigated. Our data suggest that SV is degraded by hydrolytic cleavage of methylbutanoic acid from the SV backbone. Metabolism involves demethylation of dimethylbutanoic acid, hydroxylation/dehydroxylation and β-oxidation resulting in the production of 2-hydroxyisovaleric acid (3-methyl-2-hydroxybutanoic acid), 3-hydroxybutanoic acid and lactic acid (2-hydroxypropanoic acid), and finally re-cyclisation of heptanoic acid (possibly de-esterified and cleaved methylpyranyl arm) to produce cyclohexanecarboxylic acid. Our study elucidates a pathway of colonic microbial metabolism of SV as well as demonstrates the applicability of the in vitro colon model and metabolomics to the discovery of novel drug metabolites from drug response profiles.Molecular BioSystems 11/2010; 7(2):437-46. · 3.53 Impact Factor -
Article: The gut microbiota modulates host energy and lipid metabolism in mice.
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ABSTRACT: The gut microbiota has recently been identified as an environmental factor that may promote metabolic diseases. To investigate the effect of gut microbiota on host energy and lipid metabolism, we compared the serum metabolome and the lipidomes of serum, adipose tissue, and liver of conventionally raised (CONV-R) and germ-free mice. The serum metabolome of CONV-R mice was characterized by increased levels of energy metabolites, e.g., pyruvic acid, citric acid, fumaric acid, and malic acid, while levels of cholesterol and fatty acids were reduced. We also showed that the microbiota modified a number of lipid species in the serum, adipose tissue, and liver, with its greatest effect on triglyceride and phosphatidylcholine species. Triglyceride levels were lower in serum but higher in adipose tissue and liver of CONV-R mice, consistent with increased lipid clearance. Our findings show that the gut microbiota affects both host energy and lipid metabolism and highlights its role in the development of metabolic diseases.The Journal of Lipid Research 05/2010; 51(5):1101-12. · 5.56 Impact Factor -
Article: Detection of molecular paths associated with insulitis and type 1 diabetes
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ABSTRACT: National Graduate School in Informational and Structural Biology - ISB 2009 Winter School. Ylläs, Finland, 7 - 10 Dec. 2009 -
Article: Metabolic phenotypes in preclinical autoimmune diabetes in man and mouse: pathways behind progression to overt disease
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ABSTRACT: Diabetologia Vol.53 Nr.Suppl. 1, S175 46th Annual Meeting of ESDA. Stockholm, Sweden, 20 - 24 Sept. 2010 -
Article: Statistical modeling for the prediction of non-alcoholic fatty liver disease
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ABSTRACT: HEPADIP 2010. Liver & Adipose Tissue in the Metabolic Syndrome. Lausanne, Switzerland, 18 - 20 Oct. 2010, 22 -
Article: Drug metabolome of the Simvastatin formed by human intestinal microbiota in vitro
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ABSTRACT: Molecular BioSystems Vol.7 Nr.2, 437-446 The human colon contains a diverse microbial population which contributes to degradation and metabolism of food components. Drug metabolism in the colon is generally poorly understood. Metabolomics techniques and in vitro colon models are now available which afford detailed characterization of drug metabolites in the context of colon metabolism. The aim of this work was to identify novel drug metabolites of Simvastatin (SV) by using an anaerobic human in vitro colon model at body temperature coupled with systems biology platform, excluding the metabolism of the host liver and intestinal epithelia. Comprehensive two-dimensional gas chromatography with a time-of-flight mass spectrometry (GC*GC-TOFMS) was used for the metabolomic analysis. Metabolites showing the most significant differences in the active faecal suspension were elucidated in reference with SV fragmentation and compared with controls: inactive suspension or buffer with SV, or with active suspension alone. Finally, time courses of selected metabolites were investigated. Our data suggest that SV is degraded by hydrolytic cleavage of methylbutanoic acid from the SV backbone. Metabolism involves demethylation of dimethylbutanoic acid, hydroxylation/dehydroxylation and ß-oxidation resulting in the production of 2-hydroxyisovaleric acid (3-methyl-2-hydroxybutanoic acid), 3-hydroxybutanoic acid and lactic acid (2-hydroxypropanoic acid), and finally re-cyclisation of heptanoic acid (possibly de-esterified and cleaved methylpyranyl arm) to produce cyclohexanecarboxylic acid. Our study elucidates a pathway of colonic microbial metabolism of SV as well as demonstrates the applicability of the in vitro colon model and metabolomics to the discovery of novel drug metabolites from drug response profiles. -
Article: Algorithms and tools for the preprocessing of LC–MS metabolomics data
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ABSTRACT: Metabolomics encompasses the study of small molecules in a biological sample. Liquid Chromatography coupled with Mass Spectrometry (LC–MS) profiling is an important approach for the identification and quantification of metabolites from complex biological samples. The amount and complexity of data produced in an LC–MS profiling experiment demand automatic tools for the preprocessing, analysis, and extraction of useful biological information. Data preprocessing—a topic that covers noise filtering, peak detection, deisotoping, alignment, identification, and normalization—is thus an active area of metabolomics research. Recent years have witnessed development of many software for data preprocessing, and still there is a need for further improvement of the data preprocessing pipeline. This review presents an overview of selected software tools for preprocessing LC–MS based metabolomics data and tries to provide future directions.Chemometrics and Intelligent Laboratory Systems 108(1):23-32. · 1.92 Impact Factor
Top co-authors
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Institutions
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2012
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VTT Technical Research Centre of Finland
Espoo, Province of Southern Finland, Finland
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2011
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Helsinki University Central Hospital
- Department of Psychiatry
Helsinki, Province of Southern Finland, Finland
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