434 results on '"Matej Orešič"'
Search Results
102. Metabolomics and lipidomics in NAFLD: biomarkers and non-invasive diagnostic tests
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Pablo Ortiz, Melania Gaggini, Jean-François Dufour, Matej Orešič, Amalia Gastaldelli, José M. Mato, Julia Brosnan, Quentin M. Anstee, Cristina Alonso, Tuulia Hyötyläinen, Oscar Millet, Mojgan Masoodi, and Enara Arretxe
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Glutamic Acid ,Bioinformatics ,digestive system ,Bile Acids and Salts ,Metabolomics ,Non-alcoholic Fatty Liver Disease ,Nonalcoholic fatty liver disease ,Lipidomics ,Medicine ,Humans ,Amino Acids ,610 Medicine & health ,Hepatology ,business.industry ,Non invasive ,Gastroenterology ,Diagnostic test ,Lipid metabolism ,medicine.disease ,Lipid Metabolism ,Prognosis ,Glutathione ,digestive system diseases ,Potential biomarkers ,Disease Progression ,Metabolic syndrome ,Insulin Resistance ,business ,Biomarkers - Abstract
Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases worldwide and is often associated with aspects of metabolic syndrome. Despite its prevalence and the importance of early diagnosis, there is a lack of robustly validated biomarkers for diagnosis, prognosis and monitoring of disease progression in response to a given treatment. In this Review, we provide an overview of the contribution of metabolomics and lipidomics in clinical studies to identify biomarkers associated with NAFLD and nonalcoholic steatohepatitis (NASH). In addition, we highlight the key metabolic pathways in NAFLD and NASH that have been identified by metabolomics and lipidomics approaches and could potentially be used as biomarkers for non-invasive diagnostic tests. Overall, the studies demonstrated alterations in amino acid metabolism and several aspects of lipid metabolism including circulating fatty acids, triglycerides, phospholipids and bile acids. Although we report several studies that identified potential biomarkers, few have been validated.
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- 2021
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103. Correction to 'Integration of Metabolomics and Expression of Glycerol-3-phosphate Acyltransferase (GPAM) in Breast Cancer─Link to Patient Survival, Hormone Receptor Status, and Metabolic Profiling'
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Scarlet F. Brockmöller, Elmar Bucher, Berit M. Müller, Jan Budczies, Mika Hilvo, Julian L. Griffin, Matej Orešič, Olli Kallioniemi, Kristiina Iljin, Sibylle Loibl, Silvia Darb-Esfahani, Bruno V. Sinn, Frederick Klauschen, Judith Prinzler, Nikola Bangemann, Fakher Ismaeel, Oliver Fiehn, Manfred Dietel, and Carsten Denkert
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General Chemistry ,Biochemistry - Published
- 2022
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104. Transcriptomic profiling across the nonalcoholic fatty liver disease spectrum reveals gene signatures for steatohepatitis and fibrosis
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Matej Orešič, Fabio Marra, Christopher P. Day, Federico Ravaioli, Katherine Johnson, Elisabetta Bugianesi, Jérôme Boursier, Pierre Bedossa, Olivier Govaere, Rebecca Darlay, Salvatore Petta, Jeremy M. Palmer, Quentin M. Anstee, Ramy Younes, Heather J. Cordell, Rachel Queen, Jörn M. Schattenberg, Ann K. Daly, Mattias Ekstedt, Dina Tiniakos, Leigh Alexander, Michele Vacca, Antonio Vidal-Puig, Chiara Rosso, Karine Clément, Michael Allison, Vlad Ratziu, Kristy Wonders, Simon Cockell, Bioinformatics Support Unit, Newcastle University [Newcastle], Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), Govaere O., Cockell S., Tiniakos D., Queen R., Younes R., Vacca M., Alexander L., Ravaioli F., Palmer J., Petta S., Boursier J., Rosso C., Johnson K., Wonders K., Day C.P., Ekstedt M., Oresic M., Darlay R., Cordell H.J., Marra F., Vidal-Puig A., Bedossa P., Schattenberg J.M., Clement K., Allison M., Bugianesi E., Ratziu V., Daly A.K., and Anstee Q.M.
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0301 basic medicine ,Liver Cirrhosis ,Cirrhosis ,[SDV]Life Sciences [q-bio] ,Disease ,Biology ,Transcriptome ,03 medical and health sciences ,0302 clinical medicine ,Fibrosis ,nash ,Non-alcoholic Fatty Liver Disease ,Diabetes mellitus ,Nonalcoholic fatty liver disease ,medicine ,Diabetes Mellitus ,Humans ,General Medicine ,medicine.disease ,3. Good health ,030104 developmental biology ,Diabetes Mellitus, Type 2 ,Liver ,Immunology ,030211 gastroenterology & hepatology ,GDF15 ,Steatohepatitis ,Type 2 - Abstract
International audience; The mechanisms that drive nonalcoholic fatty liver disease (NAFLD) remain incompletely understood. This large multicenter study characterized the transcriptional changes that occur in liver tissue across the NAFLD spectrum as disease progresses to cirrhosis to identify potential circulating markers. We performed high-throughput RNA sequencing on a discovery cohort comprising histologically characterized NAFLD samples from 206 patients. Unsupervised clustering stratified NAFLD on the basis of disease activity and fibrosis stage with differences in age, aspartate aminotransferase (AST), type 2 diabetes mellitus, and carriage of PNPLA3 rs738409 , a genetic variant associated with NAFLD. Relative to early disease, we consistently identified 25 differentially expressed genes as fibrosing steatohepatitis progressed through stages F2 to F4. This 25-gene signature was independently validated by logistic modeling in a separate replication cohort ( n = 175), and an integrative analysis with publicly available single-cell RNA sequencing data elucidated the likely relative contribution of specific intrahepatic cell populations. Translating these findings to the protein level, SomaScan analysis in more than 300 NAFLD serum samples confirmed that circulating concentrations of proteins AKR1B10 and GDF15 were strongly associated with disease activity and fibrosis stage. Supporting the biological plausibility of these data, in vitro functional studies determined that endoplasmic reticulum stress up-regulated expression of AKR1B10 , GDF15 , and PDGFA , whereas GDF15 supplementation tempered the inflammatory response in macrophages upon lipid loading and lipopolysaccharide stimulation. This study provides insights into the pathophysiology of progressive fibrosing steatohepatitis, and proof of principle that transcriptomic changes represent potentially tractable and clinically relevant markers of disease progression.
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- 2020
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105. The PNPLA3-I148M variant increases polyunsaturated triglycerides in human adipose tissue
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Henna Sammalkorpi, Matej Orešič, Vesa M. Olkkonen, Julia Perttilä, Panu K. Luukkonen, Marju Orho-Melander, Leanne Hodson, Sami Qadri, Antti Hakkarainen, Anne K. Penttilä, Hannele Yki-Järvinen, Tuulia Hyötyläinen, Tiina Lehtimäki, Susanna Lallukka-Brück, Amalia Gastaldelli, Anne Juuti, You Zhou, Department of Medicine, Clinicum, Doctoral Programme in Clinical Research, HUS Internal Medicine and Rehabilitation, University of Helsinki, Helsinki University Hospital Area, HUS Abdominal Center, Department of Surgery, HUS Medical Imaging Center, Department of Diagnostics and Therapeutics, and Hannele Yki-Järvinen Research Group
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lipolyysi ,rasvahapot ,Adipose tissue ,0302 clinical medicine ,rasvamaksatauti ,genetics ,triglycerides ,variantti ,2. Zero hunger ,chemistry.chemical_classification ,education.field_of_study ,Fatty liver ,rasvamaksa ,adipose tissue ,030220 oncology & carcinogenesis ,OBESITY ,030211 gastroenterology & hepatology ,INSULIN RESISTANCE ,medicine.medical_specialty ,genetiikka ,ei-alkoholiperäinen rasvamaksatauti ,fatty acids ,steatoosi ,03 medical and health sciences ,Insulin resistance ,NEFA ,Internal medicine ,NAFLD ,medicine ,Lipolysis ,Humans ,STEATOSIS ,Adiponutrin ,Genetic Predisposition to Disease ,lipidomiikka ,adiponutriini ,education ,PNPLA3 ,fatty liver ,ADIPONUTRIN ,ihonalaisrasva ,Hepatology ,Fatty acid ,Membrane Proteins ,non-alcoholic fatty liver disease ,triglyseridit ,Lipase ,medicine.disease ,insuliiniresistenssi ,Endocrinology ,chemistry ,variant ,3121 General medicine, internal medicine and other clinical medicine ,mutaatio ,lipolysis ,lipidomics ,fatty liver disease ,lihavuus ,Steatosis ,mutation ,rasvakudos - Abstract
Background & Aims\ud \ud The I148M variant in PNPLA3 is the major genetic risk factor for non‐alcoholic fatty liver disease (NAFLD). The liver is enriched with polyunsaturated triglycerides (PUFA‐TGs) in PNPLA3‐I148M carriers. Gene expression data indicate that PNPLA3 is liver‐specific in humans, but whether it functions in adipose tissue (AT) is unknown. We investigated whether PNPLA3‐I148M modifies AT metabolism in human NAFLD.\ud Methods\ud \ud Profiling of the AT lipidome and fasting serum non‐esterified fatty acid (NEFA) composition was conducted in 125 volunteers (PNPLA3 148MM/MI, n = 63; PNPLA3 148II, n = 62). AT fatty acid composition was determined in 50 volunteers homozygous for the variant (PNPLA3 148MM, n = 25) or lacking the variant (PNPLA3 148II, n = 25). Whole‐body insulin sensitivity of lipolysis was determined using [2H5]glycerol, and PNPLA3 mRNA and protein levels were measured in subcutaneous AT and liver biopsies in a subset of the volunteers.\ud Results\ud \ud PUFA‐TGs were significantly increased in AT in carriers versus non‐carriers of PNPLA3‐I148M. The variant did not alter the rate of lipolysis or the composition of fasting serum NEFAs. PNPLA3 mRNA was 33‐fold higher in the liver than in AT (P < .0001). In contrast, PNPLA3 protein levels per tissue protein were three‐fold higher in AT than the liver (P < .0001) and nine‐fold higher when related to whole‐body AT and liver tissue masses (P < .0001).\ud Conclusions\ud \ud Contrary to previous assumptions, PNPLA3 is highly abundant in AT. PNPLA3‐I148M locally remodels AT TGs to become polyunsaturated as it does in the liver, without affecting lipolysis or composition of serum NEFAs. Changes in AT metabolism do not contribute to NAFLD in PNPLA3‐I148M carriers.
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- 2020
106. Links between central CB1-receptor availability and peripheral endocannabinoids in patients with first episode psychosis
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Jarmo Hietala, Tiago Reis Marques, Heikki Laurikainen, Faith Borgan, Metsy Investigators, Tuomas Lindeman, Matej Orešič, Tuulia Hyötyläinen, Alex M. Dickens, Oliver D. Howes, Tuukka Rönkkö, Mattia Veronese, and Santosh Lamichhane
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medicine.medical_specialty ,Psychosis ,Cannabinoid receptor ,lcsh:RC435-571 ,medicine.medical_treatment ,Molecular neuroscience ,Article ,Oleoylethanolamide ,chemistry.chemical_compound ,Internal medicine ,lcsh:Psychiatry ,Cannabinoid receptor type 1 ,medicine ,Ethanolamide ,business.industry ,Anandamide ,medicine.disease ,Endocannabinoid system ,Psychiatry and Mental health ,Endocrinology ,chemistry ,Posterior cingulate ,Cannabinoid ,business ,Dyslipidemia ,Biomarkers - Abstract
There is an established, link between psychosis and metabolic abnormalities, such as altered glucose metabolism and dyslipidemia, which often precede the initiation of antipsychotic treatment. It is known that obesity-associated metabolic disorders are promoted by activation of specific cannabinoid targets (endocannabinoid system (ECS)). Our recent data suggest that there is a change in the circulating lipidome at the onset of first episode psychosis (FEP). With the aim of characterizing the involvement of the central and peripheral ECSs, and their mutual associations; here, we performed a combined neuroimaging and metabolomic study in patients with FEP and healthy controls (HC). Regional brain cannabinoid receptor type 1 (CB1R) availability was quantified in two, independent samples of patients with FEP (n = 20 and n = 8) and HC (n = 20 and n = 10), by applying three-dimensional positron emission tomography, using two radiotracers, [11C]MePPEP and [18F]FMPEP-d2. Ten endogenous cannabinoids or related metabolites were quantified in serum, drawn from these individuals during the same imaging session. Circulating levels of arachidonic acid and oleoylethanolamide (OEA) were reduced in FEP individuals, but not in those who were predominantly medication free. In HC, there was an inverse association between levels of circulating arachidonoyl glycerol, anandamide, OEA, and palmitoyl ethanolamide, and CB1R availability in the posterior cingulate cortex. This phenomenon was, however, not observed in FEP patients. Our data thus provide evidence of cross talk, and dysregulation between peripheral endocannabinoids and central CB1R availability in FEP.
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- 2020
107. Association Between Circulating Lipids and Future Weight Gain in Individuals With an At-Risk Mental State and in First-Episode Psychosis
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Heikki Laurikainen, Matej Orešič, Tuulia Hyötyläinen, Jarmo Hietala, Jaana Suvisaari, Alex M. Dickens, Partho Sen, Oliver D. Howes, Santosh Lamichhane, and Faith Borgan
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Adult ,Male ,Risk ,medicine.medical_specialty ,Psychosis ,Weight Gain ,Mass Spectrometry ,Body Mass Index ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Prospective cohort study ,Triglycerides ,030304 developmental biology ,0303 health sciences ,Receiver operating characteristic ,business.industry ,Weight change ,At risk mental state ,medicine.disease ,Psychiatry and Mental health ,Psychotic Disorders ,Schizophrenia ,Case-Control Studies ,Lipidomics ,Female ,Disease Susceptibility ,medicine.symptom ,business ,Weight gain ,Body mass index ,030217 neurology & neurosurgery ,Biomarkers ,Regular Articles ,Follow-Up Studies - Abstract
Patients with schizophrenia have a lower than average life span, largely due to the increased prevalence of cardiometabolic comorbidities. There is an unmet public health need to identify individuals with psychotic disorders who have a high risk of rapid weight gain and who are at risk of developing metabolic complications. Here, we applied mass spectrometry-based lipidomics in a prospective study comprising 48 healthy controls (CTR), 44 first-episode psychosis (FEP) patients, and 22 individuals at clinical high risk (CHR) for psychosis, from 2 study centers (Turku, Finland and London, UK). Baseline serum samples were analyzed using lipidomics, and body mass index (BMI) was assessed at baseline and after 12 months. We found that baseline triacylglycerols (TGs) with low double-bond counts and carbon numbers were positively associated with the change in BMI at follow-up. In addition, a molecular signature comprised of 2 TGs (TG[48:0] and TG[45:0]) was predictive of weight gain in individuals with a psychotic disorder, with an area under the receiver operating characteristic curve (AUROC) of 0.74 (95% CI: 0.60–0.85). When independently tested in the CHR group, this molecular signature predicted said weight change with AUROC = 0.73 (95% CI: 0.61–0.83). We conclude that molecular lipids may serve as a predictor of weight gain in psychotic disorders in at-risk individuals and may thus provide a useful marker for identifying individuals who are most prone to developing cardiometabolic comorbidities.
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- 2020
108. Publisher Correction: Building an international consortium for tracking coronavirus health status
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Natalie R. Davidson, Jay Rajagopal, Gisel Booman, Andrew T. Chan, Ljupco Kocarev, Joshua Gale, Georgina Evans, Xihong Lin, Benjamin Geiger, Matej Orešič, Hagai Rossman, Ophir Shalem, Yonatan H. Grad, André Kahles, Tim D. Spector, Svetlana Ovchinnikova, Andrea Sboner, Phil Ewels, Ron Steinherz, Simon Anders, Faisal Alquaddoomi, Olli Kallioniemi, Eran Segal, Aline Muller, Iman Hajirasouliha, Alexandros Sigaras, Amir Gavrieli, Feng Zhang, Long H. Nguyen, Jana Prodanova, Silvano Coletti, Johan Rung, Smadar Shilo, Roman Jerala, Hedi Peterson, Gunnar Rätsch, Tomer Meir, Tal Bauman, Gregory Landua, Gary King, Han Altae-Tran, Ayya Keshet, David A. Drew, Casey S. Greene, Jaak Vilo, Olivier Elemento, William E. Allen, Ximena Bonilla, Ori Cohen, Ran D. Balicer, Yuval Dor, Irene Stevens, and Paul Wilmes
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2019-20 coronavirus outbreak ,Coronavirus disease 2019 (COVID-19) ,business.industry ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Medicine ,General Medicine ,business ,medicine.disease_cause ,Virology ,General Biochemistry, Genetics and Molecular Biology ,Coronavirus - Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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- 2020
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109. Perfluoroalkyl Substances are increased in patients with Late-Onset Ulcerative colitis and induce Intestinal Barrier defects ex vivo in Murine Intestinal tissue
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Jonas Halfvarson, Tuulia Hyötyläinen, Samira Salihovic, Mélanie G. Gareau, Frida Fart, Matej Orešič, Aidan McGlinchey, and Ida Schoultz
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medicine.medical_specialty ,Bile acid ,Ussing chamber ,medicine.drug_class ,business.industry ,Gastroenterology ,Late onset ,medicine.disease ,Inflammatory bowel disease ,Ulcerative colitis ,Internal medicine ,medicine ,In patient ,business ,Barrier function ,Ex vivo - Abstract
BackgroundEnvironmental factors are strongly implicated in late-onset of inflammatory bowel disease. Here, we investigate whether high exposure to perfluoroalkyl substances correlates with (1) late-onset inflammatory bowel disease, and (2) disturbances of the bile acid pool. We further explore the effect of the specific perfluoroalkyl substance perfluoronoctanoic acid on intestinal barrier function in murine tissue.MethodsSerum levels of perfluoroalkyl substances and bile acids were assessed by ultra-performance liquid chromatography coupled to a triple-quadrupole mass spectrometer in matched samples from patients with ulcerative colitis (n=20) and Crohn’s disease (n=20) diagnosed at the age of ≥55 years. Age and sex-matched blood donors (n=20), were used as healthy controls. Ex vivo Ussing chamber experiments were performed to assess the effect of perfluoronoctanoic acid on ileal and colonic murine tissue (n=9).ResultsThe total amount of perfluoroalkyl substances was significantly increased in patients with ulcerative colitis compared to healthy controls and patients with Crohn’s disease (pEx vivo exposure to perfluoronoctanoic acid induced a significanlty altered ileal and colonic barrier function. The distribution of bile acids, as well as the correlation pattern between (1) perfluoroalkyl substances and (2) bile acids, differed between patient and control groups.ConclusionOur results demonstrate that perfluoroalkyl substances levels are increased in patients with late-onset ulcerative colitis and may contribute to the disease by inducing a dysfunctional intestinal barrier.
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- 2020
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110. Building an international consortium for tracking coronavirus health status
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Gary King, Gisel Booman, Alexandros Sigaras, Feng Zhang, Joshua Gale, Phil Ewels, Andrew T. Chan, Benjamin Geiger, Tim D. Spector, Jana Prodanova, Han Altae-Tran, André Kahles, Matej Orešič, Hagai Rossman, Casey S. Greene, Amir Gavrieli, Ophir Shalem, Roman Jerala, Eran Segal, Yonatan H. Grad, Svetlana Ovchinnikova, Long H. Nguyen, Xihong Lin, Aline Muller, Iman Hajirasouliha, Jay Rajagopal, Smadar Shilo, Silvano Coletti, Georgina Evans, Ori Cohen, Ran D. Balicer, Hedi Peterson, Tomer Meir, Ximena Bonilla, Natalie R. Davidson, Olli Kallioniemi, Paul Wilmes, David A. Drew, Ron Steinherz, Simon Anders, Tal Bauman, Gregory Landua, Jaak Vilo, Johan Rung, Ayya Keshet, Ljupco Kocarev, Gunnar Rätsch, Olivier Elemento, Yuval Dor, Irene Stevens, Andrea Sboner, William E. Allen, and Faisal Alquaddoomi
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0301 basic medicine ,2019-20 coronavirus outbreak ,Knowledge management ,Coronavirus disease 2019 (COVID-19) ,Health Status ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Pneumonia, Viral ,medicine.disease_cause ,General Biochemistry, Genetics and Molecular Biology ,Betacoronavirus ,Databases ,03 medical and health sciences ,0302 clinical medicine ,Computational platforms and environments ,Surveys and Questionnaires ,Research community ,Pandemic ,medicine ,Humans ,Pandemics ,Coronavirus ,SARS-CoV-2 ,business.industry ,COVID-19 ,General Medicine ,Publisher Correction ,030104 developmental biology ,030220 oncology & carcinogenesis ,Infectious diseases ,Tracking (education) ,Coronavirus Infections ,business - Abstract
We call upon the research community to standardize efforts to use daily self-reported data about COVID-19 symptoms in the response to the pandemic and to form a collaborative consortium to maximize global gain while protecting participant privacy.
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- 2020
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111. Deep learning meets metabolomics: a methodological perspective
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Aidan McGlinchey, Santosh Lamichhane, Vivek Bhakta Mathema, Partho Sen, Alex M. Dickens, Matej Orešič, and Sakda Khoomrung
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Computer science ,Big data ,Datasets as Topic ,01 natural sciences ,03 medical and health sciences ,Metabolomics ,Deep Learning ,Pregnancy ,Statistical inference ,Humans ,Biomarker discovery ,Molecular Biology ,030304 developmental biology ,0303 health sciences ,business.industry ,Deep learning ,010401 analytical chemistry ,Perspective (graphical) ,Data science ,0104 chemical sciences ,Variety (cybernetics) ,Identification (information) ,Female ,Artificial intelligence ,business ,Information Systems - Abstract
Deep learning (DL), an emerging area of investigation in the fields of machine learning and artificial intelligence, has markedly advanced over the past years. DL techniques are being applied to assist medical professionals and researchers in improving clinical diagnosis, disease prediction and drug discovery. It is expected that DL will help to provide actionable knowledge from a variety of ‘big data’, including metabolomics data. In this review, we discuss the applicability of DL to metabolomics, while presenting and discussing several examples from recent research. We emphasize the use of DL in tackling bottlenecks in metabolomics data acquisition, processing, metabolite identification, as well as in metabolic phenotyping and biomarker discovery. Finally, we discuss how DL is used in genome-scale metabolic modelling and in interpretation of metabolomics data. The DL-based approaches discussed here may assist computational biologists with the integration, prediction and drawing of statistical inference about biological outcomes, based on metabolomics data.
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- 2020
112. MARC1 variant rs2642438 increases hepatic phosphatidylcholines and decreases severity of non-alcoholic fatty liver disease in humans
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Marju Orho-Melander, Panu K. Luukkonen, Anne K. Penttilä, Anne Juuti, Matej Orešič, Tuulia Hyötyläinen, Johanna Arola, Hannele Yki-Järvinen, and Henna Sammalkorpi
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0301 basic medicine ,medicine.medical_specialty ,Hepatology ,business.industry ,Fatty liver ,Non alcoholic ,macromolecular substances ,Disease ,medicine.disease ,Severity of Illness Index ,3. Good health ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Endocrinology ,Liver ,Non-alcoholic Fatty Liver Disease ,Internal medicine ,medicine ,Phosphatidylcholines ,Humans ,030211 gastroenterology & hepatology ,business - Abstract
MARC1 variant rs2642438 increases hepatic phosphatidylcholines and decreases severity of non-alcoholic fatty liver disease in humans
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- 2020
113. Double Derivatization Strategy for High-Sensitivity and High-Coverage Localization of Double Bonds in Free Fatty Acids by Mass Spectrometry
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Bangfu Wu, Matej Orešič, Ping Yao, Shuling Xu, Xin Lv, Ya Xie, Zongyuan Wu, Hong Chen, and Fang Wei
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chemistry.chemical_classification ,Detection limit ,Chromatography ,Double bond ,Tertiary amine ,010401 analytical chemistry ,Protonation ,010402 general chemistry ,Mass spectrometry ,01 natural sciences ,0104 chemical sciences ,Analytical Chemistry ,chemistry.chemical_compound ,chemistry ,Structural isomer ,Acetone ,lipids (amino acids, peptides, and proteins) ,Derivatization - Abstract
Free fatty acids (FFAs) are key intermediates of lipid metabolism that have a crucial role in many critical biological processes. The specific locations of carbon-carbon double bonds (C═C) in FFAs are often associated with distinct biological functions. Despite the rapid development of analytical techniques, identification of C═C locations in FFAs with more than three C═C bonds in complex biological matrices remains a challenge. Herein, we describe a double derivatization strategy, coupled with shotgun-mass spectrometry (MS), for unambiguous and sensitive determination of a high-coverage C═C bond (from 1 to 6) locations of FFAs. Our approach is based on combination of acetone labeling of C═C bonds and N,N-diethyl-1,2-ethanediamine (DEEA) labeling of carboxyl groups within FFAs. Acetone labeling of C═C bonds via photochemical reaction provides diagnostic ions, specific to C═C locations, and DEEA labeling of carboxyl groups significantly enhances MS response of diagnostic ions, by invoking a readily protonated tertiary amine group on FFA analytes. By exploiting this double derivatization strategy, the assignment of C═C locations of FFAs with more than three C═C bonds was achieved with high sensitivity (limit of quantitation (LOQ) 0.1-1.5 nmol/L). In contrast, such assignments were not possible by acetone labeling alone, because of the low sensitivity of diagnostic ions in negative ionization mode of MS. The applicability of our method was demonstrated by profiling of FFAs, including unsaturated FFA C═C positional isomers, in liver samples from mice with nonalcoholic fatty liver disease (NAFLD) and their lean controls. The study showed that the high-specificity and high-sensitivity method developed here is promising for accurate identification and quantitation of a wide array of FFAs in biological samples.
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- 2020
114. Building an International Consortium for Tracking Coronavirus Health Status
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Ximena Bonilla, Svetlana Ovchinnikova, William E. Allen, Iman Hajirasouliha, Tal Bauman, Andrea Sboner, Roman Jerala, Hedi Peterson, Matej Orešič, Hagai Rossman, Gary King, Ori Cohen, David A. Drew, Smadar Shilo, Silvano Coletti, Gunnar Rätsch, Joshua Gale, Casey S. Greene, Benjamin Geiger, Tomer Meir, Xihong Lin, Jay Rajagopal, Tim D. Spector, Olivier Elemento, Faisal Alquaddoomi, Yuval Dor, André Kahles, Alexandros Sigaras, Olli Kallioniemi, Amir Gavrieli, Feng Zhang, Irene Stevens, Long H. Nguyen, Ron Steinherz, Simon Anders, Johan Rung, Ayya Keshet, Georgina Evans, Phil Ewels, Natalie R. Davidson, Ophir Shalem, Yonatan H. Grad, Eran Segal, Aline Muller, Gregory Landua, Jaak Vilo, Paul Wilmes, Ran D. Balicer, Gisel Booman, and Andrew T. Chan
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education.field_of_study ,Geospatial analysis ,Knowledge management ,business.industry ,Control (management) ,Population ,Globe ,Disease ,computer.software_genre ,medicine.anatomical_structure ,SPARK (programming language) ,Health care ,Pandemic ,medicine ,business ,education ,computer ,computer.programming_language - Abstract
Information is the most potent protective weapon we have to combat a pandemic, at both the individual and global level. For individuals, information can help us make personal decisions and provide a sense of security. For the global community, information can inform policy decisions and offer critical insights into the epidemic of COVID-19 disease. Fully leveraging the power of information, however, requires large amounts of data and access to it. To achieve this, we are making steps to form an international consortium, Coronavirus Census Collective (CCC, coronaviruscensuscollective.org), that will serve as a hub for integrating information from multiple data sources that can be utilized to understand, monitor, predict, and combat global pandemics. These sources may include self-reported health status through surveys (including mobile apps), results of diagnostic laboratory tests, and other static and real-time geospatial data. This collective effort to track and share information will be invaluable in predicting hotspots of disease outbreak, identifying which factors control the rate of spreading, informing immediate policy decisions, evaluating the effectiveness of measures taken by health organizations on pandemic control, and providing critical insight on the etiology of COVID-19. It will also help individuals stay informed on this rapidly evolving situation and contribute to other global efforts to slow the spread of disease.In the past few weeks, several initiatives across the globe have surfaced to use daily self-reported symptoms as a means to track disease spread, predict outbreak locations, guide population measures and help in the allocation of healthcare resources. The aim of this paper is to put out a call to standardize these efforts and spark a collaborative effort to maximize the global gain while protecting participant privacy.
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- 2020
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115. Circulating lipids associate with future weight gain in individuals with an at-risk mental state and in first-episode psychosis
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Oliver D. Howes, Jarmo Hietala, Jaana Suvisaari, Santosh Lamichhane, Alex M. Dickens, Matej Orešič, Tuulia Hyötyläinen, Partho Sen, and Heikki Laurikainen
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2. Zero hunger ,0303 health sciences ,Psychosis ,medicine.medical_specialty ,business.industry ,Weight change ,At risk mental state ,medicine.disease ,3. Good health ,03 medical and health sciences ,0302 clinical medicine ,Schizophrenia ,Internal medicine ,Lipidomics ,medicine ,medicine.symptom ,Prospective cohort study ,business ,Weight gain ,Body mass index ,030217 neurology & neurosurgery ,030304 developmental biology - Abstract
Patients with schizophrenia have a lower than average life span, largely due to the increased prevalence of cardiometabolic co-morbidities. Identification of individuals with psychotic disorders with a high risk of rapid weight gain, and the associated development of metabolic complications, is an unmet need as regards public health. Here, we applied mass spectrometry-based lipidomics in a prospective study comprising 48 controls (CTR), 44 first-episode psychosis (FEP) patients and 22 individuals at clinical-high-risk (CHR) for psychosis, from two study centers (Turku/Finland and London/UK). Baseline serum samples were analyzed by lipidomics, while body mass index (BMI) was assessed at baseline and after 12 months. We found that baseline triacylglycerols with low double bond counts and carbon numbers were positively associated with the change in BMI at follow-up. In addition, a molecular signature comprised of two triacylglycerols (TG(48:0) and TG(45:0)), was predictive of weight gain in individuals with a psychotic disorder, with an area under the receiver operating characteristic curve (AUROC) of 0.74 (95% CI: 0.60–0.85). When independently tested in the CHR group, this molecular signature predicted said weight change with AUROC = 0.73 (95% CI: 0.61–0.83). We conclude that molecular lipids may serve as a predictor of weight gain in psychotic disorders in at-risk individuals, and may thus provide a useful marker for identifying individuals who are most prone to developing cardiometabolic co-morbidities.
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- 2020
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116. Dysregulated lipid metabolism precedes onset of psychosis in people at clinical high risk
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Thomas A Pollak, Marie-Odile Krebs, Rodrigo A. Bressan, Conrad Iyegbe, van der Gaag M, Partho Sen, de Haan L, Tuulia Hyötyläinen, Phillip McGuire, Matej Orešič, Anita Riecher-Rössler, Lucia Valmaggia, Stephan Ruhrmann, Neus Barrantes-Vidal, Matthew J. Kempton, Gabriele Sachs, Alex M. Dickens, and Merete Nordentoft
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0303 health sciences ,Psychosis ,medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,Lipid metabolism ,medicine.disease ,3. Good health ,03 medical and health sciences ,0302 clinical medicine ,Ether Phospholipids ,Internal medicine ,Medicine ,business ,Lipid profile ,Carbon number ,030217 neurology & neurosurgery ,030304 developmental biology - Abstract
A key clinical challenge in the management of individuals at clinical high risk for psychosis (CHR) is that it is difficult to predict their future clinical outcomes. Here, we investigated if the levels of circulating molecular lipids are related to adverse clinical outcomes in this group. Serum lipidomic analysis was performed in 263 CHR individuals and 51 healthy controls (HC), who were then clinically monitored for up to five years. Machine learning was used to identify lipid profiles that discriminated between CHR subjects and HC, and between subgroups of CHR subjects with distinct clinical outcomes. At baseline, compared to HC, CHR subjects (independent of outcome) had higher levels of triacylglycerols (TGs) with a low acyl carbon number and a double bond count, as well as higher levels of lipids in general. CHR subjects who subsequently developed psychosis (n=50) were distinguished from those that did not (n=213) on the basis of lipid profile at baseline, using a model with an AUC = 0.81 (95% CI = 0.69-0.93). CHR subjects who became psychotic had lower levels of ether phospholipids than CHR individuals who did not (p
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- 2020
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117. Early-life exposure to perfluorinated alkyl substances modulates lipid metabolism in progression to celiac disease
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Jorma Ilonen, Heikki Hyöty, Riitta Veijola, Jorma Toppari, Mikael Knip, Suvi M. Virtanen, Partho Sen, Tuulia Hyötyläinen, Samira Salihovic, Matej Orešič, Lisanna Sinisalu, HUS Children and Adolescents, Children's Hospital, Research Programs Unit, University of Helsinki, Helsinki University Hospital Area, CAMM - Research Program for Clinical and Molecular Metabolism, and Faculty of Medicine
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PFAS ,CHILDHOOD ,Physiology ,Disease ,SUSCEPTIBILITY ,010501 environmental sciences ,01 natural sciences ,Biochemistry ,chemistry.chemical_compound ,0302 clinical medicine ,Pregnancy ,Celiac disease ,030212 general & internal medicine ,Prospective Studies ,Child ,General Environmental Science ,RISK ,chemistry.chemical_classification ,0303 health sciences ,BILE-ACIDS ,Fluorocarbons ,PFOA ,3142 Public health care science, environmental and occupational health ,Early life ,3. Good health ,Exposome ,Perfluorooctanoic acid ,Female ,Clinical cohort ,030209 endocrinology & metabolism ,03 medical and health sciences ,Lipidomics ,medicine ,Humans ,Prenatal exposure ,Triglycerides ,030304 developmental biology ,0105 earth and related environmental sciences ,Type 1 diabetes ,business.industry ,Parturition ,Infant ,Lipid metabolism ,Metabolism ,medicine.disease ,Lipid Metabolism ,Gluten ,Bile acids ,Celiac Disease ,chemistry ,PERFLUOROOCTANOIC ACID ,business - Abstract
OBJECTIVESCeliac disease (CD) is a systemic immune-mediated disorder with increased frequency in the developed countries over the last decades implicating the potential causal role of various environmental triggers in addition to gluten. Herein, we apply determination of perfluorinated alkyl substances (PFAS) and combine the results with the determination of bile acids (BAs) and molecular lipids, with the aim to elucidate the impact of prenatal exposure on risk of progression to CD in a prospective series of children prior the first exposure to gluten (at birth and at 3 months of age).METHODSWe analyzed PFAS, BAs and lipidomic profiles in 76 plasma samples at birth and at 3 months of age in the Type 1 Diabetes Prediction and Prevention (DIPP) study (n=17 progressors to CD, n=16 healthy controls, HCs).RESULTSPlasma PFAS levels showed a significant inverse association with the age of CD diagnosis in infants who later progressed to the disease. Associations between BAs and triacylglycerols (TGs) showed different patterns already at birth in CD progressors, indicative of different absorption of lipids in these infants.DISCUSSIONPFAS exposure may modulate lipid and BA metabolism, and the impact is different in the infants who develop CD later in life, in comparison to HCs. The results indicate more efficient uptake of PFAS in such infants. Higher PFAS exposure during prenatal and early life may accelerate the progression to CD in the genetically predisposed children.Study HighlightsWHAT IS KNOWNSeveral observational studies have implicated a role of early life environmental triggers other than gluten in the development of CD. This is supported by the findings showing dysregulation of lipids already prior to the first introduction of gluten.WHAT IS NEW HEREWe show that prenatal exposure to perfluorinated compounds is associated with changes in the lipid metabolism, most likely through the bile acids, and that a high exposure during prenatal and early life may accelerate the progression to CD in the genetically predisposed children.TRANSLATIONAL IMPACTExposure to environmental chemicals may impact the rate of progression to CD and should be assessed as a potential risk factor of CD in larger clinical cohort settings.
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- 2020
118. MS-based lipidomics of human blood plasma: a community-initiated position paper to develop accepted guidelines
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Xianlin Han, Tze Ping Loh, Bo Burla, Michelle K. Lin, Makoto Arita, Masanori Arita, Edward A. Dennis, Kim Ekroos, Anne K. Bendt, Michael J.O. Wakelam, Amaury Cazenave-Gassiot, Federico Torta, Oswald Quehenberger, Markus R. Wenk, Kazutaka Ikeda, Craig E. Wheelock, Andrej Shevchenko, Matej Orešič, Peter J. Meikle, and Gerhard Liebisch
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0301 basic medicine ,Sample handling ,Human blood ,business.industry ,ta1182 ,Cell Biology ,Computational biology ,Shotgun lipidomics ,Lipidome ,Biochemistry ,Biological fluid ,3. Good health ,03 medical and health sciences ,030104 developmental biology ,Endocrinology ,Lipidomics ,Blood plasma ,Position paper ,Medicine ,business - Abstract
Human blood is a self-regenerating lipid-rich biological fluid that is routinely collected in hospital settings. The inventory of lipid molecules found in blood plasma (plasma lipidome) offers insights into individual metabolism and physiology in health and disease. Disturbances in the plasma lipidome also occur in conditions that are not directly linked to lipid metabolism; therefore, plasma lipidomics based on MS is an emerging tool in an array of clinical diagnostics and disease management. However, challenges exist in the translation of such lipidomic data to clinical applications. These relate to the reproducibility, accuracy, and precision of lipid quantitation, study design, sample handling, and data sharing. This position paper emerged from a workshop that initiated a community-led process to elaborate and define a set of generally accepted guidelines for quantitative MS-based lipidomics of blood plasma or serum, with harmonization of data acquired on different instrumentation platforms across independent laboratories as an ultimate goal. We hope that other fields may benefit from and follow such a precedent.
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- 2018
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119. Analysis of microbiota in first episode psychosis identifies preliminary associations with symptom severity and treatment response
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Robert H. Yolken, Emanuel Schwarz, Matej Orešič, Johanna Maukonen, Maria Saarela, Sarven Sabunciyan, Tiina Hyytiainen, Jaana Suvisaari, Tuula Kieseppä, Outi Mantere, Department of Psychiatry, University of Helsinki, Clinicum, and HUS Psychiatry
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Male ,SEVERE INFECTIONS ,microbiome ,Gut flora ,Neuropsychological Tests ,GUT MICROBIOME ,3124 Neurology and psychiatry ,Feces ,0302 clinical medicine ,MARKERS ,Lactobacillus ,ta318 ,psychosis ,Young adult ,BRAIN ,ta515 ,response ,biology ,Microbiota ,BIPOLAR DISORDER ,3. Good health ,Psychiatry and Mental health ,Schizophrenia ,Female ,Psychology ,Adult ,Psychosis ,medicine.medical_specialty ,Treatment response ,Adolescent ,AUTOIMMUNE-DISEASES ,03 medical and health sciences ,Young Adult ,INTESTINAL MICROBIOTA ,Internal medicine ,medicine ,Humans ,Microbiome ,Bipolar disorder ,Psychiatry ,Biological Psychiatry ,Psychiatric Status Rating Scales ,medicine.disease ,biology.organism_classification ,ta3124 ,030227 psychiatry ,schizophrenia ,Psychotic Disorders ,Linear Models ,RISK-FACTORS ,FECAL MICROBIOTA ,030217 neurology & neurosurgery ,Follow-Up Studies - Abstract
The effects of gut microbiota on the central nervous system, along its possible role in mental disorders, have received increasing attention. Here we investigated differences in fecal microbiota between 28 patients with first-episode psychosis (FEP) and 16 healthy matched controls and explored whether such differences were associated with response after up to 12 months of treatment. Numbers of Lactobacillus group bacteria were elevated in FEP-patients and significantly correlated with severity along different symptom domains. A subgroup of FEP patients with the strongest microbiota differences also showed poorer response after up to 12 months of treatment. The present findings support the involvement of microbiota alterations in psychotic illness and may provide the basis for exploring the benefit of their modulation on treatment response and remission. (C) 2017 Elsevier B.V. All rights reserved.
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- 2018
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120. Quantitative genome-scale metabolic modeling of human CD4+ T cell differentiation reveals subset-specific regulation of glycosphingolipid pathways
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Omid Rasool, Alex M. Dickens, Tanja Buchacher, Ubaid Ullah Kalim, Esko Kemppainen, Matej Orešič, Partho Sen, Victoria Hinkkanen, Mohd Moin Khan, Marina Amaral Alves, Tuomas Lindeman, Tuulia Hyötyläinen, Riitta Lahesmaa, and Syed Bilal Ahmad Andrabi
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Gene knockdown ,Ceramide ,T cell ,Biology ,Sphingolipid ,General Biochemistry, Genetics and Molecular Biology ,Proinflammatory cytokine ,Cell biology ,chemistry.chemical_compound ,Metabolic pathway ,medicine.anatomical_structure ,chemistry ,Gene expression ,medicine ,Gene - Abstract
Summary T cell activation, proliferation, and differentiation involve metabolic reprogramming resulting from the interplay of genes, proteins, and metabolites. Here, we aim to understand the metabolic pathways involved in the activation and functional differentiation of human CD4+ T cell subsets (T helper [Th]1, Th2, Th17, and induced regulatory T [iTreg] cells). Here, we combine genome-scale metabolic modeling, gene expression data, and targeted and non-targeted lipidomics experiments, together with in vitro gene knockdown experiments, and show that human CD4+ T cells undergo specific metabolic changes during activation and functional differentiation. In addition, we confirm the importance of ceramide and glycosphingolipid biosynthesis pathways in Th17 differentiation and effector functions. Through in vitro gene knockdown experiments, we substantiate the requirement of serine palmitoyltransferase (SPT), a de novo sphingolipid pathway in the expression of proinflammatory cytokines (interleukin [IL]-17A and IL17F) by Th17 cells. Our findings provide a comprehensive resource for selective manipulation of CD4+ T cells under disease conditions characterized by an imbalance of Th17/natural Treg (nTreg) cells.
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- 2021
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121. Impaired hepatic lipid synthesis from polyunsaturated fatty acids in TM6SF2 E167K variant carriers with NAFLD
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Panu K. Luukkonen, Jeremy M. Palmer, Taru Tukiainen, Marja Leivonen, Marju Orho-Melander, Hannele Yki-Järvinen, Adnan Ali, Johanna Arola, Petter Vikman, Leif Groop, Matej Orešič, Tuulia Hyötyläinen, Emma Scott, P.A. Nidhina Haridas, Vesa M. Olkkonen, Quentin M. Anstee, You Zhou, Anne Juuti, Linda Ahonen, Om Prakash Dwivedi, Department of Medicine, Clinicum, Institute for Molecular Medicine Finland, II kirurgian klinikka, Department of Surgery, Medicum, Department of Pathology, Leif Groop Research Group, Hannele Yki-Järvinen Research Group, HUS Internal Medicine and Rehabilitation, and HUS Abdominal Center
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Male ,0301 basic medicine ,Apolipoprotein B ,Lipoproteins, VLDL ,chemistry.chemical_compound ,ta318 ,chemistry.chemical_classification ,INSULIN-RESISTANCE ,biology ,NONALCOHOLIC STEATOHEPATITIS ,Middle Aged ,Lipids ,Transmembrane protein ,3. Good health ,Liver ,Arachidonic acid ,LOW-DENSITY LIPOPROTEINS ,CARDIOVASCULAR-DISEASE ,Phosphatidylethanolamine N-methyltransferase ,Lipogenesis ,Fatty Acids, Unsaturated ,Phosphatidylcholines ,Female ,lipids (amino acids, peptides, and proteins) ,Polyunsaturated fatty acid ,Adult ,Heterozygote ,medicine.medical_specialty ,Genotype ,APOLIPOPROTEIN-B ,Cholesterol esters ,digestive system ,03 medical and health sciences ,Insulin resistance ,LIVER-DISEASE ,Internal medicine ,medicine ,Humans ,Fatty acids ,Triglycerides ,Hepatology ,PHOSPHATIDYLETHANOLAMINE N-METHYLTRANSFERASE ,Membrane Proteins ,nutritional and metabolic diseases ,ARACHIDONIC-ACID ,medicine.disease ,digestive system diseases ,030104 developmental biology ,Endocrinology ,chemistry ,3121 General medicine, internal medicine and other clinical medicine ,Hepatocytes ,FIBROSIS PROGRESSION ,biology.protein ,Transmembrane 6 superfamily member 2 ,SUPERFAMILY MEMBER 2 ,Non-alcoholic fatty liver disease ,TM6SF2 - Abstract
Background: Carriers of the transmembrane 6 superfamily member 2 E167K gene variant (TM6SF2(EK/KK)) have decreased expression of the TM6SF2 gene and increased risk of NAFLD and NASH. Unlike common 'obese/metabolic' NAFLD, these subjects lack hypertriglyceridemia and have lower risk of cardiovascular disease. In animals, phosphatidylcholine (PC) deficiency results in a similar phenotype. PCs surround the core of VLDL consisting of triglycerides (TGs) and cholesteryl-esters (CEs). We determined the effect of the TM6SF2 E167K on these lipids in the human liver and serum and on hepatic gene expression and studied the effect of TM6SF2 knockdown on hepatocyte handling of these lipids. Methods: Liver biopsies were taken from subjects characterized with respect to the TM6SF2 genotype, serum and liver lipidome, gene expression and histology. In vitro, after TM6SF2 knockdown in HuH-7 cells, we compared incorporation of different fatty acids into TGs, CEs, and PCs. Results: The TM6SF2(EK/KK) and TM6SF2EE groups had similar age, gender, BMI and HOMA-IR. Liver TGs and CEs were higher and liver PCs lower in the TM6SF2(EK/KK) than the TM6SF2EE group (p Conclusions: Hepatic lipid synthesis from PUFAs is impaired and could contribute to deficiency in PCs and increased intrahepatic TG in TM6SF2 E167K variant carriers. (C) 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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- 2017
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122. Sphingolipids and glycerophospholipids - The 'ying and yang' of lipotoxicity in metabolic diseases
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Sergio Rodriguez-Cuenca, Antonio Vidal-Puig, Mark Campbell, Matej Orešič, and Vanessa Pellegrinelli
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0301 basic medicine ,Ceramide ,Glycerophospholipids ,Biology ,Biochemistry ,03 medical and health sciences ,chemistry.chemical_compound ,Metabolic Diseases ,Animals ,Humans ,Sphingolipids ,Sphingosine ,Cell Membrane ,ta1182 ,Cell Biology ,Sphingolipid ,Cell biology ,Metabolic pathway ,Crosstalk (biology) ,030104 developmental biology ,chemistry ,Lipotoxicity ,lipids (amino acids, peptides, and proteins) ,Homeostasis ,Signal Transduction - Abstract
Sphingolipids in general and ceramides in particular, contribute to pathophysiological mechanisms by modifying signalling and metabolic pathways. Here, we present the available evidence for a bidirectional homeostatic crosstalk between sphingolipids and glycerophospholipids, whose dysregulation contributes to lipotoxicity induced metabolic stress. The initial evidence for this crosstalk originates from simulated models designed to investigate the biophysical properties of sphingolipids in plasma membrane representations. In this review, we reinterpret some of the original findings and conceptualise them as a sort of "ying/yang" interaction model of opposed/complementary forces, which is consistent with the current knowledge of lipid homeostasis and pathophysiology. We also propose that the dysregulation of the balance between sphingolipids and glycerophospholipids results in a lipotoxic insult relevant in the pathophysiology of common metabolic diseases, typically characterised by their increased ceramide/sphingosine pools.
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- 2017
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123. Harmonizing lipidomics: NIST interlaboratory comparison exercise for lipidomics using SRM 1950-Metabolites in Frozen Human Plasma
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Cian Monnin, Anthony D. Postle, S. J. Kumari A. Ubhayasekera, Matej Orešič, Tomas Cajka, Jacquelyn M. Weir, Candice Z. Ulmer, Stephen E. Somerville, Xueqing Zhao, Therese Koal, Renu Nandakumar, Senlin Zhou, Denis Reynaud, John A. Bowden, James E. Evans, Joost Brandsma, Rhishikesh Thakare, Jeremy P. Koelmel, Houli Jiang, Tuulia Hyötyläinen, Christoph H. Borchers, Oliver Fiehn, J. Will Thompson, Susanne Sales, Karen Lin, Christina M. Jones, Jun Han, Aveline H. Neo, Laila Abdullah, Charles N. Serhan, Mary R. Roth, Danielle J. McDougall, Alexander Triebl, Martin Trötzmüller, Yazen Alnouti, Serge Cremers, Michelle Cinel, Irwin J. Kurland, Kai Schuhmann, Craig E. Wheelock, Min Yuan, Romain A. Colas, Ruth Welti, Yingying Huang, Hiroaki Takeda, Timothy J. Garrett, Jon Rees, Takeshi Bamba, Grielof Koster, Michal A. Surma, Libin Yao, Natalie A. Mellett, Johan Kolmert, M. Arthur Moseley, Krishna Rao Maddipati, Harald Köfeler, John M. Asara, Dajana Vuckovic, Aaron M. Armando, Michael S. Gardner, Peter J. Meikle, Rebecca S. Pugh, Yoshihiro Izumi, Alexander Fauland, Antonio Checa, Jonas Bergquist, Amaury Cazenave-Gassiot, Parsram Ramrup, Zsuzsanna Kuklenyik, Alan Heckert, Hongfeng Jiang, Yunping Qiu, David A. Peake, Oswald Quehenberger, Markus R. Wenk, John R. Barr, Michael Leadley, Linda Ahonen, Barbara Rembiesa, Jiang Jiang, Martin Post, Kristaps Klavins, Susanne B. Breitkopf, Lisa St. John-Williams, Michal L. Schwartzman, Edward A. Dennis, Andrej Shevchenko, Katherine H. Gotlinger, Federico Torta, Christian Klose, Jason S. Pierce, Rainey E. Patterson, Reiko Kiyonami, and Maureen Kachman
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0301 basic medicine ,Biochemistry & Molecular Biology ,Laboratory Proficiency Testing ,International Cooperation ,sterols ,QD415-436 ,Medical Biochemistry and Metabolomics ,01 natural sciences ,Biochemistry ,03 medical and health sciences ,Endocrinology ,fatty acyls ,Lipidomics ,Humans ,Ionization mass spectrometry ,quality control ,Reference standards ,phospholipids ,Research Articles ,Observer Variation ,sphingolipids ,Chromatography ,quantitation ,Chemistry ,010401 analytical chemistry ,Standard Reference Material 1950 ,glycerolipids ,ta1182 ,Reproducibility of Results ,Cell Biology ,National Institute of Standards and Technology ,Reference Standards ,Lipid Metabolism ,Lipids ,0104 chemical sciences ,Cell and molecular biology ,Benchmarking ,030104 developmental biology ,Human plasma ,NIST ,Biochemistry and Cell Biology ,Targeted metabolomics - Abstract
As the lipidomics field continues to advance, self-evaluation within the community is critical. Here, we performed an interlaboratory comparison exercise for lipidomics using Standard Reference Material (SRM) 1950-Metabolites in Frozen Human Plasma, a commercially available reference material. The interlaboratory study comprised 31 diverse laboratories, with each laboratory using a different lipidomics workflow. A total of 1,527 unique lipids were measured across all laboratories and consensus location estimates and associated uncertainties were determined for 339 of these lipids measured at the sum composition level by five or more participating laboratories. These evaluated lipids detected in SRM 1950 serve as community-wide benchmarks for intra- and interlaboratory quality control and method validation. These analyses were performed using nonstandardized laboratory-independent workflows. The consensus locations were also compared with a previous examination of SRM 1950 by the LIPID MAPS consortium. While the central theme of the interlaboratory study was to provide values to help harmonize lipids, lipid mediators, and precursor measurements across the community, it was also initiated to stimulate a discussion regarding areas in need of improvement.
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- 2017
124. Metabolism of human liver on a genome scale in non-alcoholic fatty liver disease
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Parho Sen, Olivier Govaere, Aidan McGlinchey, Vlad Ratziu, Elisabetta Bugianesi, Jörn M. Schattenberg, Michael Allison, Simon Cockell, Ann K Daly, Tuulia Hyötyläinen, Quentin Anstee, and Matej Orešič
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Hepatology - Published
- 2020
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125. P018 Per- and polyfluoroalkyl substances (PFAS) are significantly increased in patients with late-onset of ulcerative colitis
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Aidan McGlinchey, Matej Orešič, Frida Fart, Ida Schoultz, Jonas Halfvarson, Tuulia Hyötyläinen, and Samira Salihovic
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medicine.medical_specialty ,Crohn's disease ,business.industry ,Gastroenterology ,Late onset ,General Medicine ,Serum specimen ,medicine.disease ,Inflammatory bowel disease ,Ulcerative colitis ,Internal medicine ,medicine ,In patient ,business - Abstract
Background Environmental factors have been implicated in the pathogenesis of inflammatory bowel disease (IBD), particularly late onset disease. Per- and polyfluoroalkyl substances (PFAS) are man-made chemicals with a long biological half-life that have been extensively used since the 1950s and have been proposed to interfere with the bile acid synthesis. Therefore, to investigate if late onset IBD correlates with higher PFAS levels, we measured serum levels of PFAS and bile acids in patients diagnosed with IBD later in life. Methods Serum samples were collected from patients diagnosed with ulcerative colitis (n = 20) and Crohn’s disease (n = 20) at the age of ≥55 years. Blood donors (n = 20) were used as healthy controls and were matched by gender and age. The levels of PFAS and bile acids were assessed by ultra performance liquid chromatography coupled to a triple quadrupole mass spectrometer. Results The total amount of PFAS was significantly higher in patients with ulcerative colitis compared with healthy controls (p = 0.021) or patients with Crohn’s disease (p = 0.015). No difference was found in total PFAS levels between Crohn’s disease patients and healthy controls (p = 0.841). Seven out of 30 bile acids correlated to the total PFAS level. Conclusion Our results demonstrate that PFAS levels are increased in patients with late-onset of ulcerative colitis compared with Crohn’s disease patients and healthy controls. This finding indicates that PFAS might represent an environmental risk factor for ulcerative colitis. However, additional studies assessing the functional consequences of increased PFAS in late-onset ulcerative colitis are required to confirm this hypothesis.
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- 2020
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126. Metabolomics Analytics Workflow for Epidemiological Research
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A. Heather Eliassen, Claudia Langenberg, Jiaqi Huang, Fred K. Tabung, Marinella Temprosa, Andrew J. Kim, Susan Cheng, Wei Perng, Mir Henglin, Sei Harada, Ewy Mathé, Tengda Lin, Matej Orešič, Mary C. Playdon, Wei Jie Seow, Steven C. Moore, Marc J. Gunter, Bo L. Chawes, Jan Krumsiek, Amit Joshi, Eline H. van Roekel, Andrea Gsur, Oana A. Zeleznik, Ying Wang, Epidemiologie, RS: GROW - R1 - Prevention, Tabung, Fred K [0000-0001-8193-7150], van Roekel, Eline H [0000-0002-9402-2029], Mathé, Ewy [0000-0003-4491-8107], Chawes, Bo [0000-0001-6846-6243], Oresic, Matej [0000-0002-2856-9165], Zeleznik, Oana A [0000-0002-8705-1163], and Apollo - University of Cambridge Repository
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0301 basic medicine ,medicine.medical_specialty ,Standardization ,Computer science ,Endocrinology, Diabetes and Metabolism ,data analysis ,lcsh:QR1-502 ,Biochemistry ,lcsh:Microbiology ,Article ,DISEASE ,03 medical and health sciences ,VEGETARIANS ,0302 clinical medicine ,Metabolomics ,statistical analysis ,MALE MEAT-EATERS ,Epidemiology ,medicine ,Information system ,AMINO-ACIDS ,Biomarker discovery ,Molecular Biology ,FISH-EATERS ,reporting ,pre-processing ,CANCER RISK ,business.industry ,BETA-CAROTENE ,PROFILES ,Data science ,metabolomics ,HUMAN BLOOD ,3. Good health ,Variety (cybernetics) ,analytical methods ,030104 developmental biology ,Workflow ,Analytics ,030220 oncology & carcinogenesis ,VISUALIZATION ,epidemiology ,business - Abstract
The application of metabolomics technology to epidemiological studies is emerging as a new approach to elucidate disease etiology and for biomarker discovery. However, analysis of metabolomics data is complex and there is an urgent need for the standardization of analysis workflow and reporting of study findings. To inform the development of such guidelines, we conducted a survey of 47 cohort representatives from the Consortium of Metabolomics Studies (COMETS) to gain insights into the current strategies and procedures used for analyzing metabolomics data in epidemiological studies worldwide. The results indicated a variety of applied analytical strategies, from biospecimen and data pre-processing and quality control to statistical analysis and reporting of study findings. These strategies included methods commonly used within the metabolomics community and applied in epidemiological research, as well as novel approaches to pre-processing pipelines and data analysis. To help with these discrepancies, we propose use of open-source initiatives such as the online web-based tool COMETS Analytics, which includes helpful tools to guide analytical workflow and the standardized reporting of findings from metabolomics analyses within epidemiological studies. Ultimately, this will improve the quality of statistical analyses, research findings, and study reproducibility.
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- 2019
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127. Integrated Lipidomics and Proteomics Point to Early Blood-Based Changes in Childhood Preceding Later Development of Psychotic Experiences:Evidence From the Avon Longitudinal Study of Parents and Children
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Sean Madden, Stanley Zammit, Caitriona Scaife, Meike Heurich, Linda Ahonen, Matej Orešič, Jane A. English, Tuulia Hyötyläinen, Melanie Föcking, Aoife O'Gorman, Lorraine Brennan, David Cotter, Sophie Sabherwal, Francisco Madrid-Gambin, Gerard Cagney, Ismo Mattila, Glynn Lewis, Mary Cannon, and Tommi Suvitaival
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0301 basic medicine ,Coagulation protein ,Oncology ,Male ,Parents ,Proteomics ,medicine.medical_specialty ,Longitudinal study ,Neurology ,Adolescent ,Integration ,Prodromal Symptoms ,Article ,Early life ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Lipidomics ,medicine ,Humans ,Psychotic episode ,Longitudinal Studies ,Child ,Biological Psychiatry ,business.industry ,Lysophosphatidylcholines ,Plasminogen ,Lipidome ,ALSPAC ,Lipoproteins, LDL ,030104 developmental biology ,Psychotic Disorders ,Proteome ,Cohort ,Phosphatidylcholines ,Female ,business ,human activities ,030217 neurology & neurosurgery ,Biomarkers - Abstract
Background The identification of early biomarkers of psychotic experiences (PEs) is of interest because early diagnosis and treatment of those at risk of future disorder is associated with improved outcomes. The current study investigated early lipidomic and coagulation pathway protein signatures of later PEs in subjects from the Avon Longitudinal Study of Parents and Children cohort. Methods Plasma of 115 children (12 years of age) who were first identified as experiencing PEs at 18 years of age (48 cases and 67 controls) were assessed through integrated and targeted lipidomics and semitargeted proteomics approaches. We assessed the lipids, lysophosphatidylcholines (n = 11) and phosphatidylcholines (n = 61), and the protein members of the coagulation pathway (n = 22) and integrated these data with complement pathway protein data already available on these subjects. Results Twelve phosphatidylcholines, four lysophosphatidylcholines, and the coagulation protein plasminogen were altered between the control and PEs groups after correction for multiple comparisons. Lipidomic and proteomic datasets were integrated into a multivariate network displaying a strong relationship between most lipids that were significantly associated with PEs and plasminogen. Finally, an unsupervised clustering approach identified four different clusters, with one of the clusters presenting the highest case-control ratio (p < .01) and associated with a higher concentration of smaller low-density lipoprotein cholesterol particles. Conclusions Our findings indicate that the lipidome and proteome of subjects who report PEs at 18 years of age are already altered at 12 years of age, indicating that metabolic dysregulation may contribute to an early vulnerability to PEs and suggesting crosstalk between these lysophosphatidylcholines, phosphatidylcholines, and coagulation and complement proteins.
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- 2019
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128. Targeted Clinical Metabolomics Platform for the Stratification of Diabetic Patients
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Matej Orešič, Simone Theilade, Sirkku Jäntti, Claudia Risz, Tuulia Hyötyläinen, Peter Rossing, Risto Kostiainen, Tommi Suvitaival, and Linda Ahonen
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Oncology ,0303 health sciences ,medicine.medical_specialty ,Type 1 diabetes ,Analyte ,Statin ,medicine.drug_class ,business.industry ,Metabolite ,Renal function ,030209 endocrinology & metabolism ,Repeatability ,medicine.disease ,3. Good health ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Metabolomics ,chemistry ,Internal medicine ,Diabetes mellitus ,medicine ,business ,030304 developmental biology - Abstract
BackgroundSeveral small molecule biomarkers have been reported in the literature for prediction and diagnosis of (pre)diabetes, its co-morbidities and complications. Here, we report the development and validation of a novel, quantitative, analytical method for use in the diabetes clinic. This method enables the determination of a selected panel of 36 metabolite biomarkers from human plasma.MethodsBased on a review of the literature and our own data, we selected a panel of metabolites indicative of various clinically-relevant pathogenic stages of diabetes. We combined these candidate biomarkers into a single ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method and optimized it, prioritizing simplicity of sample preparation and time needed for analysis, enabling high-throughput analysis in clinical laboratory settings.ResultsWe validated the method in terms of limit of (a) detection (LOD), (b) limit of quantitation (LOQ), (c) linearity (R2), (d) linear range, and (e) intra- and inter-day repeatability of each metabolite. The method’s performance was demonstrated in the analysis of selected samples from a diabetes cohort study. Metabolite levels were associated with clinical measurements and kidney complications in type 1 diabetes (T1D) patients. Specifically, both amino acids and amino acid-related analytes were associated with macro-albuminuria. Additionally, specific bile acids were associated with kidney function, anti-hypertensive medication, statin medication and clinical lipid measurements.ConclusionsThe developed analytical method is suitable for robust determination of selected plasma metabolites in the diabetes clinic.
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- 2019
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129. Metabolic Alterations in Human Peripheral Blood Mononuclear Cells Associate with Progression to Islet Autoimmunity and Type 1 Diabetes
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Matej Orešič, Mikael Knip, Alex M. Dickens, Jorma Toppari, Jorma Ilonen, Esko Kemppainen, Santosh Lamichhane, Heikki Hyöty, Partho Sen, Tuulia Hyötyläinen, Tuomas Lindeman, Riitta Veijola, Tuukka Rönkkö, and María Asunción López-Bascón
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Ceramide ,endocrine system diseases ,030209 endocrinology & metabolism ,medicine.disease_cause ,Peripheral blood mononuclear cell ,Autoimmunity ,Transcriptome ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Metabolomics ,immune system diseases ,medicine ,030304 developmental biology ,0303 health sciences ,geography ,Type 1 diabetes ,geography.geographical_feature_category ,business.industry ,Autoantibody ,nutritional and metabolic diseases ,Islet ,medicine.disease ,3. Good health ,chemistry ,Immunology ,business - Abstract
Previous metabolomics studies suggest that type 1 diabetes (T1D) is preceded by specific metabolic disturbances. Here we asked whether distinct metabolic patterns occur in peripheral blood mononuclear cells (PBMCs) of children later developing pancreaticβ-cell autoimmunity or overt T1D. In a longitudinal cohort setting, PBMC metabolomic analysis was applied in children who either (1) progressed to T1D (PT1D, n=34), (2) seroconverted to ≥1 islet autoantibody without progressing to T1D (P1Ab, n=27), or (3) remained autoantibody negative during follow-up (CTRL, n=10). During the first year of life, levels of most lipids and polar metabolites were lower in PT1D and P1Ab, versus CTRLs. Pathway overrepresentation analysis suggested alanine, aspartate, glutamate, glycerophospholipid and sphingolipid metabolism were overrepresented in PT1D. Genome-scale metabolic models of PBMCs in T1D progression were developed using available transcriptomics data and constrained with metabolomics data from our study. Metabolic modeling confirmed altered ceramide pathways as specifically associated with T1D progression.
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- 2019
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130. The Consortium of Metabolomics Studies (COMETS):Metabolomics in 47 Prospective Cohort Studies
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Jackie F. Price, Marc J. Gunter, Lorelei A. Mucci, Therese Tillin, Qibin Qi, Loic Le Marchand, Tamara B. Harris, Luca A. Lotta, Clara Barrios Barrera, Yoav Ben-Shlomo, Rachael Z. Stolzenberg-Solomon, Kathryn M. Rexrode, Massimo Mangino, Svati H. Shah, Sei Harada, Toru Takebayashi, David M. Herrington, A. Heather Eliassen, Clary B. Clish, Debbie A Lawlor, Cornelia M. Ulrich, Mika Kivimäki, Deron R. Herr, Juan P. Casas, Naji Younes, Cristina Menni, Joshua N. Sampson, Jessica Lasky-Su, Ioanna Tzoulaki, Gordon C. S. Smith, Ying Wang, Ulla Sovio, Wei Jie Seow, Nathan Appel, Andriy Derkach, Chin Meng Khoo, Matej Orešič, Bing Yu, Andrew Wong, Bruce S. Kristal, Lucilla Poston, Eric Boerwinkle, Charles E. Matthews, Xiao-Ou Shu, Paul Elliott, C Gieger, Howard D. Sesso, Mary C. Playdon, Wei Zheng, Adam Risch, Victoria L. Stevens, Mattias Johansson, Ewy Mathé, Jennifer Ose, Nicholas J. Wareham, Marinella Temprosa, Alexandre C. Pereira, Ruth C. Travis, Steven C. Moore, Krista A. Zanetti, Eoin Fahy, Hua Zhao, Ramachandran S. Vasan, Claudia Langenberg, Rachel S. Kelly, Caroline Dale, Ann W. Hsing, Joel N. Hirschhorn, Mukesh Verma, Abbas Dehghan, Eric S. Orwoll, Rachel A. Murphy, Elise Hoover, Demetrius Albanes, Home Office, Imperial College Healthcare NHS Trust- BRC Funding, National Institute for Health Research, Medical Research Council (MRC), UK DRI Ltd, Langenberg, Claudia [0000-0002-5017-7344], Smith, Gordon [0000-0003-2124-0997], Sovio, Ulla [0000-0002-0799-1105], Wareham, Nicholas [0000-0003-1422-2993], and Apollo - University of Cambridge Repository
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Gerontology ,Male ,Epidemiology ,Health Behavior ,Disease ,heart disease ,Global Health ,Body Mass Index ,COLORECTAL-CANCER ,0302 clinical medicine ,Interquartile range ,genetics ,NATIONAL DEATH INDEX ,030212 general & internal medicine ,Longitudinal Studies ,Prospective Studies ,Prospective cohort study ,Child ,11 Medical and Health Sciences ,Public, Environmental & Occupational Health ,Cancer ,Aged, 80 and over ,Hematologic Tests ,diabetes ,Diabetes ,Cohort ,cohort ,Middle Aged ,metabolomics ,Prospective ,Heart Disease ,030220 oncology & carcinogenesis ,Female ,Life Sciences & Biomedicine ,Bristol Population Health Science Institute ,Adult ,medicine.medical_specialty ,Adolescent ,PROSTATE-CANCER RISK ,ATHEROSCLEROSIS RISK ,National Death Index ,03 medical and health sciences ,Young Adult ,Metabolomics ,OSTEOPOROTIC FRACTURES ,MALE MEAT-EATERS ,Metabolome ,medicine ,Genetics ,Humans ,cancer ,BREAST-CANCER ,01 Mathematical Sciences ,Aged ,Study Design ,Science & Technology ,business.industry ,BETA-CAROTENE ,prospective ,BODY-MASS INDEX ,Socioeconomic Factors ,METABOLITE PROFILES ,business ,Epidemiologic Methods ,Biomarkers - Abstract
The Consortium of Metabolomics Studies (COMETS) was established in 2014 to facilitate large-scale collaborative research on the human metabolome and its relationship with disease etiology, diagnosis, and prognosis. COMETS comprises 47 cohorts from Asia, Europe, North America, and South America that together include more than 136,000 participants with blood metabolomics data on samples collected from 1985 to 2017. Metabolomics data were provided by 17 different platforms, with the most frequently used labs being Metabolon, Inc. (14 cohorts), the Broad Institute (15 cohorts), and Nightingale Health (11 cohorts). Participants have been followed for a median of 23 years for health outcomes including death, cancer, cardiovascular disease, diabetes, and others; many of the studies are ongoing. Available exposure-related data include common clinical measurements and behavioral factors, as well as genome-wide genotype data. Two feasibility studies were conducted to evaluate the comparability of metabolomics platforms used by COMETS cohorts. The first study showed that the overlap between any 2 different laboratories ranged from 6 to 121 metabolites at 5 leading laboratories. The second study showed that the median Spearman correlation comparing 111 overlapping metabolites captured by Metabolon and the Broad Institute was 0.79 (interquartile range, 0.56-0.89).
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- 2019
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131. Prenatal exposure to perfluoroalkyl substances modulates neonatal serum phospholipids, increasing risk of type 1 diabetes
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Johanna Bodin, Daniel Duberg, Mikael Knip, Jorma Ilonen, Partho Sen, Dawei Geng, Suvi M. Virtanen, Unni Cecilie Nygaard, Cecilia Carlsson, Heli Siljander, Matej Orešič, Alex M. Dickens, Santosh Lamichhane, Hubert Dirven, Hanne Friis Berntsen, Aidan McGlinchey, Karin Elisabeth Zimmer, Tuulia Hyötyläinen, Tim Sinioja, Clinicum, HUS Children and Adolescents, Children's Hospital, Research Programs Unit, CAMM - Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, and University of Helsinki
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010504 meteorology & atmospheric sciences ,endocrine system diseases ,PFAS ,CHILDHOOD ,Physiology ,DETERMINANTS ,010501 environmental sciences ,01 natural sciences ,GUT MICROBIOME ,Pathogenesis ,chemistry.chemical_compound ,Pregnancy ,PERSISTENT ORGANIC POLLUTANTS ,Finland ,Phospholipids ,lcsh:Environmental sciences ,General Environmental Science ,lcsh:GE1-350 ,Fluorocarbons ,0303 health sciences ,geography.geographical_feature_category ,medicine.diagnostic_test ,Incidence (epidemiology) ,Islet ,3. Good health ,Type 1 diabetes ,PERFLUORINATED COMPOUNDS ,Prenatal Exposure Delayed Effects ,Cohort ,ACID ,Environmental Pollutants ,Female ,medicine.medical_specialty ,Lithocholic acid ,Offspring ,METABOLISM ,Diabetes Mellitus, Experimental ,03 medical and health sciences ,Internal medicine ,Lipidomics ,medicine ,Animals ,ISLET AUTOIMMUNITY ,030304 developmental biology ,0105 earth and related environmental sciences ,geography ,Mass spectrometry ,business.industry ,medicine.disease ,TRENDS ,Bile acids ,Diabetes Mellitus, Type 1 ,Endocrinology ,chemistry ,1182 Biochemistry, cell and molecular biology ,Lipid profile ,business ,Insulitis - Abstract
In the last decade, the increasing incidence of type 1 diabetes (T1D) stabilized in Finland, coinciding with tighter regulation of per- and polyfluoroalkyl substances (PFAS). Here we applied lipidomics and quantification of PFAS to examine their effect, during pregnancy, on lipid-related markers of T1D risk in children. In a well-characterized mother-infant cohort (264 pairs), high PFAS exposure during pregnancy associated with decreased phospholipids in the offspring. This association was exacerbated with iwncreased human leukocyte antigen-conferred risk of T1D in infants. Their lipid profiles proved similar to those observed in earlier studies in young children progressing to T1D later in life. Exposure to a single PFAS compound or a PFAS-containing mixture of organic pollutants in non-obese diabetic mice resulted in their offspring seeing a similar decrease in phospholipids, with early signs of insulitis. Our findings suggest that high PFAS exposure during pregnancy contributes to risk and pathogenesis of T1D in children.
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- 2019
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132. Human PNPLA3-I148M variant increases hepatic retention of polyunsaturated fatty acids
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Matej Orešič, Maarit Hölttä-Vuori, Hannele Yki-Järvinen, Marju Orho-Melander, Markku Peltonen, Auli Nick, Leanne Hodson, Elina Ikonen, Antti Hakkarainen, Christoph Thiele, Tuulia Hyötyläinen, Susanna Lallukka-Brück, Panu K. Luukkonen, Elina Isokuortti, Nina Lundbom, You Zhou, Minerva Foundation Institute for Medical Research Helsinki, University of Bonn, Department of Neuroscience and Biomedical Engineering, University of Helsinki, National Institute for Health and Welfare, Lund University, University of Turku, Örebro University, University of Oxford, Aalto-yliopisto, Aalto University, HUS Internal Medicine and Rehabilitation, Department of Medicine, Director and Common Matters, Department of Anatomy, Medicum, University Management, HUS Medical Imaging Center, Department of Diagnostics and Therapeutics, STEMM - Stem Cells and Metabolism Research Program, and Lipid Trafficking Lab
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0301 basic medicine ,Male ,Very low-density lipoprotein ,Cholesterol, VLDL ,Phospholipase ,OXIDATION ,DISEASE ,I148M ,chemistry.chemical_compound ,0302 clinical medicine ,Transacylation ,Loss of Function Mutation ,chemistry.chemical_classification ,Fatty Acids ,food and beverages ,General Medicine ,Middle Aged ,Postprandial ,Liver ,030220 oncology & carcinogenesis ,Fatty Acids, Unsaturated ,TRIGLYCERIDE ,lipids (amino acids, peptides, and proteins) ,Female ,Polyunsaturated fatty acid ,Research Article ,EXPRESSION ,Adult ,medicine.medical_specialty ,Heterozygote ,Adolescent ,WEIGHT-LOSS ,METABOLISM ,Cell Line ,03 medical and health sciences ,Young Adult ,Internal medicine ,Cell Line, Tumor ,medicine ,Humans ,Triglycerides ,Triglyceride ,nutritional and metabolic diseases ,Membrane Proteins ,Lipase ,LIPOPROTEIN ,030104 developmental biology ,Endocrinology ,chemistry ,GREATER ,LIVER FAT ,3111 Biomedicine ,Lipoprotein ,Chylomicron - Abstract
openaire: EC/H2020/634413/EU//EPoS | openaire: EC/H2020/777377/EU//LITMUS The common patatin-like phospholipase domain-containing protein 3 (PNPLA3) variant I148M predisposes to nonalcoholic liver disease but not its metabolic sequelae. We compared the handling of labeled polyunsaturated fatty acids (PUFAs) and saturated fatty acids (SFA) in vivo in humans and in cells harboring different PNPLA3 genotypes. In 148M homozygous individuals, triglycerides (TGs) in very low-density lipoproteins (VLDL) were depleted of PUFAs both under fasting and postprandial conditions compared with 148I homozygotes, and the PUFA/SFA ratio in VLDL-TGs was lower relative to the chylomicron precursor pool. In human PNPLA3-148M and PNPLA3-KO cells, PUFA but not SFA incorporation into TGs was increased at the expense of phosphatidylcholines, and under lipolytic conditions, PUFA-containing diacylglycerols (DAGs) accumulated compared with PNPLA3-148I cells. Polyunsaturated TGs were increased, while phosphatidylcholines (PCs) were decreased in the human liver in 148M homozygous individuals as compared with 148I homozygotes. We conclude that human PNPLA3-I148M is a loss-of-function allele that remodels liver TGs in a polyunsaturated direction by impairing hydrolysis/transacylation of PUFAs from DAGs to feed phosphatidylcholine synthesis.
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- 2019
133. Cord-Blood Lipidome in Progression to Islet Autoimmunity and Type 1 Diabetes
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Heli Siljander, Matej Orešič, Linda Ahonen, Tuulia Hyötyläinen, Mikael Knip, Jorma Ilonen, Alex M. Dickens, Santosh Lamichhane, Riitta Veijola, Thomas Sparholt Dyrlund, Heikki Hyöty, Jorma Toppari, Lääketieteen ja terveysteknologian tiedekunta - Faculty of Medicine and Health Technology, Tampere University, Diabetes and Obesity Research Program, HUS Children and Adolescents, Research Programs Unit, Children's Hospital, Clinicum, University of Helsinki, and Lastentautien yksikkö
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Male ,0301 basic medicine ,endocrine system diseases ,type 1 diabetes ,lcsh:QR1-502 ,medicine.disease_cause ,Biochemistry ,Mass Spectrometry ,lcsh:Microbiology ,Autoimmunity ,chemistry.chemical_compound ,0302 clinical medicine ,immune system diseases ,PHOSPHATIDYLCHOLINE ,Child ,Chromatography, High Pressure Liquid ,geography.geographical_feature_category ,autoimmunity ,Sisätaudit - Internal medicine ,Discriminant Analysis ,Lipidome ,Fetal Blood ,Islet ,Lipids ,metabolomics ,Sphingomyelins ,3. Good health ,Area Under Curve ,Child, Preschool ,Cord blood ,Disease Progression ,cord blood ,Female ,medicine.medical_specialty ,endocrine system ,Biolääketieteet - Biomedicine ,030209 endocrinology & metabolism ,METABOLISM ,ta3111 ,Article ,Islets of Langerhans ,03 medical and health sciences ,Internal medicine ,Lipidomics ,medicine ,Humans ,Least-Squares Analysis ,Molecular Biology ,Autoantibodies ,Type 1 diabetes ,geography ,Cholesterol ,business.industry ,Autoantibody ,nutritional and metabolic diseases ,medicine.disease ,ta3123 ,Diabetes Mellitus, Type 1 ,030104 developmental biology ,Endocrinology ,ROC Curve ,chemistry ,Case-Control Studies ,DISCOVERY ,3121 General medicine, internal medicine and other clinical medicine ,lipidomics ,3111 Biomedicine ,business - Abstract
Previous studies suggest that children who progress to type 1 diabetes (T1D) later in life already have an altered serum lipid molecular profile at birth. Here, we compared cord blood lipidome across the three study groups: children who progressed to T1D (PT1D, n = 30), children who developed at least one islet autoantibody but did not progress to T1D during the follow-up (P1Ab, n = 33), and their age-matched controls (CTR, n = 38). We found that phospholipids, specifically sphingomyelins, were lower in T1D progressors when compared to P1Ab and the CTR. Cholesterol esters remained higher in PT1D when compared to other groups. A signature comprising five lipids was predictive of the risk of progression to T1D, with an area under the receiver operating characteristic curve (AUROC) of 0.83. Our findings provide further evidence that the lipidomic profiles of newborn infants who progress to T1D later in life are different from lipidomic profiles in P1Ab and CTR.
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- 2019
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134. Metabolic Modeling of Human Gut Microbiota on a Genome Scale: An Overview
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Matej Orešič and Partho Sen
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0301 basic medicine ,genome-scale metabolic modeling ,Endocrinology, Diabetes and Metabolism ,host–microbiome ,flux balance ,Genome scale ,lcsh:QR1-502 ,gut microbiome ,Computational biology ,Review ,Biology ,Biochemistry ,lcsh:Microbiology ,03 medical and health sciences ,0302 clinical medicine ,Metabolomics ,Human gut ,Metabolic modeling ,Molecular Biology ,metagenomics ,meta-omics ,metabolomics ,Gut microbiome ,030104 developmental biology ,Metagenomics ,constraint-based modeling ,metabolic reconstructions ,Functional profiling ,Shotgun metagenomics ,metabolism ,030217 neurology & neurosurgery - Abstract
There is growing interest in the metabolic interplay between the gut microbiome and host metabolism. Taxonomic and functional profiling of the gut microbiome by next-generation sequencing (NGS) has unveiled substantial richness and diversity. However, the mechanisms underlying interactions between diet, gut microbiome and host metabolism are still poorly understood. Genome-scale metabolic modeling (GSMM) is an emerging approach that has been increasingly applied to infer diet⁻microbiome, microbe⁻microbe and host⁻microbe interactions under physiological conditions. GSMM can, for example, be applied to estimate the metabolic capabilities of microbes in the gut. Here, we discuss how meta-omics datasets such as shotgun metagenomics, can be processed and integrated to develop large-scale, condition-specific, personalized microbiota models in healthy and disease states. Furthermore, we summarize various tools and resources available for metagenomic data processing and GSMM, highlighting the experimental approaches needed to validate the model predictions.
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- 2019
135. Molecular lipids in prediction of psychosis and the associated cardiometabolic co-morbidities
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Matej Orešič
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Psychiatry and Mental health ,Psychosis ,business.industry ,medicine ,Lipid metabolism ,Co morbidity ,Bioinformatics ,medicine.disease ,business ,Pathophysiology - Abstract
Lipid metabolism has been an area of increased interest in psychosis research, not only due to its link to metabolic comorbidities, but also due to its putative role in the pathophysiology of psychosis. Lipid disturbances are observed already in the period preceding the onset of psychosis. For example, we performed mass spectrometry based lipidomics in a cohort of individuals at clinical high risk for psychosis (the EU-GEI study) and found that the individuals who transitioned to psychosis within a 2-year follow-up period displayed decreased levels of ether phospholipids. This finding may be of direct (patho)physiological relevance, as ether phospholipids (particularly plasmalogens, a major subgroup of ether phospholipids) are highly enriched in the brain, are supplied to the brain by the liver, have many structural and functional roles, and may act as endogenous antioxidants. Accumulating evidence also suggests that lipid disturbances play a crucial role in the development of metabolic comorbidities associated with psychotic disorders. Our lipidomic studies have shown that psychotic patients who rapidly gain weight during follow-up have elevated triglycerides (TGs) with low double bond count and carbon number at baseline. These TGs are known to be associated with non-alcoholic fatty liver disease (NAFLD) and with increased risk of type 2 diabetes. In conclusion, although the mechanisms linking dysregulation of lipid metabolism with the pathophysiology of psychosis are currently poorly understood, findings by us and others suggest that metabolic abnormalities are evident in people who are vulnerable to psychosis, and to the associated metabolic comorbidities.DisclosureNo significant relationships.
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- 2021
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136. Systems biology approaches to study lipidomes in health and disease
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Marina Amaral Alves, Fang Wei, Aidan McGlinchey, Partho Sen, Matej Orešič, Alex M. Dickens, Henrique Caracho Ribeiro, Tuulia Hyötyläinen, and Santosh Lamichhane
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Biomedical Research ,Systems biology ,Disease ,Computational biology ,Biology ,03 medical and health sciences ,Functional diversity ,0302 clinical medicine ,Metabolomics ,Non-alcoholic Fatty Liver Disease ,Lipidomics ,Humans ,Disease biomarker ,Obesity ,Molecular Biology ,030304 developmental biology ,0303 health sciences ,Systems Biology ,Neurodegenerative Diseases ,Lipid metabolism ,Cell Biology ,Lipid Metabolism ,3. Good health ,Diabetes Mellitus, Type 2 ,Psychotic Disorders ,030217 neurology & neurosurgery - Abstract
Lipids have many important biological roles, such as energy storage sources, structural components of plasma membranes and as intermediates in metabolic and signaling pathways. Lipid metabolism is under tight homeostatic control, exhibiting spatial and dynamic complexity at multiple levels. Consequently, lipid-related disturbances play important roles in the pathogenesis of most of the common diseases. Lipidomics, defined as the study of lipidomes in biological systems, has emerged as a rapidly-growing field. Due to the chemical and functional diversity of lipids, the application of a systems biology approach is essential if one is to address lipid functionality at different physiological levels. In parallel with analytical advances to measure lipids in biological matrices, the field of computational lipidomics has been rapidly advancing, enabling modeling of lipidomes in their pathway, spatial and dynamic contexts. This review focuses on recent progress in systems biology approaches to study lipids in health and disease, with specific emphasis on methodological advances and biomedical applications.
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- 2021
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137. Hepatic ceramides dissociate steatosis and insulin resistance in patients with non-alcoholic fatty liver disease
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Sanja Sädevirta, Matej Orešič, Panu K. Luukkonen, Tuulia Hyötyläinen, Marja Leivonen, Hannele Yki-Järvinen, Johanna Arola, You Zhou, Department of Medicine, Clinicum, II kirurgian klinikka, Department of Surgery, Medicum, Department of Pathology, and Hannele Yki-Järvinen Research Group
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Male ,0301 basic medicine ,Biopsy ,VARIANT ,Adipose tissue ,GLUCOSE ,I148M ,chemistry.chemical_compound ,Patatin-like phospholipase domain containing protein 3 ,0302 clinical medicine ,High-density lipoprotein ,Non-alcoholic Fatty Liver Disease ,Risk Factors ,Nonalcoholic fatty liver disease ,Non-alcoholic steatohepatitis ,Fatty liver ,GENETIC-VARIATION ,Middle Aged ,3. Good health ,ADIPOSE-TISSUE ,HISTOLOGICAL SEVERITY ,Liver ,Lipogenesis ,Female ,030211 gastroenterology & hepatology ,OBESE SUBJECTS ,Adult ,medicine.medical_specialty ,Adolescent ,Biology ,Free fatty acids ,Ceramides ,Young Adult ,03 medical and health sciences ,Insulin resistance ,Diabetes mellitus ,Internal medicine ,medicine ,Humans ,PNPLA3 ,Aged ,Hepatology ,nutritional and metabolic diseases ,DIABETES-MELLITUS ,ACIDS ,medicine.disease ,R1 ,030104 developmental biology ,Endocrinology ,chemistry ,3121 General medicine, internal medicine and other clinical medicine ,Dihydroceramides ,Insulin Resistance ,Steatosis - Abstract
Background & Aims: Recent data in mice have identified de novo ceramide synthesis as the key mediator of hepatic insulin resistance (IR) that in humans characterizes increases in liver fat due to IR ('Metabolic NAFLD' but not that due to the I148M gene variant in PNPLA3 ('PNPLA3 NAFLD'). We determined which bioactive lipids co-segregate with IR in the human liver. Methods: Liver lipidome was profiled in liver biopsies from 125 subjects that were divided into equally sized groups based on median HOMA-IR ('High and Low HOMA-IR', n = 62 and n = 63) or PNPLA3 genotype (PNPIA3(148MM/MI), n = 61 vs. PNPLA3(148II), n = 64). The subjects were also divided into 4 groups who had either IR, the I148M gene variant, both of the risk factors or neither. Results: Steatosis and NASH prevalence were similarly increased in 'High HOMA-IR' and PNPLA3(148MM/MI) groups compared to their respective control groups. The 'High HOMA-IR' but not the PNPLA3(148MM/MI) group had features of IR. The liver in 'High HOMA-IR' vs. low HOMA-IR' was markedly enriched in saturated and monounsaturated triacylglycerols and free fatty acids, dihydroceramides (markers of de novo ceramide synthesis) and ceramides. Markers of other ceramide synthetic pathways were unchanged. In PNPLA3(148MM/MI) vs. PNPLA3(148II), the increase in liver fat was due to polyunsaturated triacylglycerols while other lipids were unchanged. Similar changes were observed when data were analyzed using the 4 subgroups. Conclusions: Similar increases in liver fat and NASH are associated with a metabolically harmful saturated, ceramide-enriched liver lipidome in 'Metabolic NAFLD' but not in 'PNPLA3 NAFLD'. This difference may explain why metabolic but not PNPLA3 NAFLD increases the risk of type 2 diabetes and cardiovascular disease. (C) 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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- 2016
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138. Bioanalytical techniques in nontargeted clinical lipidomics
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Matej Orešič and Tuulia Hyötyläinen
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0301 basic medicine ,Aging ,Sex Characteristics ,010401 analytical chemistry ,Clinical Biochemistry ,Nanotechnology ,General Medicine ,Biology ,Lipid Metabolism ,Postprandial Period ,01 natural sciences ,Data science ,Diet ,0104 chemical sciences ,Analytical Chemistry ,03 medical and health sciences ,Medical Laboratory Technology ,Cell and molecular biology ,030104 developmental biology ,Lipidomics ,Humans ,Metabolomics ,General Pharmacology, Toxicology and Pharmaceutics - Abstract
Lipidomic analysis aims at comprehensive characterization of molecular lipids in biological systems. Due to the central role of lipid metabolism in many devastating diseases, lipidomics is being increasingly applied in biomedical research. Over the past years, advances in analytical techniques and bioinformatics enabled increasingly comprehensive and accurate coverage of lipids both in tissues and biofluids, yet many challenges remain. This review highlights recent progress in the domain of analytical lipidomics, with main emphasis on non-targeted methodologies for large scale clinical applications, as well as discusses some of the key challenges and opportunities in this field.
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- 2016
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139. Longitudinal plasma metabolic profiles, infant feeding, and islet autoimmunity in the MIDIA study
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Matej Orešič, Kjersti S. Rønningen, Tuulia Hyötyläinen, Per Medbøe Thorsby, Håkon Bøås, Jens P. Berg, Lars C. Stene, German Tapia, Benedicte Jørgenrud, and Milaim Pepaj
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0301 basic medicine ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Metabolite ,030209 endocrinology & metabolism ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,Internal Medicine ,medicine ,Seroconversion ,geography ,Type 1 diabetes ,geography.geographical_feature_category ,Methionine ,business.industry ,Case-control study ,Ornithine ,Islet ,medicine.disease ,030104 developmental biology ,Endocrinology ,chemistry ,Pediatrics, Perinatology and Child Health ,business ,Breast feeding - Abstract
Aims The aim of this study was to investigate the longitudinal plasma metabolic profiles in healthy infants and the potential association with breastfeeding duration and islet autoantibodies predictive of type 1 diabetes. Method Up to four longitudinal plasma samples from age 3 months from case children who developed islet autoimmunity (n = 29) and autoantibody-negative control children (n = 29) with the HLA DR4-DQ8/DR3-DQ2 genotype were analyzed using two-dimensional gas chromatography coupled to a time-of-flight mass spectrometer for detection of small polar metabolites. Results Plasma metabolite levels were found to depend strongly on age, with fold changes varying up to 50% from age 3 to 24 months (p
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- 2016
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140. Human serum metabolites associate with severity and patient outcomes in traumatic brain injury
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Ismo Mattila, Matej Orešič, Ari Katila, Henna Ala-Seppälä, Olli Tenovuo, Anna Kyllönen, Maja H. Kamstrup-Nielsen, Janek Frantzén, Sirkku Jäntti, Jussi P. Posti, Iiro Heino, Henna-Riikka Maanpää, Riikka S.K. Takala, Peter J. Hutchinson, Jussi Tallus, Keri L.H. Carpenter, Jonathan P. Coles, Tuulia Hyötyläinen, Hester F. Lingsma, David K. Menon, and Public Health
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Male ,0301 basic medicine ,lcsh:Medicine ,Severity of Illness Index ,Workflow ,0302 clinical medicine ,Brain Injuries, Traumatic ,ta318 ,Prospective Studies ,Young adult ,Cause of death ,mass spectrometry ,Aged, 80 and over ,lcsh:R5-920 ,traumatic brain injury ,General Medicine ,Middle Aged ,Prognosis ,metabolomics ,3. Good health ,Metabolome ,Female ,lcsh:Medicine (General) ,Research Paper ,Adult ,medicine.medical_specialty ,Validation study ,Adolescent ,Traumatic brain injury ,ta3111 ,ta3112 ,General Biochemistry, Genetics and Molecular Biology ,Head trauma ,Young Adult ,03 medical and health sciences ,Internal medicine ,medicine ,Humans ,Glasgow Coma Scale ,Aged ,business.industry ,lcsh:R ,Reproducibility of Results ,biomarkers ,medicine.disease ,Serum samples ,ta3124 ,Surgery ,Patient Outcome Assessment ,030104 developmental biology ,ROC Curve ,Orthopedic surgery ,Tomography, X-Ray Computed ,business ,030217 neurology & neurosurgery - Abstract
Traumatic brain injury (TBI) is a major cause of death and disability worldwide, especially in children and young adults. TBI is an example of a medical condition where there are still major lacks in diagnostics and outcome prediction. Here we apply comprehensive metabolic profiling of serum samples from TBI patients and controls in two independent cohorts. The discovery study included 144 TBI patients, with the samples taken at the time of hospitalization. The patients were diagnosed as severe (sTBI; n = 22), moderate (moTBI; n = 14) or mild TBI (mTBI; n = 108) according to Glasgow Coma Scale. The control group (n = 28) comprised of acute orthopedic non-brain injuries. The validation study included sTBI (n = 23), moTBI (n = 7), mTBI (n = 37) patients and controls (n = 27). We show that two medium-chain fatty acids (decanoic and octanoic acids) and sugar derivatives including 2,3-bisphosphoglyceric acid are strongly associated with severity of TBI, and most of them are also detected at high concentrations in brain microdialysates of TBI patients. Based on metabolite concentrations from TBI patients at the time of hospitalization, an algorithm was developed that accurately predicted the patient outcomes (AUC = 0.84 in validation cohort). Addition of the metabolites to the established clinical model (CRASH), comprising clinical and computed tomography data, significantly improved prediction of patient outcomes. The identified ‘TBI metabotype’ in serum, that may be indicative of disrupted blood-brain barrier, of protective physiological response and altered metabolism due to head trauma, offers a new avenue for the development of diagnostic and prognostic markers of broad spectrum of TBIs., Graphical Abstract Image 1, Highlights • The study reports that serum metabolites are sensitive to severity of TBI as well as predict the patient outcomes. • The findings are indicative of disruption in blood brain barrier and of protective response and altered TBI metabolism. • Metabolites significantly improved the prediction of patient outcomes when added to the established clinical model. Traumatic brain injury (TBI) is an example of a medical condition where there are still major lacks in diagnostics, outcome prediction, and the therapy development. Since the blood-brain barrier prevents diffusion of most water-soluble molecules with molecular mass over 500 Da, here we hypothesized that circulating small molecules (metabolites) are a potential source of TBI markers. Based on serum metabolomic studies in two independent cohorts, we found that metabolites are sensitive to severity of TBI as well as predict the patient outcomes. The findings of this study may pave the way for new diagnostic tools for TBI.
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- 2016
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141. Imbalance of plasma amino acids, metabolites and lipids in patients with lysinuric protein intolerance (LPI)
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Ismo Mattila, Harri Niinikoski, Maaria Tringham, Olli Simell, Anu Olkku, Johanna Kurko, Heli Nygren, Matej Orešič, Mari Vähä-Mäkilä, Päivi Pöhö, Tuulia Hyötyläinen, Niina Lietzen, Kirsti Näntö-Salonen, Juha Mykkänen, and Laura Tanner
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0301 basic medicine ,Male ,Endocrinology, Diabetes and Metabolism ,Metabolite ,030232 urology & nephrology ,chemistry.chemical_compound ,0302 clinical medicine ,Endocrinology ,Amino Acids ,Child ,Finland ,2. Zero hunger ,chemistry.chemical_classification ,Middle Aged ,Lipids ,metabolomics ,3. Good health ,Amino acid ,Biochemistry ,Aminoaciduria ,Disease Progression ,Phosphatidylcholines ,Carbohydrate Metabolism ,Female ,Glomerular Filtration Rate ,Adult ,medicine.medical_specialty ,Adolescent ,03 medical and health sciences ,Young Adult ,Internal medicine ,Lipidomics ,medicine ,Humans ,Amino Acid Metabolism, Inborn Errors ,Nitrites ,Triglycerides ,Aged ,Lysine ,Lipid metabolism ,ta3121 ,medicine.disease ,Lipid Metabolism ,ta3123 ,Lysinuric protein intolerance ,4-Hydroxyphenylacetic acid ,030104 developmental biology ,lysinuric protein intolerance ,chemistry ,combined hyperlipidemia ,lipidomics ,Amino Acids, Essential ,Steatosis ,Energy Metabolism ,chronic kidney disease - Abstract
Background Lysinuric protein intolerance (LPI [MIM 222700]) is an aminoaciduria with defective transport of cationic amino acids in epithelial cells in the small intestine and proximal kidney tubules due to mutations in the SLC7A7 gene. LPI is characterized by protein malnutrition, failure to thrive and hyperammonemia. Many patients also suffer from combined hyperlipidemia and chronic kidney disease (CKD) with an unknown etiology. Methods Here, we studied the plasma metabolomes of the Finnish LPI patients (n = 26) and healthy control individuals (n = 19) using a targeted platform for analysis of amino acids as well as two analytical platforms with comprehensive coverage of molecular lipids and polar metabolites. Results Our results demonstrated that LPI patients have a dichotomy of amino acid profiles, with both decreased essential and increased non-essential amino acids. Altered levels of metabolites participating in pathways such as sugar, energy, amino acid and lipid metabolism were observed. Furthermore, of these metabolites, myo-inositol, threonic acid, 2,5-furandicarboxylic acid, galactaric acid, 4-hydroxyphenylacetic acid, indole-3-acetic acid and beta-aminoisobutyric acid associated significantly (P < 0.001) with the CKD status. Lipid analysis showed reduced levels of phosphatidylcholines and elevated levels of triacylglycerols, of which long-chain triacylglycerols associated (P
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- 2016
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142. Modeling strategies to study metabolic pathways in progression to type 1 diabetes – Challenges and opportunities
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Matej Orešič and Tijana Marinković
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0301 basic medicine ,endocrine system ,endocrine system diseases ,0206 medical engineering ,Biophysics ,02 engineering and technology ,Biology ,medicine.disease_cause ,Models, Biological ,Biochemistry ,Autoimmunity ,03 medical and health sciences ,Metabolomics ,Lipidomics ,medicine ,Humans ,Metabolic modeling ,Seroconversion ,Molecular Biology ,geography ,Type 1 diabetes ,geography.geographical_feature_category ,Islet ,medicine.disease ,Metabolic pathway ,Diabetes Mellitus, Type 1 ,030104 developmental biology ,Immunology ,Disease Progression ,Metabolic Networks and Pathways ,020602 bioinformatics - Abstract
Seroconversion to islet autoimmunity is preceded by metabolic disturbances in children who later progress to overt type 1 diabetes (T1D). The underlying metabolic pathways and the interaction of metabolic and immune system factors involved in progression to the disease are however poorly understood. There is a clear need for mathematical models which capture the temporal and spatial complexity of early pathogenesis of T1D. Here we review the early attempts to model the development of islet autoimmunity and T1D, including the models which emphasize the potential beneficial role of autoimmune response in specific circumstances, such as to 'correct' for the early metabolic disturbances. We also highlight the genome-scale metabolic modeling as a promising new avenue to study metabolism and its interactions with the immune system in T1D.
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- 2016
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143. A healthy Nordic diet alters the plasma lipidomic profile in adults with features of metabolic syndrome in a multicenter randomized dietary intervention
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Ursula Schwab, Tuulia Hyötyläinen, Kjeld Hermansen, Matej Orešič, Heli Nygren, Jussi Paananen, Marjukka Kolehmainen, Matti Uusitupa, Gunilla Önning, Matti Marklund, Maria Lankinen, Markku J. Savolainen, Inga Thorsdottir, Ingibjorg Gunnarsdottir, Lieselotte Cloetens, Janne Hukkanen, Lars O. Dragsted, Fredrik Rosqvist, Lea Brader, Kaisa Poutanen, Björn Åkesson, Ulf Risérus, and Tuulikki Seppänen-Laakso
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0301 basic medicine ,medicine.medical_specialty ,Medicine (miscellaneous) ,030209 endocrinology & metabolism ,law.invention ,lipids ,03 medical and health sciences ,0302 clinical medicine ,Randomized controlled trial ,SDG 3 - Good Health and Well-being ,law ,Intervention (counseling) ,Internal medicine ,Lipidomics ,Medicine ,human ,Cardiometabolic risk ,Nutrition and Dietetics ,business.industry ,ta3141 ,medicine.disease ,nordic diet ,030104 developmental biology ,Endocrinology ,nutrition ,randomized controlled trial ,population characteristics ,lipidomics ,Metabolic syndrome ,business - Abstract
BACKGROUND: A healthy Nordic diet is associated with improvements in cardiometabolic risk factors, but the effect on lipidomic profile is not known.OBJECTIVE: The aim was to investigate how a healthy Nordic diet affects the fasting plasma lipidomic profile in subjects with metabolic syndrome.METHODS: Men and women (n = 200) with features of metabolic syndrome [mean age: 55 y; body mass index (in kg/m(2)): 31.6] were randomly assigned to either a healthy Nordic (n = 104) or a control (n = 96) diet for 18 or 24 wk at 6 centers. Of the participants, 156 completed the study with plasma lipidomic measurements. The healthy Nordic diet consisted of whole grains, fruits, vegetables, berries, vegetable oils and margarines, fish, low-fat milk products, and low-fat meat. An average Nordic diet served as the control diet and included low-fiber cereal products, dairy fat-based spreads, regular-fat milk products, and a limited amount of fruits, vegetables, and berries. Lipidomic profiles were measured at baseline, week 12, and the end of the intervention (18 or 24 wk) by using ultraperformance liquid chromatography mass spectrometry. The effects of the diets on the lipid variables were analyzed with linear mixed-effects models. Data from centers with 18- or 24-wk duration were also analyzed separately.RESULTS: Changes in 21 plasma lipids differed significantly between the groups at week 12 (false discovery rate P < 0.05), including increases in plasmalogens and decreases in ceramides in the healthy Nordic diet group compared with the control group. At the end of the study, changes in lipidomic profiles did not differ between the groups. However, when the intervention lasted 24 wk, changes in 8 plasma lipids that had been identified at 12 wk, including plasmalogens, were sustained. There were no differences in changes in plasma lipids between groups with an intervention of 18 wk. By the dietary biomarker score, adherence to diet did not explain the difference in the results related to the duration of the study.CONCLUSIONS: A healthy Nordic diet transiently modified the plasma lipidomic profile, specifically by increasing the concentrations of antioxidative plasmalogens and decreasing insulin resistance-inducing ceramides. This trial was registered at clinicaltrials.gov as NCT00992641.
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- 2016
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144. Metabolomics approaches to identify biomarkers of non-alcoholic fatty liver disease
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Aidan McGlinchey, Dawei Geng, Olivier Govaere, Vlad Ratziu, Elisabetta Bugianesi, Jörn M. Schattenberg, Ann K Daly, Tuulia Hyötyläinen, Quentin Anstee, and Matej Orešič
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Hepatology - Published
- 2020
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145. A computational framework to integrate high-throughput '-omics' datasets for the identification of potential mechanistic links
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Matej Orešič, Trine Nielsen, Søren Brunak, Sofia K. Forslund, Oluf Pedersen, Valborg Gudmundsdottir, Helle Krogh Pedersen, Torben Hansen, Peer Bork, S. Dusko Ehrlich, Anders Østergaard Petersen, Falk Hildebrand, Henrik Nielsen, Tuulia Hyötyläinen, Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR), Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), Structural and Computational Biology Unit, European Molecular Biology Laboratory, European Molecular Biology Laboratory [Grenoble] (EMBL), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Department of Bio and Health Informatics, Technical University of Denmark [Lyngby] (DTU), Örebro University, MetaGenoPolis, Institut National de la Recherche Agronomique (INRA), Université Paris Saclay (COmUE), King's College Hospital (KCH), Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn, Dis Syst Biol,Ctr Prot Res, Copenhagen, Denmark, Partenaires INRAE, Tech Univ Denmark, Dept Bio & Hlth Informat, Lyngby, Denmark, University of Turku, Åbo Akademi University [Turku], Clinical-Microbiomics, MetaCardis [HEALTH-2012-305312], Innovative Medicines Initiative Joint Undertaking [115317], Novo Nordisk Foundation [NNF14CC0001], Agence Nationale de la Recherche MetaGenoPolis grant 'Investissements d'avenir' [ANR-11-DPBS-0001], Lundbeck Foundation [R218-2016-1367], European Union, EFPIA, European Project: 201052,EC:FP7:HEALTH,FP7-HEALTH-2007-A,METAHIT(2008), University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH), Danmarks Tekniske Universitet = Technical University of Denmark (DTU), and University of Copenhagen = Københavns Universitet (UCPH)
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0301 basic medicine ,Serum ,Computer science ,[SDV]Life Sciences [q-bio] ,Computational biology ,Proteomics ,computer.software_genre ,General Biochemistry, Genetics and Molecular Biology ,Workflow ,Database normalization ,03 medical and health sciences ,0302 clinical medicine ,Metabolome ,Humans ,Metabolomics ,Microbiome ,Gastrointestinal Microbiome ,Computational Biology ,Omics ,030104 developmental biology ,Phenotype ,Identification (biology) ,computer ,030217 neurology & neurosurgery ,Software ,Data integration - Abstract
International audience; We recently presented a three-pronged association study that integrated human intestinal microbiome data derived from shotgun-based sequencing with untargeted serum metabolome data and measures of host physiology. Metabolome and microbiome data are high dimensional, posing a major challenge for data integration. Here, we present a step-by-step computational protocol that details and discusses the dimensionality-reduction techniques used and methods for subsequent integration and interpretation of such heterogeneous types of data. Dimensionality reduction was achieved through a combination of data normalization approaches, binning of co-abundant genes and metabolites, and integration of prior biological knowledge. The use of prior knowledge to overcome functional redundancy across microbiome species is one central advance of our method over available alternative approaches. Applying this framework, other investigators can integrate various '-omics' readouts with variables of host physiology or any other phenotype of interest (e.g., connecting host and microbiome readouts to disease severity or treatment outcome in a clinical cohort) in a three-pronged association analysis to identify potential mechanistic links to be tested in experimental settings. Although we originally developed the framework for a human metabolome-microbiome study, it is generalizable to other organisms and environmental metagenomes, as well as to studies including other -omics domains such as transcriptomics and proteomics. The provided R code runs in similar to 1 h on a standard PC.
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- 2018
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146. Effect of perfluorooctanesulfonic acid (PFOS) on the liver lipid metabolism of the developing chicken embryo
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Magnus Engwall, Nikolai Scherbak, Tuulia Hyötyläinen, Dawei Geng, Cecilia Carlsson, Matej Orešič, Ayan Au Musse, and Viktoria Wigh
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Male ,Perfluorooctanesulfonic acid ,animal structures ,Health, Toxicology and Mutagenesis ,Phosphatidylethanolamine N-Methyltransferase ,0211 other engineering and technologies ,02 engineering and technology ,Chick Embryo ,010501 environmental sciences ,ta3111 ,Ceramides ,01 natural sciences ,Diglycerides ,chemistry.chemical_compound ,Lipidomics ,Animals ,ta318 ,Phospholipids ,Triglycerides ,0105 earth and related environmental sciences ,chemistry.chemical_classification ,Phosphatidylethanolamine ,021110 strategic, defence & security studies ,Fluorocarbons ,Chemistry ,Fatty Acids ,Public Health, Environmental and Occupational Health ,Fatty acid ,Lipid metabolism ,General Medicine ,Metabolism ,Lipidome ,Peroxisome ,Lipid Metabolism ,Pollution ,Mitochondria ,Biochemistry ,Alkanesulfonic Acids ,Liver ,lipids (amino acids, peptides, and proteins) ,Female ,Lipid Peroxidation ,Chickens - Abstract
Perfluorooctanesulfonate (PFOS) is a well-known contaminant in the environment and it has shown to disrupt multiple biological pathways, particularly those related with lipid metabolism. In this study, we have studied the impact of in ovo exposure to PFOS on lipid metabolism in livers in developing chicken embryos using lipidomics for detailed characterization of the liver lipidome. We used an avian model (Gallus gallus domesticus) for in ovo treatment at two levels of PFOS. The lipid profile of the liver of the embryo was investigated by ultra-high performance liquid chromatography combined with quadrupole-time-of-flight mass spectrometry and by gas chromatography mass spectrometry. Over 170 lipids were identified, covering phospholipids, ceramides, di- and triacylglycerols, cholesterol esters and fatty acid composition of the lipids. The PFOS exposure caused dose dependent changes in the lipid levels, which included upregulation of specific phospholipids associated with the phosphatidylethanolamine N-methyltransferase (PEMT) pathway, triacylglycerols with low carbon number and double bond count as well as of lipotoxic ceramides and diacylglycerols. Our data suggest that at lower levels of exposure, mitochondrial fatty acid β-oxidation is suppressed while the peroxisomal fatty acid β -oxidation is increased. At higher doses, however, both β -oxidation pathways are upregulated.
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- 2018
147. Persistent alterations in plasma lipid profiles prior to introduction of gluten in the diet associate with progression to celiac disease
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Jorma Ilonen, Heikki Hyöty, Cecilia Carlsson, Mikael Knip, Partho Sen, Matej Orešič, Riitta Veijola, Jorma Toppari, Satu Simell, Suvi M. Virtanen, and Tuulia Hyötyläinen
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chemistry.chemical_classification ,0303 health sciences ,Type 1 diabetes ,business.industry ,Physiology ,nutritional and metabolic diseases ,Lipid metabolism ,medicine.disease ,Gluten ,Small intestine ,3. Good health ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,chemistry ,Lipidomics ,Lipogenesis ,medicine ,030211 gastroenterology & hepatology ,Gluten free ,business ,030304 developmental biology ,Polyunsaturated fatty acid - Abstract
Background and AimsCeliac disease (CD) is a chronic enteropathy characterized by an autoimmune reaction in the small intestine in genetically-susceptible individuals. Gluten is the required environmental trigger of clinical CD, but the underlying causes of the autoimmune reaction remain unknown. Herein, we apply lipidomics to elucidate the early events preceding clinical CD in a prospective study of children observed from birth until diagnosis of CD and subsequent introduction of a gluten-free diet.MethodsMass spectrometry–based lipidomics profiling was applied to a longitudinal series of 233 plasma samples from the Type 1 Diabetes Prediction and Prevention (DIPP) study, spanning the period between birth and the introduction of a gluten–free diet following CD diagnosis (n=23 CD progressors, n=23 controls matched for gender, HLA risk, period of birth, and age).Results23 children progressed to CD at a mean age of 4.8 years. They showed increased amounts of triacylglycerols (TGs) of low carbon number and double bond count and a decreased level of phosphatidylcholines by 3 months of age as compared to controls. These differences were exacerbated with age but were not observed at birth. No significant differences were observed in essential (dietary) TGs such as those containing polyunsaturated fatty acids.ConclusionOur findings suggest that abnormal lipid metabolism associated with development of clinical CD may occur prior to the introduction of gluten to the diet. Moreover, our data suggest that the specific TGs found elevated in CD progressors may be due to a host response to compromised intake of essential lipids in the small intestine, requiring de novo lipogenesis.
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- 2018
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148. Serum Metabolites Associated with Computed Tomography Findings after Traumatic Brain Injury
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Henna-Riikka Maanpää, Matej Orešič, Joanne G. Outtrim, Anna Kyllönen, Jussi Tallus, David K. Menon, Virginia F. J. Newcombe, Jonathan P. Coles, Jussi P. Posti, Henna Ala-Seppälä, Ismo Mattila, Ari Katila, Keri L.H. Carpenter, Riikka S.K. Takala, Peter J. Hutchinson, Tuulia Hyötyläinen, Olli Tenovuo, Janek Frantzén, and Alex M. Dickens
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0301 basic medicine ,Adult ,Male ,medicine.medical_specialty ,Neurology ,Adolescent ,Traumatic brain injury ,Metabolite ,Computed tomography ,ta3111 ,ta3112 ,03 medical and health sciences ,chemistry.chemical_compound ,Young Adult ,0302 clinical medicine ,Text mining ,Brain Injuries, Traumatic ,Medicine ,Humans ,Aged ,ta3126 ,Aged, 80 and over ,Glial fibrillary acidic protein ,biology ,medicine.diagnostic_test ,business.industry ,Area under the curve ,ta3121 ,Middle Aged ,medicine.disease ,ta3124 ,030104 developmental biology ,chemistry ,Cohort ,biology.protein ,Female ,Neurology (clinical) ,Radiology ,business ,Tomography, X-Ray Computed ,030217 neurology & neurosurgery ,Biomarkers - Abstract
There is a need to rapidly detect patients with traumatic brain injury (TBI) who require head computed tomography (CT). Given the energy crisis in the brain following TBI, we hypothesized that serum metabolomics would be a useful tool for developing a set of biomarkers to determine the need for CT and to distinguish among different types of injuries observed. Logistical regression models using metabolite data from the discovery cohort (n = 144, Turku, Finland) were used to distinguish between patients with traumatic intracranial findings and those with negative findings on head CT. The resultant models were then tested in the validation cohort (n = 66, Cambridge, United Kingdom). The levels of glial fibrillary acidic protein and ubiquitin C-terminal hydrolase-L1 were also quantified in the serum from the same patients. Despite there being significant differences in the protein biomarkers in patients with TBI, the model that determined the need for a CT scan validated poorly (area under the curve [AUC] = 0.64: Cambridge patients). However, using a combination of six metabolites (two amino acids, three sugar derivatives, and one ketoacid) it was possible to discriminate patients with intracranial abnormalities on CT and patients with a normal CT (AUC = 0.77 in Turku patients and AUC = 0.73 in Cambridge patients). Further, a combination of three metabolites could distinguish between diffuse brain injuries and mass lesions (AUC = 0.87 in Turku patients and AUC = 0.68 in Cambridge patients). This study identifies a set of validated serum polar metabolites, which associate with the need for a CT scan. Additionally, serum metabolites can also predict the nature of the brain injury. These metabolite markers may prevent unnecessary CT scans, thus reducing the cost of diagnostics and radiation load.
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- 2018
149. Dynamics of Plasma Lipidome in Progression to Islet Autoimmunity and Type 1 Diabetes – Type 1 Diabetes Prediction and Prevention Study (DIPP)
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Linda Ahonen, Jorma Ilonen, Mikael Knip, Heikki Hyöty, Matej Orešič, Santosh Lamichhane, Thomas Sparholt Dyrlund, Esko Kemppainen, Jorma Toppari, Heli Siljander, Tuulia Hyötyläinen, Riitta Veijola, Lääketieteen ja biotieteiden tiedekunta - Faculty of Medicine and Life Sciences, University of Tampere, Diabetes and Obesity Research Program, HUS Children and Adolescents, Research Programs Unit, Children's Hospital, Clinicum, Lastentautien yksikkö, and Mikael Knip / Principal Investigator
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Male ,endocrine system diseases ,CHILDHOOD ,lcsh:Medicine ,Datasets as Topic ,CHILDREN ,Autoimmunity ,medicine.disease_cause ,0302 clinical medicine ,Longitudinal Studies ,Prospective Studies ,lcsh:Science ,Child ,POPULATION ,Finland ,RISK ,0303 health sciences ,geography.geographical_feature_category ,CHOLESTEROL ,Sisätaudit - Internal medicine ,Lipidome ,Islet ,Prognosis ,AMINO-ACID ,3. Good health ,Seroconversion ,Child, Preschool ,Disease Progression ,Female ,Sphingomyelin ,endocrine system ,030209 endocrinology & metabolism ,METABOLISM ,Article ,03 medical and health sciences ,Islets of Langerhans ,INFLAMMATION ,Lipidomics ,medicine ,Humans ,Metabolomics ,030304 developmental biology ,Autoantibodies ,geography ,Type 1 diabetes ,business.industry ,lcsh:R ,COMPONENT ANALYSIS ,Autoantibody ,Infant ,nutritional and metabolic diseases ,Lipid metabolism ,medicine.disease ,Lipid Metabolism ,Diabetes Mellitus, Type 1 ,DISCOVERY ,3121 General medicine, internal medicine and other clinical medicine ,Immunology ,lcsh:Q ,3111 Biomedicine ,business - Abstract
Type 1 diabetes (T1D) is one of the most prevalent autoimmune diseases among children in Western countries. Earlier metabolomics studies suggest that T1D is preceded by dysregulation of lipid metabolism. Here we used a lipidomics approach to analyze molecular lipids in a prospective series of 428 plasma samples from 40 children who progressed to T1D (PT1D), 40 children who developed at least a single islet autoantibody but did not progress to T1D during the follow-up (P1Ab) and 40 matched controls (CTR). Sphingomyelins were found to be persistently downregulated in PT1D when compared to the P1Ab and CTR groups. Triacylglycerols and phosphatidylcholines were mainly downregulated in PT1D as compared to P1Ab at the age of 3 months. Our study suggests that children who progressed to islet autoimmunity or overt T1D are characterized by distinct lipidomic signatures, which may be helpful in the identification of at-risk children before the initiation of autoimmunity.
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- 2018
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150. Platform for systems medicine research and diagnostic applications in psychotic disorders - The METSY project
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Markus Butz-Ostendorf, Heikki Laurikainen, Jarmo Hietala, Carmen Moreno, Juha Pajula, Mark van Gils, Alexander Fischer, Tuulia Hyötyläinen, Dieter Maier, Oliver D. Howes, Faith Borgan, Tommi Suvitaival, Elisabeth Frank, Joost Janssen, Jaana Suvisaari, and Matej Orešič
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Adult ,Psychosis ,Endocannabinoid system ,Bioinformatics ,Systems biology ,Neuroimaging ,Decision support systems ,Psykiatri ,03 medical and health sciences ,0302 clinical medicine ,SDG 3 - Good Health and Well-being ,Functional neuroimaging ,medicine ,Humans ,Metabolomics ,Psychiatry ,business.industry ,Neuropsychology ,Psychoses ,Lipid metabolism ,Decision Support Systems, Clinical ,Prognosis ,medicine.disease ,3. Good health ,030227 psychiatry ,Systems medicine ,Psychiatry and Mental health ,Early Diagnosis ,Psychotic Disorders ,Schizophrenia ,Female ,business ,030217 neurology & neurosurgery ,Biomarkers ,Endocannabinoids - Abstract
Psychotic disorders are associated with metabolic abnormalities including alterations in glucose and lipid metabolism. A major challenge in the treatment of psychosis is to identify patients with vulnerable metabolic profiles who may be at risk of developing cardiometabolic co-morbidities. It is established that both central and peripheral metabolic organs use lipids to control energy balance and regulate peripheral insulin sensitivity. The endocannabinoid system, implicated in the regulation of glucose and lipid metabolism, has been shown to be dysregulated in psychosis. It is currently unclear how these endocannabinoid abnormalities relate to metabolic changes in psychosis. Here we review recent research in the field of metabolic co-morbidities in psychotic disorders as well as the methods to study them and potential links to the endocannabinoid system. We also describe the bioinformatics platforms developed in the EU project METSY for the investigations of the biological etiology in patients at risk of psychosis and in first episode psychosis patients. The METSY project was established with the aim to identify and evaluate multi-modal peripheral and neuroimaging markers that may be able to predict the onset and prognosis of psychiatric and metabolic symptoms in patients at risk of developing psychosis and first episode psychosis patients. Given the intrinsic complexity and widespread role of lipid metabolism, a systems biology approach which combines molecular, structural and functional neuroimaging methods with detailed metabolic characterisation and multi-variate network analysis is essential in order to identify how lipid dysregulation may contribute to psychotic disorders. A decision support system, integrating clinical, neuropsychological and neuroimaging data, was also developed in order to aid clinical decision making in psychosis. Knowledge of common and specific mechanisms may aid the etiopathogenic understanding of psychotic and metabolic disorders, facilitate early disease detection, aid treatment selection and elucidate new targets for pharmacological treatments.
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- 2018
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