title: Serum metabolomic profiling highlights pathways associated with liver fat content in a general population sample.
abstract: Fatty liver disease (FLD) is an important intermediate trait along the cardiometabolic disease spectrum and strongly associates with type 2 diabetes. Knowledge of biological pathways implicated in FLD is limited. An untargeted metabolomic approach might unravel novel pathways related to FLD.
  
  
  
  In a population-based sample (n=555) from Northern Germany, liver fat content was quantified as liver signal intensity using magnetic resonance imaging. Serum metabolites were determined using a non-targeted approach. Partial least squares regression was applied to derive a metabolomic score, explaining variation in serum metabolites and liver signal intensity. Associations of the metabolomic score with liver signal intensity and FLD were investigated in multivariable-adjusted robust linear and logistic regression models, respectively. Metabolites with a variable importance in the projection >1 were entered in in silico overrepresentation and pathway analyses.
  
  
  
  In univariate analysis, the metabolomics score explained 23.9% variation in liver signal intensity. A 1-unit increment in the metabolomic score was positively associated with FLD (n=219; odds ratio: 1.36; 95% confidence interval: 1.27-1.45) adjusting for age, sex, education, smoking and physical activity. A simplified score based on the 15 metabolites with highest variable importance in the projection statistic showed similar associations. Overrepresentation and pathway analyses highlighted branched-chain amino acids and derived gamma-glutamyl dipeptides as significant correlates of FLD.
  
  
  
  A serum metabolomic profile was associated with FLD and liver fat content. We identified a simplified metabolomics score, which should be evaluated in prospective studies.
authors.affiliation: Institute of Epidemiology, Kiel University, Kiel, Germany.|Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Koch
authors.affiliation: Institute of Medical Informatics and Statistics, Kiel University, Kiel, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Freitag-Wolf
authors.affiliation: Institute of Epidemiology, Kiel University, Kiel, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Schlesinger
authors.affiliation: Department of Radiology, University of Cologne, Cologne, MA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Borggrefe
authors.affiliation: Division of Cancer Medicine, Department of Transplantation Medicine, Surgery and Transplantation, Norwegian PSC Research Center, Oslo University Hospital, Rikshospitalet, Oslo, Norway.|K.G. Jebsen Inflammation Research Center, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.|Division of Cancer Medicine, Surgery and Transplantation, Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway.|Division of Cancer Medicine, Section of Gastroenterology, Department of Transplantation Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
authors.forename: J R
authors.initials: JR
authors.lastname: Hov
authors.affiliation: Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
authors.forename: M K
authors.initials: MK
authors.lastname: Jensen
authors.affiliation: Nutritional Epidemiology, Department of Nutrition and Food Science, Rheinische Friedrich-Wilhelms-University Bonn, Bonn, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Pick
authors.affiliation: Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany.|DZHK (German Centre for Cardiovascular Research), Partner Site Greifswald, Greifswald, Germany.|Department of Study of Health in Pomerania/Clinical-Epidemiological Research, Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
authors.forename: M R P
authors.initials: MRP
authors.lastname: Markus
authors.affiliation: Institute of Epidemiology, Kiel University, Kiel, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Höpfner
authors.affiliation: Institute of Epidemiology, Kiel University, Kiel, Germany.|PopGen Biobank, University Medical Center Schleswig-Holstein, Kiel, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Jacobs
authors.affiliation: Cologne Center for Genomics, University of Cologne, Cologne, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Siegert
authors.affiliation: Institute of Experimental Genetics, Genome Analysis Center, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Artati
authors.affiliation: Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, Neuherberg, Germany.|Deutsches Zentrum für Diabetesforschung (DZD), German Centere for Diabetes Research, Neuherberg, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Kastenmüller
authors.affiliation: Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Römisch-Margl
authors.affiliation: Institute of Experimental Genetics, Genome Analysis Center, Helmholtz Zentrum München, Neuherberg, Germany.|Deutsches Zentrum für Diabetesforschung (DZD), German Centere for Diabetes Research, Neuherberg, Germany.|Experimental Genetics, Technical University of Munich, Freising, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Adamski
authors.affiliation: Hannover Unified Biobank, Hannover Medical School, Hannover, Germany.|Institute for Human Genetics, Hannover Medical School, Hanover, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Illig
authors.affiliation: Cologne Center for Genomics, University of Cologne, Cologne, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Nothnagel
authors.affiliation: Division of Cancer Medicine, Department of Transplantation Medicine, Surgery and Transplantation, Norwegian PSC Research Center, Oslo University Hospital, Rikshospitalet, Oslo, Norway.|K.G. Jebsen Inflammation Research Center, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.|Division of Cancer Medicine, Surgery and Transplantation, Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway.|Division of Cancer Medicine, Section of Gastroenterology, Department of Transplantation Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
authors.forename: T H
authors.initials: TH
authors.lastname: Karlsen
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.|Institute of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Schreiber
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Franke
authors.affiliation: Institute of Medical Informatics and Statistics, Kiel University, Kiel, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Krawczak
authors.affiliation: Nutritional Epidemiology, Department of Nutrition and Food Science, Rheinische Friedrich-Wilhelms-University Bonn, Bonn, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Nöthlings
authors.affiliation: Institute of Epidemiology, Kiel University, Kiel, Germany.|PopGen Biobank, University Medical Center Schleswig-Holstein, Kiel, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Lieb
mesh_terms: D000368:Aged; D000428:Alcohol Drinking / Q000009:adverse effects; D018070:Biological Specimen Banks; D015415:Biomarkers / Q000097:blood; D015331:Cohort Studies; D019295:Computational Biology; D003430:Cross-Sectional Studies; D004151:Dipeptides / Q000097:blood; D005103:Expert Systems; D005235:Fatty Liver, Alcoholic / Q000097:blood* / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D018698:Glutamic Acid / Q000031:analogs & derivatives / Q000097:blood; D006801:Humans; D050356:Lipid Metabolism; D008099:Liver / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000503:physiopathology; D008279:Magnetic Resonance Imaging; D008297:Male; D055432:Metabolomics / Q000379:methods; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000097:blood* / Q000000981:diagnostic imaging / Q000378:metabolism; D057566:Self Report; D012720:Severity of Illness Index
chemical_list: D015415:Biomarkers; D004151:Dipeptides; D018698:Glutamic Acid