title: Genome-scale metabolic modelling of hepatocytes reveals serine deficiency in patients with non-alcoholic fatty liver disease.
abstract: Several liver disorders result from perturbations in the metabolism of hepatocytes, and their underlying mechanisms can be outlined through the use of genome-scale metabolic models (GEMs). Here we reconstruct a consensus GEM for hepatocytes, which we call iHepatocytes2322, that extends previous models by including an extensive description of lipid metabolism. We build iHepatocytes2322 using Human Metabolic Reaction 2.0 database and proteomics data in Human Protein Atlas, which experimentally validates the incorporated reactions. The reconstruction process enables improved annotation of the proteomics data using the network centric view of iHepatocytes2322. We then use iHepatocytes2322 to analyse transcriptomics data obtained from patients with non-alcoholic fatty liver disease. We show that blood concentrations of chondroitin and heparan sulphates are suitable for diagnosing non-alcoholic steatohepatitis and for the staging of non-alcoholic fatty liver disease. Furthermore, we observe serine deficiency in patients with NASH and identify PSPH, SHMT1 and BCAT1 as potential therapeutic targets for the treatment of non-alcoholic steatohepatitis.
authors.affiliation: 1] Department of Chemical and Biological Engineering, Chalmers University of Technology, Kamivangen 10, Gothenburg SE-412 96, Sweden [2].
authors.forename: Adil
authors.initials: A
authors.lastname: Mardinoglu
authors.affiliation: 1] Department of Chemical and Biological Engineering, Chalmers University of Technology, Kamivangen 10, Gothenburg SE-412 96, Sweden [2].
authors.forename: Rasmus
authors.initials: R
authors.lastname: Agren
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala SE-751 85, Sweden.
authors.forename: Caroline
authors.initials: C
authors.lastname: Kampf
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala SE-751 85, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Asplund
authors.affiliation: 1] Department of Proteomics, KTH-Royal Institute of Technology, Stockholm SE-106 91, Sweden [2] Science for Life Laboratory, KTH-Royal Institute of Technology, Stockholm SE-171 21, Sweden.
authors.forename: Mathias
authors.initials: M
authors.lastname: Uhlen
authors.affiliation: 1] Department of Chemical and Biological Engineering, Chalmers University of Technology, Kamivangen 10, Gothenburg SE-412 96, Sweden [2] Science for Life Laboratory, KTH-Royal Institute of Technology, Stockholm SE-171 21, Sweden.
authors.forename: Jens
authors.initials: J
authors.lastname: Nielsen
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood; D002807:Chondroitin / Q000097:blood; D030541:Databases, Genetic; D005260:Female; D016678:Genome / Q000235:genetics*; D012696:Glycine Hydroxymethyltransferase; D006497:Heparan Sulfate / Q000097:blood; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D008957:Models, Genetic; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D010768:Phosphoserine; D012694:Serine / Q000172:deficiency*; D000637:Transaminases; D059467:Transcriptome; D055815:Young Adult
chemical_list: D015415:Biomarkers; D002807:Chondroitin; D012696:Glycine Hydroxymethyltransferase; D006497:Heparan Sulfate; D010768:Phosphoserine; D012694:Serine; D000637:Transaminases; C520541:SHMT protein, human; C490590:BCAT1 protein, human