title: Genome-scale study reveals reduced metabolic adaptability in patients with non-alcoholic fatty liver disease.
abstract: Non-alcoholic fatty liver disease (NAFLD) is a major risk factor leading to chronic liver disease and type 2 diabetes. Here we chart liver metabolic activity and functionality in NAFLD by integrating global transcriptomic data, from human liver biopsies, and metabolic flux data, measured across the human splanchnic vascular bed, within a genome-scale model of human metabolism. We show that an increased amount of liver fat induces mitochondrial metabolism, lipolysis, glyceroneogenesis and a switch from lactate to glycerol as substrate for gluconeogenesis, indicating an intricate balance of exacerbated opposite metabolic processes in glycemic regulation. These changes were associated with reduced metabolic adaptability on a network level in the sense that liver fat accumulation puts increasing demands on the liver to adaptively regulate metabolic responses to maintain basic liver functions. We propose that failure to meet excessive metabolic challenges coupled with reduced metabolic adaptability may lead to a vicious pathogenic cycle leading to the co-morbidities of NAFLD.
authors.affiliation: Department of Systems Medicine, Steno Diabetes Center, Niels Steensens Vej 6, Gentofte, DK-2820, Denmark.|VTT Technical Research Centre of Finland, Espoo, FI-02044 VTT, Finland.
authors.forename: Tuulia
authors.initials: T
authors.lastname: Hyötyläinen
authors.affiliation: Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Livnat
authors.initials: L
authors.lastname: Jerby
authors.affiliation: Department of Medicine, Division of Diabetes, University of Helsinki, Helsinki, FI-00014, Finland.|Minerva Foundation Institute for Medical Research, Helsinki FI-00290, Finland.
authors.forename: Elina M
authors.initials: EM
authors.lastname: Petäjä
authors.affiliation: Department of Systems Medicine, Steno Diabetes Center, Niels Steensens Vej 6, Gentofte, DK-2820, Denmark.|VTT Technical Research Centre of Finland, Espoo, FI-02044 VTT, Finland.
authors.forename: Ismo
authors.initials: I
authors.lastname: Mattila
authors.affiliation: VTT Technical Research Centre of Finland, Espoo, FI-02044 VTT, Finland.|Faculty of Pharmacy, University of Helsinki, Helsinki FI-00014, Finland.
authors.forename: Sirkku
authors.initials: S
authors.lastname: Jäntti
authors.affiliation: Institute of Biotechnology, DNA Sequencing and Genomics Laboratory, University of Helsinki, Helsinki FI-00014, Finland.
authors.forename: Petri
authors.initials: P
authors.lastname: Auvinen
authors.affiliation: Institute of Clinical Physiology, National Research Council, Pisa 56124, Italy.
authors.forename: Amalia
authors.initials: A
authors.lastname: Gastaldelli
authors.affiliation: Department of Medicine, Division of Diabetes, University of Helsinki, Helsinki, FI-00014, Finland.|Minerva Foundation Institute for Medical Research, Helsinki FI-00290, Finland.
authors.forename: Hannele
authors.initials: H
authors.lastname: Yki-Järvinen
authors.affiliation: Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv 69978, Israel.|Center for BioInformatics and Computational Biology, Department of Computer Science, University of Maryland, College Park, Maryland 20742, USA.
authors.forename: Eytan
authors.initials: E
authors.lastname: Ruppin
authors.affiliation: Department of Systems Medicine, Steno Diabetes Center, Niels Steensens Vej 6, Gentofte, DK-2820, Denmark.|VTT Technical Research Centre of Finland, Espoo, FI-02044 VTT, Finland.|Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku FI-20520, Finland.
authors.forename: Matej
authors.initials: M
authors.lastname: Orešič
mesh_terms: D000222:Adaptation, Physiological / Q000235:genetics*; D000328:Adult; D001786:Blood Glucose / Q000378:metabolism*; D016022:Case-Control Studies; D005260:Female; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D005943:Gluconeogenesis; D005990:Glycerol / Q000378:metabolism*; D006801:Humans; D050152:Intra-Abdominal Fat / Q000378:metabolism*; D019344:Lactic Acid / Q000378:metabolism*; D008066:Lipolysis; D008099:Liver / Q000378:metabolism*; D008297:Male; D064688:Metabolic Flux Analysis; D055442:Metabolome; D008875:Middle Aged; D008930:Mitochondria, Liver / Q000378:metabolism*; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics*; D013152:Splanchnic Circulation
chemical_list: D001786:Blood Glucose; D019344:Lactic Acid; D005990:Glycerol
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