Genome-scale study reveals reduced metabolic adaptability in patients with non-alcoholic fatty liver disease

Hyötyläinen, Tuulia,1971-Örebro universitet,Institutionen för naturvetenskap och teknik,Department of Systems Medicine, Steno Diabetes Center, Gentofte, Denmark; VTT Technical Research Centre of Finland, Espoo, Finland (author)

Funding Agencies:EU FP6 project HEPADIP, Projektnr: LSHM-CT-2005-018734Academy of Finland Centre of Excellence in Molecular Systems Immunology and Physiology Research-SyMMyS, Projektnr: 250114Edmond J. Safra program in bioinformatics in TAUIsraeli Science FoundationEU/EFPIA Innovative Medicines Initiative Joint Undertaking (EMIF), Projektnr: 115372
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.

Jerby, LivnatBlavatnik School of Computer Science, Tel Aviv University, Tel Aviv, Israel (author)
Petäjä, Elina M.Department of Medicine, Division of Diabetes, University of Helsinki, Helsinki, Finland; Minerva Foundation Institute for Medical Research, Helsinki, Finland (author)
Mattila, IsmoDepartment of Systems Medicine, Steno Diabetes Center, Gentofte, Denmark; VTT Technical Research Centre of Finland, Espoo, Finland (author)
Jäntti, SirkkuVTT Technical Research Centre of Finland, Espoo, Finland; Faculty of Pharmacy, University of Helsinki, Helsinki, Finland (author)
Auvinen, PetriInstitute of Biotechnology, DNA Sequencing and Genomics Laboratory, University of Helsinki, Helsinki, Finland (author)
Gastaldelli, AmaliaInstitute of Clinical Physiology, National Research Council, Pisa, Italy (author)
Yki-Järvinen, HanneleDepartment of Medicine, Division of Diabetes, University of Helsinki, Helsinki, Finland; Minerva Foundation Institute for Medical Research, Helsinki, Finland (author)
Ruppin, EytanBlavatnik School of Computer Science, Tel Aviv University, Tel Aviv, Israel; Center for BioInformatics and Computational Biology, Department of Computer Science, University of Maryland, Maryland, USA (author)
Oresic, Matej,1967-Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland(Swepub:oru)moc (author)
Örebro universitetInstitutionen för naturvetenskap och teknik (creator_code:org_t)

In:Nature CommunicationsLondon, United Kingdom : Nature Publishing Group72041-1723

By the author/editor: Hyötyläinen, Tuu ...; Jerby, Livnat; Petäjä, Elina M.; Mattila, Ismo; Jäntti, Sirkku; Auvinen, Petri; show more...; Gastaldelli, Ama ...; Yki-Järvinen, Ha ...; Ruppin, Eytan; Oresic, Matej, 1 ...; show less...

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Endocrinology an ...

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