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Nat Commun. 2016 Feb 3;7:8994. doi: 10.1038/ncomms9994.

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

Author information

1
Department of Systems Medicine, Steno Diabetes Center, Niels Steensens Vej 6, Gentofte, DK-2820, Denmark.
2
VTT Technical Research Centre of Finland, Espoo, FI-02044 VTT, Finland.
3
Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv 69978, Israel.
4
Department of Medicine, Division of Diabetes, University of Helsinki, Helsinki, FI-00014, Finland.
5
Minerva Foundation Institute for Medical Research, Helsinki FI-00290, Finland.
6
Faculty of Pharmacy, University of Helsinki, Helsinki FI-00014, Finland.
7
Institute of Biotechnology, DNA Sequencing and Genomics Laboratory, University of Helsinki, Helsinki FI-00014, Finland.
8
Institute of Clinical Physiology, National Research Council, Pisa 56124, Italy.
9
Center for BioInformatics and Computational Biology, Department of Computer Science, University of Maryland, College Park, Maryland 20742, USA.
10
Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku FI-20520, Finland.

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.

PMID:
26839171
PMCID:
PMC4742839
DOI:
10.1038/ncomms9994
[Indexed for MEDLINE]
Free PMC Article
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