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

Tuulia Hyötyläinen, Livnat Jerby, Elina M. Petäjä, Ismo Mattila, Sirkku Jäntti, Petri Auvinen, Amalia Gastaldelli, Hannele Yki-Järvinen, Eytan Ruppin () and Matej Orešič ()
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Tuulia Hyötyläinen: Steno Diabetes Center, Niels Steensens Vej 6, Gentofte, DK-2820, Denmark
Livnat Jerby: Blavatnik School of Computer Science, Tel Aviv University
Elina M. Petäjä: University of Helsinki
Ismo Mattila: Steno Diabetes Center, Niels Steensens Vej 6, Gentofte, DK-2820, Denmark
Sirkku Jäntti: VTT Technical Research Centre of Finland
Petri Auvinen: Institute of Biotechnology, DNA Sequencing and Genomics Laboratory, University of Helsinki
Amalia Gastaldelli: Institute of Clinical Physiology, National Research Council
Hannele Yki-Järvinen: University of Helsinki
Eytan Ruppin: Blavatnik School of Computer Science, Tel Aviv University
Matej Orešič: Steno Diabetes Center, Niels Steensens Vej 6, Gentofte, DK-2820, Denmark

Nature Communications, 2016, vol. 7, issue 1, 1-9

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms9994

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