Genome-scale metabolic modelling of hepatocytes reveals serine deficiency in patients with non-alcoholic fatty liver disease

Adil Mardinoglu, Rasmus Agren, Caroline Kampf, Anna Asplund, Mathias Uhlen and Jens Nielsen ()
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Adil Mardinoglu: Chalmers University of Technology, Kamivangen 10, Gothenburg SE-412 96, Sweden
Rasmus Agren: Chalmers University of Technology, Kamivangen 10, Gothenburg SE-412 96, Sweden
Caroline Kampf: Genetics and Pathology, Science for Life Laboratory, Uppsala University
Anna Asplund: Genetics and Pathology, Science for Life Laboratory, Uppsala University
Mathias Uhlen: KTH—Royal Institute of Technology
Jens Nielsen: Chalmers University of Technology, Kamivangen 10, Gothenburg SE-412 96, Sweden

Nature Communications, 2014, vol. 5, issue 1, 1-11

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms4083

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