Comparison of metabolic states using genome-scale metabolic models

PLoS Comput Biol. 2021 Nov 8;17(11):e1009522. doi: 10.1371/journal.pcbi.1009522. eCollection 2021 Nov.

Abstract

Genome-scale metabolic models (GEMs) are comprehensive knowledge bases of cellular metabolism and serve as mathematical tools for studying biological phenotypes and metabolic states or conditions in various organisms and cell types. Given the sheer size and complexity of human metabolism, selecting parameters for existing analysis methods such as metabolic objective functions and model constraints is not straightforward in human GEMs. In particular, comparing several conditions in large GEMs to identify condition- or disease-specific metabolic features is challenging. In this study, we showcase a scalable, model-driven approach for an in-depth investigation and comparison of metabolic states in large GEMs which enables identifying the underlying functional differences. Using a combination of flux space sampling and network analysis, our approach enables extraction and visualisation of metabolically distinct network modules. Importantly, it does not rely on known or assumed objective functions. We apply this novel approach to extract the biochemical differences in adipocytes arising due to unlimited vs blocked uptake of branched-chain amino acids (BCAAs, considered as biomarkers in obesity) using a human adipocyte GEM (iAdipocytes1809). The biological significance of our approach is corroborated by literature reports confirming our identified metabolic processes (TCA cycle and Fatty acid metabolism) to be functionally related to BCAA metabolism. Additionally, our analysis predicts a specific altered uptake and secretion profile indicating a compensation for the unavailability of BCAAs. Taken together, our approach facilitates determining functional differences between any metabolic conditions of interest by offering a versatile platform for analysing and comparing flux spaces of large metabolic networks.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / metabolism
  • Algorithms
  • Amino Acids, Branched-Chain / metabolism
  • Citric Acid Cycle
  • Computational Biology
  • Computer Simulation
  • Fatty Acids / metabolism
  • Genome, Human
  • Humans
  • Metabolic Diseases / genetics
  • Metabolic Diseases / metabolism
  • Metabolic Flux Analysis / statistics & numerical data
  • Metabolic Networks and Pathways / genetics*
  • Models, Biological*
  • Models, Genetic
  • Obesity / genetics
  • Obesity / metabolism
  • Principal Component Analysis

Substances

  • Amino Acids, Branched-Chain
  • Fatty Acids

Grants and funding

This research has been made possible with the support of the Dutch Province of Limburg, The Netherlands. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.