Large-Scale Modeling Approach Reveals Functional Metabolic Shifts during Hepatic Differentiation

Nathalie Poupin (1) , Anne Corlu (2) , Nicolas J. Cabaton (1) , Hélène Dubois-Pot-Schneider (2) , Cécile Canlet (3) , Elodie Person (1) , Sandrine S. Bruel (1) , Clément Frainay (1) , Florence Vinson (4) , Florence Maurier (4) , Fabrice Morel (2) , Marie-Anne Robin (2) , Bernard Fromenty (2) , Daniel Zalko (1) , Fabien Jourdan (1)

1 ToxAlim-MeX - Métabolisme et Xénobiotiques
2 NuMeCan - Nutrition, Métabolismes et Cancer
3 E20 Metatoul-AXIOM - Analyse de Xénobiotiques, Identification, Métabolisme
4 ToxAlim - ToxAlim

Being able to explore the metabolism of broad metabolizing cells is of critical importance in many research fields. This article presents an original modeling solution combining metabolic network and omics data to identify modulated metabolic pathways and changes in metabolic functions occurring during differentiation of a human hepatic cell line (HepaRG). Our results confirm the activation of hepato-specific functionalities and newly evidence modulation of other metabolic pathways, which could not be evidenced from transcriptomic data alone. Our method takes advantage of the network structure to detect changes in metabolic pathways that do not have gene annotations and exploits flux analyses techniques to identify activated metabolic functions. Compared to the usual cell-specific metabolic network reconstruction approaches, it limits false predictions by considering several possible network configurations to represent one phenotype rather than one arbitrarily selected network. Our approach significantly enhances the comprehensive and functional assessment of cell metabolism, opening further perspectives to investigate metabolic shifts occurring within various biological contexts.

Keywords: global metabolic shifts; genome-scale metabolic modeling; HepaRG cell line; transcriptomics and metabolomics; hepatic differentiation

Domains: Life Sciences [q-bio]; Life Sciences [q-bio]; Human health and pathology; Hépatology and Gastroenterology

Nathalie Poupin, Anne Corlu, Nicolas J. Cabaton, Hélène Dubois-Pot-Schneider, Cécile Canlet, et al.. Large-Scale Modeling Approach Reveals Functional Metabolic Shifts during Hepatic Differentiation. Journal of Proteome Research, 2019, 18 (1), pp.204-216. ⟨10.1021/acs.jproteome.8b00524⟩. ⟨hal-01937261⟩