Amino acid levels determine metabolism and CYP450 function of hepatocytes and hepatoma cell lines

Ruben Boon (), Manoj Kumar, Tine Tricot, Ilaria Elia, Laura Ordovas, Frank Jacobs, Jennifer One, Jonathan Smedt, Guy Eelen, Matthew Bird, Philip Roelandt, Ginevra Doglioni, Kim Vriens, Matteo Rossi, Marta Aguirre Vazquez, Thomas Vanwelden, François Chesnais, Adil El Taghdouini, Mustapha Najimi, Etienne Sokal, David Cassiman, Jan Snoeys, Mario Monshouwer, Wei-Shou Hu, Christian Lange, Peter Carmeliet, Sarah-Maria Fendt and Catherine M. Verfaillie ()
Additional contact information
Ruben Boon: Stem Cell Institute, KU Leuven
Manoj Kumar: Stem Cell Institute, KU Leuven
Tine Tricot: Stem Cell Institute, KU Leuven
Ilaria Elia: VIB Center for Cancer Biology, VIB
Laura Ordovas: Stem Cell Institute, KU Leuven
Frank Jacobs: Janssen Research and Development
Jennifer One: University of Minnesota
Jonathan Smedt: Stem Cell Institute, KU Leuven
Guy Eelen: KU Leuven
Matthew Bird: KU Leuven
Philip Roelandt: Stem Cell Institute, KU Leuven
Ginevra Doglioni: VIB Center for Cancer Biology, VIB
Kim Vriens: VIB Center for Cancer Biology, VIB
Matteo Rossi: VIB Center for Cancer Biology, VIB
Marta Aguirre Vazquez: Stem Cell Institute, KU Leuven
Thomas Vanwelden: Stem Cell Institute, KU Leuven
François Chesnais: Stem Cell Institute, KU Leuven
Adil El Taghdouini: Universit Catholique de Louvain & Cliniques Universitaires St Luc, Institut de Recherche Clinique et Expérimentale (IREC)
Mustapha Najimi: Universit Catholique de Louvain & Cliniques Universitaires St Luc, Institut de Recherche Clinique et Expérimentale (IREC)
Etienne Sokal: Universit Catholique de Louvain & Cliniques Universitaires St Luc, Institut de Recherche Clinique et Expérimentale (IREC)
David Cassiman: KU Leuven
Jan Snoeys: University of Minnesota
Mario Monshouwer: University of Minnesota
Wei-Shou Hu: University of Minnesota
Christian Lange: KU Leuven
Peter Carmeliet: KU Leuven
Sarah-Maria Fendt: VIB Center for Cancer Biology, VIB
Catherine M. Verfaillie: Stem Cell Institute, KU Leuven

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract Predicting drug-induced liver injury in a preclinical setting remains challenging, as cultured primary human hepatocytes (PHHs), pluripotent stem cell-derived hepatocyte-like cells (HLCs), and hepatoma cells exhibit poor drug biotransformation capacity. We here demonstrate that hepatic functionality depends more on cellular metabolism and extracellular nutrients than on developmental regulators. Specifically, we demonstrate that increasing extracellular amino acids beyond the nutritional need of HLCs and HepG2 cells induces glucose independence, mitochondrial function, and the acquisition of a transcriptional profile that is closer to PHHs. Moreover, we show that these high levels of amino acids are sufficient to drive HLC and HepG2 drug biotransformation and liver-toxin sensitivity to levels similar to those in PHHs. In conclusion, we provide data indicating that extracellular nutrient levels represent a major determinant of cellular maturity and can be utilized to guide stem cell differentiation to the hepatic lineage.

Date: 2020
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DOI: 10.1038/s41467-020-15058-6

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