Glycine: The missing link between carbohydrate and xenobiotic metabolism in the maturing human hepatocyte

Maria Victoria Pozo Garcia; Tuğçe S. Çobanoğlu; Konstantina Riga; Suraj Sharma; Paul Jennings; J. Chris Vos; Sofia Moco

doi:10.1016/j.isci.2026.116113

Glycine: The missing link between carbohydrate and xenobiotic metabolism in the maturing human hepatocyte

Maria Victoria Pozo Garcia
, Tuğçe S. Çobanoğlu
, Konstantina Riga
, Suraj Sharma
, Paul Jennings
, J. Chris Vos
, Sofia Moco

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

Modulation of cellular metabolism is crucial in pluripotent stem cell (PSC) development and differentiation. Glycine was shown to promote liver cell maturation, boosting Cytochrome P450 (CYP) isoform 3A4 activity, a key enzyme in phase I metabolism. This study examines the remodeling of central and xenobiotic metabolism during the glycine-supplemented differentiation of induced PSCs (iPSCs) into hepatocyte-like cells (HLCs) and HepG2 into a metabolically active form (mHepG2). In these cell systems, glycine promoted oxidative metabolism and mitochondrial function, collagen, glycogen, bile acid anabolism, one-carbon metabolism, and heme biosynthesis, typical of a hepatocyte phenotype. While the metabolic effects of glycine were divergent in mHepG2 and HLCs, in both cases, heme synthesis was boosted by glycine incorporation, a vital feature in supporting xenobiotic metabolism through the heme-containing enzymes CYPs. From this study, a link between glycine supplementation, carbohydrate metabolism, and enhancement of the xenobiotic machinery is established through metabolic plasticity in the maturing hepatocyte.

Original language	English
Article number	116113
Pages (from-to)	1-15, e1-e7
Number of pages	23
Journal	iScience
Volume	29
Issue number	6
Early online date	28 May 2026
DOIs	https://doi.org/10.1016/j.isci.2026.116113
Publication status	Published - 19 Jun 2026

Funding

V.P.G., K.R., and S.M. are thankful for the access to the qPCR instrument from Dr. Seino Jongkees, at the VU Amsterdam. VPG and SM thank Daniëlle Gramsbergen and Dr. Johan van Heerden, at the VU Amsterdam, for contributing to the production of 13C yeast extract, and Prof. Dr. Ines Heiland for her valuable insights into isotope tracing dynamics. All authors thank Prof. Dr. Catherine Verfaillie and Dr. Sreya Ghosh for kindly providing the SBAD2-3X cells. This work was supported by the project RISK-HUNT3R: RISK assessment of chemicals integrating Human-centric Next generation Testing strategies promoting the 3Rs. RISK-HUNT3R has received funding from the European Union's Horizon 2020 research and innovation program under grant agreement No 964537 and is part of the ASPIS cluster. This work reflects only the authors’ views, and the European Commission is not responsible for any use that may be made of the information it contains. V.P.G., K.R., and S.M. are thankful for the access to the qPCR instrument from Dr. Seino Jongkees, at the VU Amsterdam. VPG and SM thank Daniëlle Gramsbergen and Dr. Johan van Heerden, at the VU Amsterdam, for contributing to the production of 13 C yeast extract, and Prof. Dr. Ines Heiland for her valuable insights into isotope tracing dynamics. All authors thank Prof. Dr. Catherine Verfaillie and Dr. Sreya Ghosh for kindly providing the SBAD2-3X cells. This work was supported by the project RISK-HUNT3R : RISK assessment of chemicals integrating Human-centric Next generation Testing strategies promoting the 3Rs. RISK-HUNT3R has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No 964537 and is part of the ASPIS cluster. This work reflects only the authors’ views, and the European Commission is not responsible for any use that may be made of the information it contains.

Funders	Funder number
Daniëlle Gramsbergen and Dr. Johan van Heerden
European Commission
Horizon 2020 Framework Programme	964537

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title = "Glycine: The missing link between carbohydrate and xenobiotic metabolism in the maturing human hepatocyte",

abstract = "Modulation of cellular metabolism is crucial in pluripotent stem cell (PSC) development and differentiation. Glycine was shown to promote liver cell maturation, boosting Cytochrome P450 (CYP) isoform 3A4 activity, a key enzyme in phase I metabolism. This study examines the remodeling of central and xenobiotic metabolism during the glycine-supplemented differentiation of induced PSCs (iPSCs) into hepatocyte-like cells (HLCs) and HepG2 into a metabolically active form (mHepG2). In these cell systems, glycine promoted oxidative metabolism and mitochondrial function, collagen, glycogen, bile acid anabolism, one-carbon metabolism, and heme biosynthesis, typical of a hepatocyte phenotype. While the metabolic effects of glycine were divergent in mHepG2 and HLCs, in both cases, heme synthesis was boosted by glycine incorporation, a vital feature in supporting xenobiotic metabolism through the heme-containing enzymes CYPs. From this study, a link between glycine supplementation, carbohydrate metabolism, and enhancement of the xenobiotic machinery is established through metabolic plasticity in the maturing hepatocyte.",

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doi = "10.1016/j.isci.2026.116113",

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AU - Pozo Garcia, Maria Victoria

AU - Çobanoğlu, Tuğçe S.

AU - Riga, Konstantina

AU - Sharma, Suraj

AU - Jennings, Paul

AU - Vos, J. Chris

AU - Moco, Sofia

PY - 2026/6/19

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N2 - Modulation of cellular metabolism is crucial in pluripotent stem cell (PSC) development and differentiation. Glycine was shown to promote liver cell maturation, boosting Cytochrome P450 (CYP) isoform 3A4 activity, a key enzyme in phase I metabolism. This study examines the remodeling of central and xenobiotic metabolism during the glycine-supplemented differentiation of induced PSCs (iPSCs) into hepatocyte-like cells (HLCs) and HepG2 into a metabolically active form (mHepG2). In these cell systems, glycine promoted oxidative metabolism and mitochondrial function, collagen, glycogen, bile acid anabolism, one-carbon metabolism, and heme biosynthesis, typical of a hepatocyte phenotype. While the metabolic effects of glycine were divergent in mHepG2 and HLCs, in both cases, heme synthesis was boosted by glycine incorporation, a vital feature in supporting xenobiotic metabolism through the heme-containing enzymes CYPs. From this study, a link between glycine supplementation, carbohydrate metabolism, and enhancement of the xenobiotic machinery is established through metabolic plasticity in the maturing hepatocyte.

AB - Modulation of cellular metabolism is crucial in pluripotent stem cell (PSC) development and differentiation. Glycine was shown to promote liver cell maturation, boosting Cytochrome P450 (CYP) isoform 3A4 activity, a key enzyme in phase I metabolism. This study examines the remodeling of central and xenobiotic metabolism during the glycine-supplemented differentiation of induced PSCs (iPSCs) into hepatocyte-like cells (HLCs) and HepG2 into a metabolically active form (mHepG2). In these cell systems, glycine promoted oxidative metabolism and mitochondrial function, collagen, glycogen, bile acid anabolism, one-carbon metabolism, and heme biosynthesis, typical of a hepatocyte phenotype. While the metabolic effects of glycine were divergent in mHepG2 and HLCs, in both cases, heme synthesis was boosted by glycine incorporation, a vital feature in supporting xenobiotic metabolism through the heme-containing enzymes CYPs. From this study, a link between glycine supplementation, carbohydrate metabolism, and enhancement of the xenobiotic machinery is established through metabolic plasticity in the maturing hepatocyte.

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ER -

Glycine: The missing link between carbohydrate and xenobiotic metabolism in the maturing human hepatocyte

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