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

Summary 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.