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

<h2>Summary</h2> 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.