Abstract The hypoxia-inducible factor-1α (HIF-1α) has canonically been described as a primary regulator of glucose metabolism in hypoxic cells through transcriptional upregulation of all 10 glycolytic enzymes. Here, using 13C-glucose and 13C-glutamine tracing in intestinal epithelial cells with defined HIF1A genetic perturbations, we demonstrate that hypoxia-induced glycolysis can occur independently of HIF-1-driven transcription. While hypoxia modulates glucose-derived carbon flux into anabolic branches of glycolysis independent of HIF-1α, HIF-1α plays an important role in modulating glucose and glutamine utilisation within the TCA cycle. These alterations in substrate utilisation highlight the layered regulatory framework whereby HIF-1α regulates distinct aspects of glucose and glutamine metabolism in intestinal epithelial cells to impact the rate of intestinal epithelial cell growth and promote metabolic adaptation to hypoxia.
Kierans et al. (Fri,) studied this question.