Regulation of hypoxia-inducible factor 1 by glucose availability under hypoxic conditions

Hypoxia-inducible transcription factor 1 (HIF-1), consisting of HIF-1 alpha and HIF-1 beta subunits, regulates the expression of a variety of genes involved in diverse adaptive processes in response to hypoxia. While oxygen availability regulates HIF-1 alpha by proteolytic degradation, some growth factors regulate HIF-1 alpha by protein synthesis in part through mammalian target of rapamycin complex 1 (TORC1) pathway. We herein report the role of nutrient availability on the regulation of HIF-1. A reduced availability of glucose, not amino acids, results in a decrease of the expression of HIF1-dependent genes and HIF-1 alpha protein in response to hypoxia. HIF-1 alpha mRNA expression was not significantly suppressed and DMOG, an inhibitor for proteasomal degradation of HIF-1 alpha, did not induce HIF-1 alpha protein expression under hypoxia combined with glucose depletion. In comparison to the effect in the presence of glucose, glucose depletion under hypoxia induced a much stronger activation of the AMP-dependent kinase pathway and phosphorylation of eIF2 alpha, and nearly complete inhibition of the TORC1 pathway. These findings imply that the reduced availability of glucose under hypoxia downregulates HIF-1 in part through the inhibition of HIF-1 alpha mRNA translation, which is occasionally observed in pathophysiological situations such as ischemic diseases.