The SCLC2A1 gene, which encodes a type 1 glucose transporter (GLUT1), responds to both HIF1α and HIF2α. Thus, both factors increase the cellular uptake of glucose.
HIF1α activates the transcription of genes encoding enzymes involved in glycolysis. HIF1α stimulates the synthesis of hexokinases 1 and 2. Hexokinase is one of the key enzymes in the glycolytic pathway. In addition, HIF1α stimulates the synthesis of phosphofructokinase, fructose-1,6-bisphosphate aldolase and phosphoglycerate kinase.
The LDHA gene encodes an isoenzyme of lactate dehydrogenase, and the PDK1 gene encodes an isoenzyme of the pyruvate dehydrogenase kinase. Under aerobic conditions, pyruvate is decarboxylated and oxidized by pyruvate dehydrogenase to generate acetyl coenzyme A (Acetyl-CoA). Pyruvate dehydrogenase kinase phosphorylates and inhibits pyruvate dehydrogenase. HIF1α stimulates the synthesis of pyruvate dehydrogenase kinase and, in this way, reduces the mitochondrial oxidative metabolism of pyruvate. Under anaerobic conditions, lactate dehydrogenase generates lactate from pyruvate. HIF1α stimulates the synthesis of lactate dehydrogenase and consequently the synthesis of lactate. This pathway is known as anaerobic glycolysis, since it is preferred at oxygen shortage.
