Figure 5.

Glucose metabolism is regulated by hypoxia-inducible factors (HIFs). During glycolysis, glucose enters the cytoplasm through the glucose transporter (GLUT) and is transformed into glucose 6-phosphate by hexokinase (HK). Eight successive enzymatic reactions then occur to produce 2 molecules of pyruvate, 2 ATP and 2 NADH. At the end, cytosolic pyruvate has two possibilities: transformation into lactate by the enzyme lactate dehydrogenase A (LDHA)—lactate being then exported through the monocarboxylate transporter (MCT), or transferred into the mitochondria and transformed into Acetyl-CoA via the pyruvate dehydrogenase complex (PDH complex). In the second option, Acetyl-coA goes into the Krebs cycle to produce 2 ATP, 6 NADH, and 2 FADH₂. NADH and FADH₂ will further be used in redox reactions in the electron transport chain (ETC) to produce more ATP via oxidative phosphorylation (OXPHOS). HIF intervenes in several steps during glucose metabolism: by inducing GLUT it allows more entry of glucose (1) and by inducing hexokinase (2) and PFKFB3 (3), it enhances glycolysis. Note that non-laminar blood flow decreases the expression of Kruppel-like factor 2 (KLF2), which has otherwise an inhibitory action on HIF-1 and PFKFB3 expression. VEGF and its receptor VEGFR2 are also induced by HIF-1 and enhance PFKFB3 expression. Further, pyruvate is pushed towards lactate transformation by up-regulation of LDHA (4) and some isoforms of MCT (5). At the same time, HIF prevents the PDH complex from transforming pyruvate into Acetyl-coA (6). Green: activation by HIF, Red: inhibition by HIF.