Fig.2.

Regulation of hepatic gluconeogenesis by HIF-2. Liver hypoxia, refeeding, vascular endothelial growth factor (VEGF) inhibitors or prolyl 4 hydroxylase domain-containing protein (PHD) inhibitors stabilize hypoxia-inducible factor (HIF)-2α in the liver. HIF-2α improves insulin sensitivity by increasing insulin receptor substrate (IRS)-2 levels directly at transcriptional level or indirectly through transrepression by sterol regulatory binding protein (SREBP)-1c. IRS-2 decreases gluconeogenesis by enhancing AKT-mediated repression of gluconeogenic genes. In addition, HIF-2α attenuates postprandial glucagon signaling through ERK1/2-dependent increase in phosphodiesterase (PDE) mediated hydrolysis of intracellular cyclic AMP (cAMP), resulting in a decrease in protein kinase A (PKA)-mediated activation of cAMP response element-binding protein (CREB). Lastly, HIF-2α-mediated increase in systemic erythropoietin (EPO) levels inhibit gluconeogenesis through a STAT3-dependent mechanism.