A central role for hypoxia-inducible factor (HIF)-2α in hepatic glucose homeostasis.

Hepatic glucose production is regulated by hormonal and dietary factors. At fasting, 80% of glucose released into the circulation is derived from the liver, among which gluconeogenesis accounts for 55% and the rest by glycogenolysis. Studies suggest a complex mechanism involved in the regulation of hepatic glucose metabolism during fasting and post-absorptive phase. Oxygen plays a key role in numerous metabolic pathways such as TCA cycle, gluconeogenesis, glycolysis and fatty acid oxidation. Oxygenation of the gastrointestinal tract including liver and intestine is dynamically regulated by changes in the blood flow and metabolic activity. Cellular adaptation to low oxygen is mediated by the transcription factors HIF-1α and HIF-2α. HIF-1α regulates glycolytic genes whereas HIF-2α is known to primarily regulate genes involved in cell proliferation and iron metabolism. This review focuses on the role of the oxygen sensing signaling in the regulation of hepatic glucose output with an emphasis on hypoxia inducible factor (HIF)-2α. Recent studies have established a metabolic role of HIF-2α in systemic glucose homeostasis. Understanding the HIF-2α dependent mechanism in hepatic metabolism will greatly enhance our potential to utilize the oxygen sensing mechanisms to treat metabolic diseases.