Ramakrishnan Sadeesh K, Shah Yatrik M
Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA.
Internal Medicine, Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, MI, USA.
Nutr Healthy Aging. 2017 Dec 7;4(3):207-216. doi: 10.3233/NHA-170022.
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.
肝葡萄糖生成受激素和饮食因素调节。在禁食状态下，释放到循环中的葡萄糖80%来自肝脏，其中糖异生占55%，其余来自糖原分解。研究表明，在禁食和吸收后阶段，肝葡萄糖代谢的调节涉及复杂机制。氧气在众多代谢途径中起关键作用，如三羧酸循环、糖异生、糖酵解和脂肪酸氧化。包括肝脏和肠道在内的胃肠道的氧合作用受血流和代谢活动变化的动态调节。细胞对低氧的适应由转录因子HIF-1α和HIF-2α介导。HIF-1α调节糖酵解基因，而HIF-2α主要调节参与细胞增殖和铁代谢的基因。本综述重点关注氧感应信号在调节肝葡萄糖输出中的作用，尤其强调缺氧诱导因子（HIF）-2α。最近的研究确立了HIF-2α在全身葡萄糖稳态中的代谢作用。了解肝脏代谢中HIF-2α依赖性机制将极大地增强我们利用氧感应机制治疗代谢性疾病的潜力。
