FoxO integration of insulin signaling with glucose and lipid metabolism.
FoxO integration of insulin signaling with glucose and lipid metabolism.
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DOI：
10.1530/joe-17-0002
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发表时间：
2017-05
期刊：
影响因子：
--
通讯作者：
Dong HH
中科院分区：
文献类型：
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作者：
Lee S;Dong HH
哺乳动物叉头盒O家族由FoxO1、FoxO3、FoxO4和FoxO6蛋白组成。这四种FoxO亚型在体内普遍表达，它们共享一个被称为“叉头盒”的氨基酸结合域。它们介导胰岛素或胰岛素样生长因子对细胞代谢、生长、分化、氧化应激、衰老、自噬和衰老等关键功能的抑制作用。FoxO基因的基因突变或FoxO蛋白的异常表达与人类和动物的代谢性疾病、癌症或寿命改变有关。在FoxO家族中，FoxO6是特征最少的成员，在肝脏、骨骼肌和大脑中发挥关键作用。FoxO6表达改变与胰岛素抵抗、饮食性肥胖和2型糖尿病的发病机制以及神经退行性疾病的风险相关。FoxO6在进化上与其他FoxO亚型不同。FoxO6介导胰岛素作用于靶基因的机制与其他FoxO成员有着根本的不同。在这里，我们将重点回顾FoxO6与其他FoxO亚型在健康和疾病中的作用。我们回顾了FoxO6整合胰岛素信号到肝脏糖脂代谢的独特机制。我们强调FoxO6失调在糖尿病空腹高血糖和高脂血症的双重发病机制中的重要性。我们回顾了FoxO6在记忆巩固中的作用及其在神经退行性疾病和衰老中的作用。我们讨论了FoxO6抑制改善糖尿病糖脂代谢的潜在治疗选择。
The forkhead box O family consists of FoxO1, FoxO3, FoxO4 and FoxO6 proteins in mammals. Expressed ubiquitously in the body, the four FoxO isoforms share in common the amino DNA binding domain, known as “forkhead box” domain. They mediate the inhibitory action of insulin or insulin-like growth factor on key functions involved in cell metabolism, growth, differentiation, oxidative stress, senescence, autophagy and aging. Genetic mutations in FoxO genes or abnormal expression of FoxO proteins are associated with metabolic disease, cancer or altered lifespan in humans and animals. Of the FoxO family, FoxO6 is the least characterized member and is shown to play pivotal roles in the liver, skeletal muscle and brain. Altered FoxO6 expression is associated with the pathogenesis of insulin resistance, dietary obesity and type 2 diabetes, and risk of neurodegeneration disease. FoxO6 is evolutionally divergent from other FoxO isoforms. FoxO6 mediates insulin action on target genes in a mechanism that is fundamentally different from other FoxO members. Here we focus our review on the role of FoxO6, in contrast with other FoxO isoforms, in health and disease. We review the distinctive mechanism by which FoxO6 integrates insulin signaling to hepatic glucose and lipid metabolism. We highlight the importance of FoxO6 dysregulation in the dual pathogenesis of fasting hyperglycemia and hyperlipidemia in diabetes. We review the role of FoxO6 in memory consolidation and its contribution to neurodegeneration disease and aging. We discuss the potential therapeutic option of pharmacological FoxO6 inhibition for improving glucose and lipid metabolism in diabetes.