Novel roles of hypoxia response system in glucose metabolism and obesity
Novel roles of hypoxia response system in glucose metabolism and obesity
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DOI：
10.1016/j.tcm.2014.03.004
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发表时间：
2014-07-01
影响因子：
9.3
通讯作者：
Sunagawa, Kenji
中科院分区：
文献类型：
--
作者：
Ichiki, Toshihiro;Sunagawa, Kenji
氧气对于线粒体中通过氧化磷酸化产生 ATP 至关重要。后生动物配备了缺氧反应系统，包括缺氧诱导因子 (HIP)、脯氨酰羟化酶结构域蛋白 (PHD) 和 von Hippel-Lindau 泛素连接酶系统，以对抗或适应缺氧条件。 PHD 是一种氧敏感酶，负责 HIP-α 羟基化以及随后在常氧条件下的蛋白酶体降解。在缺氧条件下，PHD 活性受到抑制，HIP 转录活性增加，从而诱导涉及葡萄糖代谢、血管生成和红细胞生成的多种基因。肥胖是糖尿病和心血管疾病的一个关键危险因素，全球流行的肥胖引发了对脂肪组织生物学的深入研究，研究表明脂肪组织作为影响整个身体的内分泌器官。最近的研究还表明，随着脂肪组织量的扩大而发生的脂肪组织炎症和缺氧在胰岛素抵抗的发展中发挥着重要作用，其中PHD/HIF通路至关重要。 PHD/HIF 通路可能是治疗肥胖及相关疾病的一个有吸引力的潜在靶标。 (C) 2014 Elsevier Inc. 保留所有权利。
Oxygen is essential for ATP production in mitochondria through oxidative phosphorylation. Metazoans are equipped with the hypoxia response system that includes hypoxia-inducible factor (HIP), prolyl hydroxylase domain protein (PHD), and von Hippel-Lindau ubiquitin ligase system to combat or adapt hypoxic conditions. PHD is an oxygen-sensing enzyme that is responsible for HIP-alpha hydroxylation and subsequent proteasomal degradation at normoxic conditions. In hypoxic conditions, PHD activity is inhibited and transcriptional activity of HIP is increased, resulting in the induction of a broad range of genes that are involved in glucose metabolism, angiogenesis, and erythropoiesis. A worldwide epidemic of obesity, a critical risk factor for diabetes and cardiovascular diseases, has led to intense studies on adipose tissue biology, which revealed that adipose tissue functions as an endocrine organ that affects the whole body. Recent studies also suggest that inflammation and hypoxia of adipose tissue that occur as adipose tissue mass expands play an important role in the development of insulin resistance, in which PHD/HIF pathway is critically involved. The PHD/HIF pathway may be an attractive and potential target for the treatment of obesity and associated diseases. (C) 2014 Elsevier Inc. All rights reserved.