Hypoxia-inducible factor-1α regulates β cell function in mouse and human islets
Hypoxia-inducible factor-1α regulates β cell function in mouse and human islets
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DOI：
10.1172/jci35846
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发表时间：
2010-06-01
影响因子：
15.9
通讯作者：
Gunton, Jenny E.
中科院分区：
文献类型：
--
作者：
Cheng, Kim;Ho, Kenneth;Gunton, Jenny E.
缺氧诱导因子-1 α（HIF-1 α）是一种调节细胞应激反应的转录因子。虽然HIF-1 α蛋白的水平受到严格调控，但最近的研究表明，它在含氧量正常的条件下可以发挥作用。我们假设HIF-1 α是正常β细胞功能和储备所必需的，并且失调可能有助于2型糖尿病（T2 D）的发病机制。在这里，我们表明，HIF-1 α蛋白是目前在小鼠和人类的含氧量正常的β细胞和胰岛低水平。HIF-1 α水平降低会损害葡萄糖刺激的ATP生成和β细胞功能。具有β细胞特异性Hif 1a破坏的C57 BL/6小鼠（本文中称为β-Hif 1a缺失小鼠）表现出葡萄糖耐受不良、β细胞功能障碍，并且在高脂肪饮食下发展出严重的葡萄糖耐受不良。通过铁螯合作用抑制HIP-1 α的降解来增加HIP-1 α的水平，显著改善了高脂饮食对照小鼠的胰岛素分泌和葡萄糖耐量，但在β-Hif 1a缺失小鼠中没有。增加HIF-1 α水平显著增加了人T2 D胰岛中ARNT和其他基因的表达，并改善了它们的功能。进一步的分析表明，HIF-1 α在小鼠β细胞系中与Arnt启动子结合，表明直接调节。总之，这些发现表明HIF-1 α在β细胞储备和ARNT表达调节中的重要作用，并证明HIF-1 α是T2 D β细胞功能障碍的潜在治疗靶点。
Hypoxia-inducible factor-1 alpha (HIF-1 alpha) is a transcription factor that regulates cellular stress responses. While the levels of HIF-1 alpha protein are tightly regulated, recent studies suggest that it can be active under normoxic conditions. We hypothesized that HIF-1 alpha is required for normal beta cell function and reserve and that dysregulation may contribute to the pathogenesis of type 2 diabetes (T2D). Here we show that HIF-1 alpha protein is present at low levels in mouse and human normoxic beta cells and islets. Decreased levels of HIF-1 alpha impaired glucose-stimulated ATP generation and beta cell function. C57BL/6 mice with beta cell-specific Hif1a disruption (referred to herein as beta-Hif1a-null mice) exhibited glucose intolerance, beta cell dysfunction, and developed severe glucose intolerance on a high-fat diet. Increasing HIP-1 alpha levels by inhibiting its degradation through iron chelation markedly improved insulin secretion and glucose tolerance in control mice fed a high-fat diet but not in beta-Hif1a-null mice. Increasing HIF-1 alpha levels markedly increased expression of ARNT and other genes in human T2D islets and improved their function. Further analysis indicated that HIF-1 alpha was bound to the Arnt promoter in a mouse beta cell line, suggesting direct regulation. Taken together, these findings suggest an important role for HIF-1 alpha in beta cell reserve and regulation of ARNT expression and demonstrate that HIF-1 alpha is a potential therapeutic target for the beta cell dysfunction of T2D.