Foxo1 mediates insulin action on apoC-III and triglyceride metabolism.
Foxo1 mediates insulin action on apoC-III and triglyceride metabolism.
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DOI：
10.1172/jci19992
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发表时间：
2004-11
期刊：
影响因子：
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通讯作者：
J. Altomonte;Lin Cong;S. Harbaran;Anja Richter;Jing Xu;M. Meseck;Hengjiang Dong
中科院分区：
文献类型：
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作者：
J. Altomonte;Lin Cong;S. Harbaran;Anja Richter;Jing Xu;M. Meseck;Hengjiang Dong
载脂蛋白apoC-III在血浆甘油三酯代谢中起重要作用。它主要在肝脏中产生，其肝脏表达受胰岛素抑制。为了阐明胰岛素抑制apoC-III表达的机制，我们通过腺病毒介导的基因转移将叉头盒O 1（Foxo 1）cDNA转移到肝细胞中。Foxo 1刺激肝脏apoC-III表达，并与Foxo 1结合apoC-III启动子中共有位点的能力相关。Foxo 1结合位点的缺失或突变会消除胰岛素反应和Foxo 1介导的刺激。同样，Foxo 1也介导胰岛素对肠上皮细胞中肠apoC-III表达的作用。此外，肝脏中Foxo 1的产生增加了肝脏apoC-III的表达，导致小鼠血浆甘油三酯水平升高和脂肪耐受性受损。表达组成型活性Foxo 1等位基因的转基因小鼠表现出高胆固醇血症。此外，我们发现，肝脏Foxo 1的表达成为失调的结果，胰岛素缺乏或胰岛素抵抗，最终在显著升高Foxo 1生产，沿着其偏斜的核分布，在糖尿病NOD或db/db小鼠的肝脏。虽然胰岛素反应的丧失与apoC-III的产生不受限制和甘油三酯代谢受损有关，但这些数据表明Foxo 1在糖尿病高脂血症的发病机制中提供了胰岛素缺乏或抵抗与apoC-III产生异常之间的分子联系。
The apolipoprotein apoC-III plays an important role in plasma triglyceride metabolism. It is predominantly produced in liver, and its hepatic expression is inhibited by insulin. To elucidate the inhibitory mechanism of insulin in apoC-III expression, we delivered forkhead box O1 (Foxo1) cDNA to hepatocytes by adenovirus-mediated gene transfer. Foxo1 stimulated hepatic apoC-III expression and correlated with the ability of Foxo1 to bind to its consensus site in the apoC-III promoter. Deletion or mutation of the Foxo1 binding site abolished insulin response and Foxo1-mediated stimulation. Likewise, Foxo1 also mediated insulin action on intestinal apoC-III expression in enterocytes. Furthermore, elevated Foxo1 production in liver augmented hepatic apoC-III expression, resulting in increased plasma triglyceride levels and impaired fat tolerance in mice. Transgenic mice expressing a constitutively active Foxo1 allele exhibited hypertriglyceridemia. Moreover, we show that hepatic Foxo1 expression becomes deregulated as a result of insulin deficiency or insulin resistance, culminating in significantly elevated Foxo1 production, along with its skewed nuclear distribution, in livers of diabetic NOD or db/db mice. While loss of insulin response is associated with unrestrained apoC-III production and impaired triglyceride metabolism, these data suggest that Foxo1 provides a molecular link between insulin deficiency or resistance and aberrant apoC-III production in the pathogenesis of diabetic hypertriglyceridemia.