FoxO1 mediates insulin-dependent regulation of hepatic VLDL production in mice
FoxO1 mediates insulin-dependent regulation of hepatic VLDL production in mice
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DOI：
10.1172/jc132914
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发表时间：
2008-06-01
影响因子：
15.9
通讯作者：
Dong, H. Henry
中科院分区：
文献类型：
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作者：
Kamagate, Adama;Qu, Shen;Dong, H. Henry
高胆固醇血症可引起富含胆固醇的VLDL的过量产生。微粒体甘油三酯转移蛋白（MTP）在受胰岛素调节的限速步骤中促进VLDL的产生。为了表征其潜在机制，我们研究了叉头盒O1（FoxO1）对肝脏MTP的调节，FoxO1是一种在肝脏胰岛素信号传导中起关键作用的转录因子。在HepG2细胞中，MTP的表达被FoxO1诱导，并被胰岛素抑制。这种效应与FoxO1结合和刺激MTP启动子活性的能力相关。MTP启动子内FoxO1靶位点的缺失或突变使FoxO1结合失效，并导致MTP表达的胰岛素依赖性调节被取消。我们产生了表达组成型活性FoxO1转基因的小鼠，发现FoxO1活性增加与MTP表达增强、VLDL产生增加和血浆甘油三酯水平升高相关。相反，RNAi介导的肝脏FoxO1沉默与成年小鼠MTP和VLDL产生减少有关。此外，我们发现，肝脏FoxO1丰度和MTP的生产增加与甘油三酯代谢异常的小鼠。这些数据表明，FoxO1介导的MTP生产的胰岛素调节和MTP水平的增加可能是VLDL过度生产和糖尿病高胆固醇血症的致病因素。
Excessive production of triglyceride-rich VLDL is attributable to hypertriglyceridemia. VLDL production is facilitated by microsomal triglyceride transfer protein (MTP) in a rate-limiting step that is regulated by insulin. To characterize the underlying mechanism, we studied hepatic MTP regulation by forkhead box O1 (FoxO1), a transcription factor that plays a key role in hepatic insulin signaling. In HepG2 cells, MTP expression was induced by FoxO1 and inhibited by exposure to insulin. This effect correlated with the ability of FoxO1 to bind and stimulate MTP promoter activity. Deletion or mutation of the FoxO1 target site within the MTP promoter disabled FoxO1 binding and resulted in abolition of insulin-dependent regulation of MTP expression. We generated mice that expressed a constitutively active FoxO1 transgene and found that increased FoxO1 activity was associated with enhanced MTP expression, augmented VLDL production, and elevated plasma triglyceride levels. In contrast, RNAi-mediated silencing of hepatic FoxO1 was associated with reduced MTP and VLDL production in adult mice. Furthermore, we found that hepatic FoxO1 abundance and MTP production were increased in mice with abnormal triglyceride metabolism. These data suggest that FoxO1 mediates insulin regulation of MTP production and that augmented MTP levels may be a causative factor for VLDL overproduction and hypertriglyceridemia in diabetes.