Role of STAT-3 in regulation of hepatic gluconeogenic genes and carbohydrate metabolism in vivo
Role of STAT-3 in regulation of hepatic gluconeogenic genes and carbohydrate metabolism in vivo
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DOI：
10.1038/nm980
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发表时间：
2004-02-01
期刊：
影响因子：
82.9
通讯作者：
Kasuga, M
中科院分区：
文献类型：
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作者：
Inoue, H;Ogawa, W;Kasuga, M
转录因子，信号转导和转录激活因子-3 （STAT-3）参与多种生理过程。本研究表明，使用Cre-loxP系统获得的肝特异性STAT-3缺陷小鼠显示胰岛素抵抗与肝脏糖异生基因表达增加相关。利用腺病毒介导的基因转移恢复这些小鼠的肝脏STAT-3表达，纠正了代谢异常和肝脏糖异生基因表达的改变。在培养的肝细胞中，STAT-3的过表达会抑制糖异生基因的表达，而不依赖于过氧化物酶体增殖体激活受体- γ辅助激活因子-1 α (pgc -1 α)，这是糖异生基因的上游调节因子。在糖尿病小鼠中，通过感染腺病毒载体实现了一种组成型活性STAT-3的肝脏特异性表达，显著降低了血糖、血浆胰岛素浓度和肝脏糖异生基因的表达。因此，肝脏STAT-3信号对于正常的葡萄糖稳态至关重要，可能为糖尿病的治疗提供新的靶点。
The transcription factor, signal transducer and activator of transcription-3 (STAT-3) contributes to various physiological processes. Here we show that mice with liver-specific deficiency in STAT-3, achieved using the Cre-loxP system, show insulin resistance associated with increased hepatic expression of gluconeogenic genes. Restoration of hepatic STAT-3 expression in these mice, using adenovirus-mediated gene transfer, corrected the metabolic abnormalities and the alterations in hepatic expression of gluconeogenic genes. Overexpression of STAT-3 in cultured hepatocytes inhibited gluconeogenic gene expression independently of peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha), an upstream regulator of gluconeogenic genes. Liver-specific expression of a constitutively active form of STAT-3, achieved by infection with an adenovirus vector, markedly reduced blood glucose, plasma insulin concentrations and hepatic gluconeogenic gene expression in diabetic mice. Hepatic STAT-3 signaling is thus essential for normal glucose homeostasis and may provide new therapeutic targets for diabetes mellitus.