TFE3 transcriptionally activates hepatic IRS-2, participates in insulin signaling and ameliorates diabetes
TFE3 transcriptionally activates hepatic IRS-2, participates in insulin signaling and ameliorates diabetes
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DOI：
10.1038/nm1334
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发表时间：
2006-01-01
期刊：
影响因子：
82.9
通讯作者：
Yamada, N
中科院分区：
文献类型：
--
作者：
Nakagawa, Y;Shimano, H;Yamada, N
利用表达克隆策略，我们已经确定TFE3是一种基本的螺旋-环-螺旋蛋白，是代谢基因的反式激活因子，通过其启动子中的E-box进行调节。腺病毒介导的TFE3在培养和体内肝细胞中的表达强烈地激活了IRS-2和Akt的表达，并增强了Akt、糖原合成酶K3β和P70S6激酶等胰岛素信号通路的磷酸化。TFE3还诱导了己糖激酶II(HK2)和胰岛素诱导基因1(INSIG1)的表达。这些变化导致了代谢后果，例如肝脏中糖原和蛋白质合成的激活，但不是脂肪生成。总体而言，正常小鼠和不同糖尿病模型小鼠的血糖水平都显著降低，包括链脲佐菌素治疗的db/db和kk小鼠。启动子分析表明，IRS2、HK2和INSIG1是TFE3的直接靶点。胰岛素耗竭和抵抗时胰岛素信号的激活表明TFE3可能成为糖尿病的治疗靶点。
Using an expression cloning strategy, we have identified TFE3, a basic helix-loop-helix protein, as a transactivator of metabolic genes that are regulated through an E-box in their promoters. Adenovirus-mediated expression of TFE3 in hepatocytes in culture and in vivo strongly activated expression of IRS-2 and Akt and enhanced phosphorylation of insulin-signaling kinases such as Akt, glycogen synthase kinase 3 beta and p70S6 kinase. TFE3 also induced hexokinase II (HK2) and insulin-induced gene 1 (INSIG1). These changes led to metabolic consequences, such as activation of glycogen and protein synthesis, but not lipogenesis, in liver. Collectively, plasma glucose levels were markedly reduced both in normal mice and in different mouse models of diabetes, including streptozotocin-treated, db/db and KK mice. Promoter analyses showed that IRS2, HK2 and INSIG1 are direct targets of TFE3. Activation of insulin signals in both insulin depletion and resistance suggests that TFE3 could be a therapeutic target for diabetes.