A critical role of STAT1 in streptozotocin-induced diabetic liver injury in mice: controlled by ATF3.
A critical role of STAT1 in streptozotocin-induced diabetic liver injury in mice: controlled by ATF3.
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DOI：
10.1016/j.cellsig.2009.07.011
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发表时间：
2009-12
影响因子：
4.8
通讯作者：
Kim WH
中科院分区：
文献类型：
--
作者：
Kim JY;Lee SH;Song EH;Park YM;Lim JY;Kim DJ;Choi KH;Park SI;Gao B;Kim WH
众所周知，使用链脲佐菌素会加速糖尿病性肝损伤以及 I 型糖尿病，但其潜在机制却知之甚少。在这里，我们研究了链脲佐菌素 (STZ) 诱导的 I 型糖尿病模型中糖尿病性肝损伤的分子机制。 STZ 给药诱导的 1 型糖尿病和慢性肝损伤与 STAT1 增加有关，STAT1 因其促进肝脏和胰腺中肝细胞凋亡的能力而与糖尿病性肝损伤有关，而在 STAT1−/− 小鼠中，STAT1 均受到强烈抑制。同样，STZ 诱导的 ATF3（一种应激诱导基因）在 IFN-γ−/− 小鼠的肝脏中被完全消除，但在 STAT1−/− 小鼠中却没有。 siRNA 或显性失活 DNA 对 STAT1 的抑制不会影响 ATF3 蛋白的表达，但会阻止 IFN-γ 诱导的 ATF3 从细胞质转位到细胞核中。相反，使用 siRNA 抑制 ATF3 可减少 STAT1 蛋白表达和 IFN-γ/STZ 诱导的肝细胞凋亡。此外，GST Pulldown 和 co-IP 测定表明 STAT1 与 ATF3 的 C 端结构域结合。这种直接相互作用通过抑制 STAT1 的泛素化以及蛋白酶体活性来增加 STAT1 的稳定性。我们的结果表明 STAT1 是导致 STZ 诱导的糖尿病和糖尿病性肝损伤的常见信号通路。 ATF3 作为 STAT1 稳定性的有效调节剂，加速 STZ 诱导的糖尿病和糖尿病性肝损伤。
It is well-established that the administration of streptozotocin accelerates diabetic liver injury as well as type-I diabetes, however the underlying mechanisms are poorly understood. Here we investigated the molecular mechanisms of diabetic liver injury in a model of streptozotocin (STZ)-induced type-I diabetes. STZ administration induced type-1 diabetes and chronic liver injury was associated with increased STAT1, which is implicated in diabetic liver injury by virtue of its ability to promote hepatocyte apoptosis, in the liver and pancreas, which were all strongly inhibited in STAT1−/− mice. Similarly, STZ-induced ATF3, a stress-inducible gene, was completely abolished in the liver of IFN-γ−/− mice, but not in STAT1−/− mice. Inhibition of STAT1 by siRNA or dominant-negative DNA did not affect ATF3 protein expression but blocked IFN-γ-induced ATF3 translocation from the cytosol into the nucleus. In contrast, inhibition of ATF3 by using siRNA diminished STAT1 protein expression and IFN-γ/STZ-induced hepatocyte apoptosis. Furthermore, GST pulldown and co-IP assay showed that STAT1 bound to C-terminal domain of ATF3. Such direct interaction increased the stability of STAT1 by inhibiting its ubiquitination as well as proteasome activity. Our results suggest that STAT1 is a common signaling pathway contributing to STZ-induced diabetes and diabetic liver injury. ATF3 functions as a potent regulator of STAT1 stability, accelerating STZ-induced diabetes and diabetic liver injury.