Division of Intractable Diseases, Center for Biomedical Sciences, National Institutes of Health, #194 Tongillo, Eunpyeong-gu, Seoul 122-701, Korea.
Cell Signal. 2009 Dec;21(12):1758-67. doi: 10.1016/j.cellsig.2009.07.011. Epub 2009 Jul 30.
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-gamma(-/-) mice, but not in STAT1(-/-) mice. Inhibition of STAT1 by siRNA or dominant-negative DNA did not affect ATF3 protein expression but blocked IFN-gamma-induced ATF3 translocation from the cytosol into the nucleus. In contrast, inhibition of ATF3 by using siRNA diminished STAT1 protein expression and IFN-gamma/STZ-induced hepatocyte apoptosis. Furthermore, GST pull-down 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.
已有研究证实，链脲佐菌素（streptozotocin，STZ）的给药会加速糖尿病肝损伤和 1 型糖尿病的发生，但其中的具体机制尚不清楚。在此，我们研究了 STZ 诱导的 1 型糖尿病模型中糖尿病肝损伤的分子机制。STZ 给药诱导了 1 型糖尿病，慢性肝损伤与 STAT1 的增加相关，STAT1 通过促进肝细胞凋亡而参与糖尿病肝损伤，在肝脏和胰腺中均强烈抑制 STAT1(-/-) 小鼠中的 STAT1。同样，IFN-γ(-/-) 小鼠肝脏中的 STZ 诱导的 ATF3（一种应激诱导基因）完全被消除，但在 STAT1(-/-) 小鼠中没有被消除。siRNA 或显性负性 DNA 抑制 STAT1 不影响 ATF3 蛋白表达，但阻断 IFN-γ诱导的 ATF3 从细胞质向核内易位。相比之下，使用 siRNA 抑制 ATF3 会减少 STAT1 蛋白表达和 IFN-γ/STZ 诱导的肝细胞凋亡。此外，GST 下拉和 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其泛素化和蛋白酶体活性增加了 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肝损伤的共同信号通路。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肝损伤。
