Bile acids induce mitochondrial ROS, which promote activation of receptor tyrosine kinases and signaling pathways in rat hepatocytes
Bile acids induce mitochondrial ROS, which promote activation of receptor tyrosine kinases and signaling pathways in rat hepatocytes
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DOI：
10.1002/hep.20385
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发表时间：
2004-10-01
期刊：
影响因子：
13.5
通讯作者：
Dent, P
中科院分区：
文献类型：
--
作者：
Fang, YW;Han, SI;Dent, P
先前的研究表明，在肝细胞中，脱氧胆酸（DCA）促进蛋白酪氨酸磷酸酶（PTPases）的失活和ERBB1和细胞外调节激酶（ERK） 1/2通路的激活。目前的研究已经确定了这些事件发生的生化机制。DCA和牛磺酸去氧胆酸（TDCA） （100 μ mol/L）可激活鼠原代肝细胞ERBB1、胰岛素受体、ERK1/2和AKT通路。活性氧（ROS）清除剂n -乙酰半胱氨酸（NAC）和Trolox （TX）以及环孢素A （CsA）和BKA可阻断DCA-和tdca诱导的受体和信号通路的激活。DCA激活了HuH7人肝癌细胞中的ERK1/2通路，该通路被ERBB1抑制剂、NAC、TX、CsA或BKA细胞孵育阻断。DCA在线粒体缺陷的HuH7 Rho 0细胞中没有激活ERK1/2通路。在HuH7细胞和原代肝细胞中，DCA增强了ROS的产生，这一作用在Rho 0细胞和CsA或BKA预先孵育的细胞中被消除。在肝细胞和HuH7细胞中，DCA抑制PTPase活性。用CsA或BKA孵育肝细胞可阻止dca诱导的PTPase活性抑制。Rho 0细胞线粒体功能的丧失也消除了DCA对PTPase活性的抑制作用。综上所述，DCA和TDCA在肝细胞中引起ROS的产生依赖于代谢活跃的线粒体。ROS的产生对于PTPase失活、受体酪氨酸激酶激活以及ERK1/2和AKT通路的信号增强至关重要。
Previous studies have demonstrated in hepatocytes that deoxycholic acid (DCA) promotes inactivation of protein tyrosine phosphatases (PTPases) and activation of ERBB1 and the extracellular-regulated kinase (ERK) 1/2 pathway. The present studies have determined the biochemical mechanism(s) through which these events occur. DCA and taurodeoxycholic acid (TDCA) (100 mumol/L) caused activation of ERBB1, insulin receptor, and the ERK1/2 and AKT pathways in primary rodent hepatocytes. DCA- and TDCA-induced receptor and signaling pathway activations were blocked by the reactive oxygen species (ROS) scavengers N-acetyl cysteine (NAC) and Trolox (TX), as well as by cyclosporin A (CsA) and bongkrekic acid (BKA). DCA activated the ERK1/2 pathway in HuH7 human hepatoma cells that was blocked by the incubation of cells with an ERBB1 inhibitor, NAC, TX, CsA, or BKA. DCA did not activate the ERK1/2 pathway in mitochondria-defective HuH7 Rho 0 cells. In HuH7 cells and primary hepatocytes, DCA enhanced the production of ROS, an effect that was abolished in Rho 0 cells and by prior incubation of cells with CsA or BKA. In hepatocytes and HuH7 cells, DCA inhibited PTPase activity. Incubation of hepatocytes with either CsA or BKA prevented DCA-induced inhibition of PTPase activity. Loss of mitochondrial function in Rho 0 cells also abolished the inhibitory effects of DCA on PTPase activity. In conclusion, DCA and TDCA cause ROS generation in hepatocytes that is dependent on metabolically active mitochondria. The generation of ROS is essential for PTPase inactivation, receptor tyrosine kinase activation, and enhanced signaling down the ERK1/2 and AKT pathways.