Mechanism for HIF-1 activation by cholesterol under normoxia: A redox signaling pathway for liver damage
Mechanism for HIF-1 activation by cholesterol under normoxia: A redox signaling pathway for liver damage
复制标题
DOI：
10.1016/j.freeradbiomed.2014.03.007
复制
发表时间：
2014-06-01
影响因子：
7.4
通讯作者：
Tirosh, Oren
中科院分区：
文献类型：
--
作者：
Anavi, Sarit;Hahn-Obercyger, Michal;Tirosh, Oren
胆固醇和缺氧诱导因子-1 （HIF-1）的慢性激活分别与肝脏疾病的发病和进展有关。在AML12肝细胞中，与胆固醇一起培养2小时后，HIF-1 α蛋白的积累明显增加，而在6小时后，HIF-1转录活性增强。对分子机制的研究表明，胆固醇抑制HIF-1 α的降解。在2小时胆固醇处理的细胞中观察到线粒体功能障碍和线粒体活性氧（ROS）生成增强，同时一氧化氮（NO）水平升高。进一步的分析表明，HIF-1 α在后期（6 h）稳定，而不是在2 h后，与胆固醇孵育依赖于NO的产生。为了阐明线粒体功能障碍在HIF-1 α稳定中的作用，我们制备了线粒体dna缺失的肝细胞。在这些细胞中，胆固醇激活HIF-1通路的能力被取消。同样，过氧化氢酶过表达也能减弱胆固醇诱导的HIF-1 α积累。这些结果表明胆固醇以ROS和no依赖的方式促进HIF-1的激活。慢性肝脏激活HIF-1由胆固醇可能介导其在肝脏中的有害作用。(C) 2014爱思唯尔公司版权所有。
Cholesterol and chronic activation of hypoxia-inducible factor-1 (HIF-1) have been separately implicated in the pathogenesis and progression of liver diseases. In AML12 hepatocytes increased HIF-1 alpha protein accumulation was evident after 2 h of incubation with cholesterol, whereas enhanced HIF-1 transcriptional activity was observed after 6 h. Investigations into the molecular mechanism have shown that cholesterol inhibited HIF-1 alpha degradation. Mitochondrial dysfunction and enhanced mitochondrial reactive oxygen species (ROS) generation were observed in 2-h cholesterol-treated cells along with augmented nitric oxide (NO) levels. Further analysis indicated that HIF-1 alpha stabilization at later time (6 h), but not after 2 h, of incubation with cholesterol was dependent on NO production. To elucidate the role of mitochondrial dysfunction in HIF-1 alpha stabilization, mitochondrial DNA-depleted hepatocytes were prepared. In these cells the ability of cholesterol to activate the HIF-1 pathway was abolished. Similarly, catalase overexpression also attenuated cholesterol-induced HIF-1 alpha accumulation. These results demonstrate that cholesterol promotes HIF-1 activation in a ROS- and NO-dependent manner. Chronic liver activation of HIF-1 by cholesterol may mediate its deleterious effects in the liver. (C) 2014 Elsevier Inc. All rights reserved.