Hepatic hypoxia-inducible factors inhibit PPARα expression to exacerbate acetaminophen induced oxidative stress and hepatotoxicity
Hepatic hypoxia-inducible factors inhibit PPARα expression to exacerbate acetaminophen induced oxidative stress and hepatotoxicity
复制标题
肝缺氧诱导因子抑制 PPARα 表达，加剧对乙酰氨基酚诱导的氧化应激和肝毒性
DOI：
10.1016/j.freeradbiomed.2017.06.002
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发表时间：
2017-09-01
影响因子：
7.4
通讯作者：
Xia, Qiang
中科院分区：
文献类型：
--
作者：
Li, Dawei;Du, Yingdong;Xia, Qiang
氧化应激在对乙酰氨基酚（APAP）诱导的肝细胞坏死的发病机制中具有关键作用，并且鉴定减轻氧化应激的新方法对于预防/逆转该疾病至关重要。本研究探讨了HIF-1和HIF-2在APAP诱导的氧化应激发病机制中的作用及其可能机制。在本研究中，我们初步发现，敲除HIF-1 α或HIF-2 α可降低APAP毒性，双敲除可提供最佳保护。APAP处理导致小鼠肝脏中HIF-1 α和HIF-2 α的稳定。此外，HIF缺乏的保护作用与减轻氧化应激有关。进一步的实验证明，细胞代谢中的主要调节因子PPARalpha解释了HIF缺陷引起的对APAP毒性的保护作用。HIF的失活促进了肝脏中过氧化物酶体增殖物激活受体a（PPARa）的表达，这反过来又激活了核因子红细胞2相关因子2（Nrf 2）。PPARa或Nrf 2的敲低否定了HIF缺乏所提供的肝保护作用。最后，通过荧光素酶报告基因和EMSA研究，PPARa启动子的检测确定了肝细胞中的HIF结合位点和HIF依赖的PPARa抑制。综上所述，我们的研究结果表明，HIF是肝脏中PPARa的关键抑制因子，从而在面对APAP时损害了对氧化应激的适应性防御机制。这些发现对APAP肝毒性的病因学和治疗学具有重要意义。HIF和PPARa之间的功能联系可能比APAP损伤在肝脏生理学和其他病理条件中具有更多的意义。
Oxidative stress has a critical role in the pathogenesis of acetaminophen (APAP) induced hepatocellular necrosis, and the identification of novel approaches to attenuate oxidative stress is essential to prevent/revert the disease. This study investigated the role of both HIF-1 and HIF-2 in the pathogenesis of APAP-induced oxidative stress, as well as the underlying mechanisms. In the present study, we initially found that knockout of HIF-1 alpha or HIF-2 alpha reduced APAP toxicity, and double knockout afforded the best protection. APAP treatment led to stabilization of both HIF-1 alpha and HIF-2 alpha in mouse livers. Moreover, the protective effects of HIF deficiency were related to the attenuated oxidative stress. Further experiments proved that PPAR alpha, a master regulator in cellular metabolism accounted for the HIF deficiency-caused protective impact on APAP toxicity. Inactivation of HIFs promoted the expression of peroxisome proliferator-activated receptor a (PPARa) in the liver, which in turn activated nuclear factor erythroid 2-related factor 2 (Nrf2). Knockdown of PPARa or Nrf2 negated the hepatoprotection afforded by HIF deficiency. At last, examination of the PPARa promoter identified a HIF-binding site and HIF-dependent repression of PPARa in hepatocytes by luciferase reporter and EMSA study. Taken together, Our results demonstrate that HIFs are key suppressors of PPARa in the liver, thereby compromising the adaptive defense mechanisms against oxidative stress when confronted with APAP. These findings are important to the etiology and therapeutics of APAP hepatotoxicity. The functional link between HIFs and PPARa may have more implications in liver physiology and other pathologic conditions than APAP injury.