Cyanate Induces Oxidative Stress Injury and Abnormal Lipid Metabolism in Liver through Nrf2/HO-1
Cyanate Induces Oxidative Stress Injury and Abnormal Lipid Metabolism in Liver through Nrf2/HO-1
复制标题
氰酸盐通过Nrf2/HO-1诱导肝脏氧化应激损伤和脂质代谢异常
DOI：
10.3390/molecules24183231
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发表时间：
2019-09-01
期刊：
影响因子：
4.6
通讯作者：
Ran, Jian-Hua
中科院分区：
文献类型：
--
作者：
Hu, Ling;Tian, Kuan;Ran, Jian-Hua
慢性肾脏病（CKD）已成为影响公众健康的主要问题之一。大量临床数据表明，CKD患者高脂血症的患病率显著高于普通人群。脂质代谢紊乱会损害肾实质，并促进心血管疾病（CVD）的发生。氰酸盐是一种尿毒症毒素，近年来受到广泛关注。通常情况下，0.8%摩尔浓度的尿素会转化为氰酸盐，而在吸烟、炎症或暴露于环境污染时，髓过氧化物酶（MPO）会催化硫氰酸盐的氧化，在炎症部位生成氰酸盐。氰酸盐的重要生理功能之一是蛋白质羰基化，这是一种非酶促的蛋白质翻译后修饰。蛋白质上的氨甲酰化反应能够不可逆地改变蛋白质的结构和功能，从而引发病理性的分子和细胞反应。此外，近期研究表明，氰酸盐可通过产生大量活性氧（ROS）直接损伤血管组织。氧化应激会导致肝脏脂质代谢紊乱，这也是导致肝硬化和肝纤维化的重要机制。然而，氰酸盐对肝脏的影响尚不清楚。在本研究中，我们探究了氰酸盐对小鼠和HL - 7702细胞氧化应激损伤及脂质代谢异常的影响。结果显示，氰酸盐通过影响肝脏中总胆固醇（TC）、高密度脂蛋白（HDL）、低密度脂蛋白（LDL）、超氧化物歧化酶（SOD）、过氧化氢酶（CAT）的含量，诱导高脂血症和氧化应激。氰酸盐抑制核因子E2相关因子2（Nrf2）、血红素加氧酶 - 1（HO - 1）以及5'-单磷酸腺苷激活蛋白激酶（AMPK）的磷酸化，激活mTOR通路。抗氧化剂叔丁基对苯二酚（TBHQ）也是Nrf2的激活剂，用其处理细胞后，细胞的氧化应激显著降低。Nrf2的活性得到恢复，mTOR的磷酸化减少。综上所述，氰酸盐可通过抑制Nrf2/HO - 1通路诱导氧化应激损伤和脂质沉积，而Nrf2抑制剂可缓解这种情况。
Chronic kidney disease (CKD) is problem that has become one of the major issues affecting public health. Extensive clinical data suggests that the prevalence of hyperlipidemia in CKD patients is significantly higher than in the general population. Lipid metabolism disorders can damage the renal parenchyma and promote the occurrence of cardiovascular disease (CVD). Cyanate is a uremic toxin that has attracted widespread attention in recent years. Usually, 0.8% of the molar concentration of urea is converted into cyanate, while myeloperoxidase (MPO) catalyzes the oxidation of thiocyanate to produce cyanate at the site of inflammation during smoking, inflammation, or exposure to environmental pollution. One of the important physiological functions of cyanate is protein carbonylation, a non-enzymatic post-translational protein modification. Carbamylation reactions on proteins are capable of irreversibly changing protein structure and function, resulting in pathologic molecular and cellular responses. In addition, recent studies have shown that cyanate can directly damage vascular tissue by producing large amounts of reactive oxygen species (ROS). Oxidative stress leads to the disorder of liver lipid metabolism, which is also an important mechanism leading to cirrhosis and liver fibrosis. However, the influence of cyanate on liver has remained unclear. In this research, we explored the effects of cyanate on the oxidative stress injury and abnormal lipid metabolism in mice and HL-7702 cells. In results, cyanate induced hyperlipidemia and oxidative stress by influencing the content of total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), superoxide dismutase (SOD), catalase (CAT) in liver. Cyanate inhibited NF-E2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and the phosphorylation of adenosine 5′monophosphate-activated protein kinase (AMPK), activated the mTOR pathway. Oxidative stress on the cells reduced significantly by treating with TBHQ, an antioxidant, which is also an activator of Nrf2. The activity of Nrf2 was rehabilitated and phosphorylation of mTOR decreased. In conclusion, cyanate could induce oxidative stress damage and lipid deposition by inhibiting Nrf2/HO-1 pathway, which was rescued by inhibitor of Nrf2.