Homocysteine downregulates gene expression of heme oxygenase-1 in hepatocytes.
Homocysteine downregulates gene expression of heme oxygenase-1 in hepatocytes.
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同型半胱氨酸下调肝细胞中血红素加氧酶-1 的基因表达。
DOI：
10.1186/1743-7075-11-55
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发表时间：
2014
影响因子：
4.5
通讯作者：
Wang N
中科院分区：
文献类型：
--
作者：
Luo X;Xiao L;Yang H;Zhang R;Jiang M;Ni J;Lei T;Wang N
高同型半胱氨酸血症（HHcy）是脂肪肝、肝纤维化等肝脏疾病的独立危险因素。然而，这种促氧化作用的同型半胱氨酸（Hcy）在肝细胞的机制仍然在很大程度上未知。因此，我们研究了Hcy对血红素加氧酶-1（HO-1）基因表达的影响，HO-1是血红素代谢的主要限速酶，也是维持细胞氧化还原稳态的关键抗氧化解毒酶。在体内，将20只8周龄的雄性C57 BL/6小鼠随机分为两组。一组小鼠喂食普通饲料（普通饲料组; n = 10），另一组小鼠喂食蛋氨酸补充饲料（蛋氨酸组，1 mg kg-1 day-1 L-蛋氨酸溶于饮用水; n = 10），持续4周。在体外，用不同剂量的同型半胱氨酸（Hcy）刺激HepG 2细胞。补充蛋氨酸4周后，C57 BL/6小鼠血浆Hcy浓度显著升高，肝脏HO-1表达显著降低。此外，与对照组相比，补充蛋氨酸的小鼠肝脏中SOD酶活性受损，氧化应激标志物如丙二醛（MDA）水平升高。在培养的肝细胞中，同型半胱氨酸处理降低HO-1的mRNA和蛋白水平的剂量依赖性。然而，Hcy对HO-1的主要转录调节因子Nrf 2的基因表达没有影响。相反，同型半胱氨酸诱导的Bach 1，HO-1的转录抑制因子的表达。此外，Hcy刺激Bach 1的核定位，但阻止Nrf 2。此外，我们发现Bach 1的敲低减弱了Hcy对HO-1表达的抑制。总的来说，我们的研究结果表明，Bach 1通过抑制HO-1表达在Hcy触发的ROS生成中起着重要作用，这可能是由于Bach 1和Nrf 2之间的相互作用受到干扰。本文的在线版本（doi：10.1186/1743-7075-11-55）包含补充材料，可供授权用户使用。
Hyperhomocysteinemia (HHcy) is an independent risk factor for liver diseases, such as fatty liver and hepatic fibrosis. However, the mechanisms underlying this pro-oxidative effect of homocysteine (Hcy) in hepatocytes remain largely unknown. Thus, we investigated the effect of Hcy on the gene expression of heme oxygenase-1 (HO-1), the primary rate-limiting enzyme in heme catabolism and a key anti-oxidant detoxification enzyme in maintaining cellular redox homeostasis. In vivo, twenty male C57BL/6 mice at 8 weeks of age were randomly divided into two groups. One group was fed a chow diet (chow group; n = 10), the other group of mice was fed a methionine-supplemented diet (Met group, 1 mg kg−1 day−1 L-methionine in drinking water; n = 10) for 4 weeks. In vitro, HepG2 cells were stimulated with different doses of homocysteine (Hcy). Four weeks’ methionine supplementation caused a significant increase of plasma Hcy concentration and a decrease of HO-1 expression in the liver of C57BL/6 mice than mice received chow diet. Besides, SOD enzyme activities were impaired and the level of oxidative stress markers, such as malondialdehyde (MDA) were elevated in the liver from mice supplemented with methionine compared with control mice. In cultured hepatocytes, Hcy treatment reduced both the mRNA and protein levels of HO-1 dose-dependently. However, Hcy had no effect on the gene expression of Nrf2, the major transcriptional regulator of HO-1. Instead, Hcy induced the expression of Bach1, a transcriptional repressor of HO-1. In addition, Hcy stimulated the nuclear localization of Bach1 but prevented that of Nrf2. Furthermore, we found that knockdown of Bach1 attenuated the suppression of the HO-1 expression by Hcy. Collectively, our results demonstrated that Bach1 plays an important role in Hcy-triggered ROS generations through inhibiting HO-1 expression, likely, resulting from the disturbed interplay between Bach1 and Nrf2. The online version of this article (doi:10.1186/1743-7075-11-55) contains supplementary material, which is available to authorized users.
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DOI：
10.1165/rcmb.2006-0340tr
发表时间：
2007-02-01
影响因子：
6.4
作者：
Alam, Jawed;Cook, Julia L.
通讯作者：
Cook, Julia L.
影响因子：
4.3
作者：
Huang, Xiao-Shan;Chen, He-Ping;Huang, Qi-Ren
通讯作者：
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影响因子：
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作者：
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影响因子：
4.2
作者：
Liu, Chi;Wang, Qing;Ling, Wenhua
通讯作者：
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影响因子：
11.4
作者：
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