The effect of alcohol and hydrogen peroxide on liver hepcidin gene expression in mice lacking antioxidant enzymes, glutathione peroxidase-1 or catalase.
The effect of alcohol and hydrogen peroxide on liver hepcidin gene expression in mice lacking antioxidant enzymes, glutathione peroxidase-1 or catalase.
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DOI：
10.3390/biom5020793
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发表时间：
2015-05-06
期刊：
影响因子：
5.5
通讯作者：
Lu S
中科院分区：
文献类型：
--
作者：
Harrison-Findik DD;Lu S
本研究研究了谷胱甘肽过氧化物酶-1 (gpx-1−/−) 和过氧化氢酶 (catalase−/−) 敲除小鼠中酒精和过氧化氢 (H2O2) 对铁调素（关键铁调节分子）的调节作用。对于酒精研究，在饮用水中加入 10% 乙醇，持续 7 天。通过 2'-7'-二氯二氢荧光素二乙酸酯 (DCFH-DA) 测量，与野生型小鼠相比，Gpx-1−/− 的肝脏 H2O2 水平显着高于过氧化氢酶−/−。 gpx-1−/− 小鼠肝脏铁调素表达的基础水平减弱。酒精会增加过氧化氢酶−/− 和野生型小鼠中 H2O2 的产生，但不会增加 gpx-1−/− 小鼠的 H2O2 产量。在酒精喂养的过氧化氢酶−/−和野生型小鼠中，铁调素的表达受到抑制。相反，酒精会升高 gpx-1−/− 小鼠的铁调素表达。 Gpx-1−/− 小鼠还表现出比过氧化氢酶−/− 小鼠更高水平的基础肝脏 CHOP 蛋白表达。在 gpx-1−/− 小鼠中，酒精诱导 CHOP 和较小程度的 GRP78/BiP 表达，但不诱导 XBP1 剪接或 CREBH 与铁调素基因启动子的结合。在 gpx-1−/− 小鼠中观察到的肝脏 ATF4 mRNA 水平的上调被酒精减弱。总之，我们的研究结果强烈表明 H2O2 抑制体内铁调素的表达。在没有 gpx-1 的情况下，酒精和 H2O2 协同诱导 CHOP，通过独立于 CREBH 的 ER 应激刺激肝脏铁调素基因表达。
This study investigates the regulation of hepcidin, the key iron-regulatory molecule, by alcohol and hydrogen peroxide (H2O2) in glutathione peroxidase-1 (gpx-1−/−) and catalase (catalase−/−) knockout mice. For alcohol studies, 10% ethanol was administered in the drinking water for 7 days. Gpx-1−/− displayed significantly higher hepatic H2O2 levels than catalase−/− compared to wild-type mice, as measured by 2'-7'-dichlorodihydrofluorescein diacetate (DCFH-DA). The basal level of liver hepcidin expression was attenuated in gpx-1−/− mice. Alcohol increased H2O2 production in catalase−/− and wild-type, but not gpx-1−/−, mice. Hepcidin expression was inhibited in alcohol-fed catalase−/− and wild-type mice. In contrast, alcohol elevated hepcidin expression in gpx-1−/− mice. Gpx-1−/− mice also displayed higher level of basal liver CHOP protein expression than catalase−/− mice. Alcohol induced CHOP and to a lesser extent GRP78/BiP expression, but not XBP1 splicing or binding of CREBH to hepcidin gene promoter, in gpx-1−/− mice. The up-regulation of hepatic ATF4 mRNA levels, which was observed in gpx-1−/− mice, was attenuated by alcohol. In conclusion, our findings strongly suggest that H2O2 inhibits hepcidin expression in vivo. Synergistic induction of CHOP by alcohol and H2O2, in the absence of gpx-1, stimulates liver hepcidin gene expression by ER stress independent of CREBH.