Overexpression of Peroxiredoxin 6 Does Not Prevent Ethanol-Mediated Oxidative Stress and May Play a Role in Hepatic Lipid Accumulation
Overexpression of Peroxiredoxin 6 Does Not Prevent Ethanol-Mediated Oxidative Stress and May Play a Role in Hepatic Lipid Accumulation
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DOI：
10.1124/jpet.109.152983
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发表时间：
2009-07-01
影响因子：
3.5
通讯作者：
Petersen, Dennis R.
中科院分区：
文献类型：
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作者：
Roede, James R.;Orlicky, David J.;Petersen, Dennis R.
氧化应激与许多疾病的病因有关，包括酒精性肝病（ALD）。过氧还蛋白6是一种胞质过氧化物酶，已被证明可以保护各种组织，如皮肤、肺和心肌，免受急性氧化损伤。因此，假设过氧化物还蛋白6也可以保护肝脏免受慢性乙醇摄入过程中产生的氧化应激。为了验证这一点，我们给野生型过氧还蛋白6敲除小鼠（KO）和转基因过表达过氧还蛋白6小鼠（TG）喂食含乙醇的饲料。评估了ALD的各种生物标志物，以及慢性乙醇消耗对抗氧化防御的影响。酒精摄入9周后，所有背景的小鼠均表现出血浆丙氨酸转氨酶活性升高、肝纤维化、CYP2E1诱导和脂质过氧化；然而，肝脏甘油三酯积累似乎在乙醇喂养的TG小鼠中加剧。抗氧化蛋白的表达和活性对慢性乙醇消耗的反应也有所不同。例如，在乙醇喂养的KO和TG小鼠中，过氧化氢酶和谷胱甘肽转移酶活性显著诱导，同时谷胱甘肽过氧化物酶活性水平升高。这些抗氧化防御的改变可能是由于遗传操作或乙醇介导的反应引起的代偿反应。综上所述，乙醇喂养的KO和乙醇喂养的TG小鼠均发生早期ALD，过氧化物还氧蛋白6可能在乙醇介导的肝脏脂质积累中起作用。
Oxidative stress is implicated in the etiology of many diseases, including alcoholic liver disease (ALD). Peroxiredoxin 6 is a cytosolic peroxidase that has been demonstrated to protect various tissues, such as skin, lung, and cardiac muscle, against acute oxidative insults. Consequently, peroxiredoxin 6 was hypothesized to also protect the liver from oxidative stress generated during the process of chronic ethanol ingestion. To test this, wild-type peroxiredoxin 6 knockout mice (KO), and transgenic peroxiredoxin 6 overexpressing mice (TG) were fed an ethanol-containing diet. Various biomarkers of ALD were assessed, along with the effects of chronic ethanol consumption on the antioxidant defenses. After 9 weeks of ethanol consumption, all backgrounds exhibited elevations of plasma alanine aminotransferase activity, hepatosteatosis, CYP2E1 induction, and lipid peroxidation; however, hepatic triglyceride accumulation seemed to be exacerbated in ethanol-fed TG mice. Differences in antioxidant protein expression and activity in response to chronic ethanol consumption were also observed. Examples include significant inductions of catalase and glutathione transferase activity in ethanol-fed KO and TG mice, along with elevated levels of glutathione peroxidase activity. These alterations in antioxidant defenses could be attributed to either compensatory responses due to the genetic manipulations or ethanol-mediated responses. In conclusion, both ethanol-fed KO and ethanol-fed TG mice developed early stage ALD and peroxiredoxin 6 may play a role in ethanol-mediated hepatic lipid accumulation.