Double Knockout of Peroxiredoxin 4 (Prdx4) and Superoxide Dismutase 1 (Sod1) in Mice Results in Severe Liver Failure.
Double Knockout of Peroxiredoxin 4 (Prdx4) and Superoxide Dismutase 1 (Sod1) in Mice Results in Severe Liver Failure.
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DOI：
10.1155/2018/2812904
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发表时间：
2018
影响因子：
--
通讯作者：
Fujii J
中科院分区：
文献类型：
--
作者：
Homma T;Kurahashi T;Lee J;Nabeshima A;Yamada S;Fujii J
缺乏超氧化物歧化酶1（Sod 1）（一种抗氧化酶）的小鼠容易发生肝脏脂肪变性。过氧化物氧还蛋白4（Prdx 4）通过过氧化氢的作用催化蛋白质中二硫键的形成，从而降低氧化应激并支持氧化蛋白质折叠以分泌脂蛋白。由于活性氧升高诱导内质网应激，这种负链反应可能参与非酒精性脂肪性肝病和更晚期脂肪性肝炎（NASH）的发展。在目前的研究中，我们产生了Prdx 4和Sod 1双敲除（DKO; Prdx 4 −/ySod 1 −/−）小鼠，并检查了与单敲除和野生型小鼠相比，Prdx 4和Sod 1的联合缺失是否会加重肝脏病理学。在DKO小鼠中，富含甘油三酯的脂蛋白的分泌显著受损，导致肝脏脂肪变性加重。同时观察肝脏中caspase-3的活化。Prdxs的过度氧化是氧化应激的标志，发生在与Sod 1 −/−和Prdx 4 −/y小鼠独特相关的不同亚型中，并且在DKO小鼠肝脏中的作用是累加的。由于DKO小鼠在相对年轻的阶段自发地发展严重的肝功能衰竭，因此它们有可能用作肝脏疾病的模型和测试其他潜在的治疗方法。
Mice that are deficient in superoxide dismutase 1 (Sod1), an antioxidative enzyme, are susceptible to developing liver steatosis. Peroxiredoxin 4 (Prdx4) catalyzes disulfide bond formation in proteins via the action of hydrogen peroxide and hence decreases oxidative stress and supports oxidative protein folding for the secretion of lipoproteins. Because elevated reactive oxygen species induce endoplasmic reticulum stress, this negative chain reaction is likely involved in the development of nonalcoholic fatty liver diseases and more advanced steatohepatitis (NASH). In the current study, we generated Prdx4 and Sod1 double knockout (DKO; Prdx4−/ySod1−/−) mice and examined whether the combined deletion of Prdx4 and Sod1 aggravated liver pathology compared to single knockout and wild-type mice. The secretion of triglyceride-rich lipoprotein was strikingly impaired in the DKO mice, leading to aggravated liver steatosis. Simultaneously, the activation of caspase-3 in the liver was observed. The hyperoxidation of Prdxs, a hallmark of oxidative stress, occurred in different isoforms that are uniquely associated with Sod1−/− and Prdx4−/y mice, and the effect was additive in DKO mouse livers. Because DKO mice spontaneously develop severe liver failure at a relatively young stage, they have the potential for use as a model for hepatic disorders and for testing other potential treatments.
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