Peroxiredoxin 4 Protects Against Nonalcoholic Steatohepatitis and Type 2 Diabetes in a Nongenetic Mouse Model
Peroxiredoxin 4 Protects Against Nonalcoholic Steatohepatitis and Type 2 Diabetes in a Nongenetic Mouse Model
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DOI：
10.1089/ars.2012.4946
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发表时间：
2013-12-10
影响因子：
6.6
通讯作者：
Sasaguri, Yasuyuki
中科院分区：
文献类型：
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作者：
Nabeshima, Atsunori;Yamada, Sohsuke;Sasaguri, Yasuyuki
目的：摄入高果糖饮食可导致代谢综合征的发展，表现为非酒精性脂肪性肝炎(NASH)和/或2型糖尿病(T2 DM)，氧化应激在其中起关键作用。过氧化还蛋白4(PRDX4)是PRDX抗氧化剂家族中唯一的分泌型成员。然而，它在NASH和/或T2 DM发生中的作用尚未被研究。结果：为了阐明PRDX4在代谢综合征中的作用，我们建立了一种非遗传性的T2 DM小鼠模型，方法是在小鼠注射相对较小剂量的链脲佐菌素后给予hfrd。与野生型(WT)相比，人PRDX4转基因(TG)小鼠的胰岛素抵抗显著改善，表现为较低的血糖和胰岛素浓度以及较快的糖耐量试验反应。与WT组相比，TG组的肝脏也表现出不那么严重的水泡性脂肪变性、炎症和纤维化，并伴随着较低的脂质浓度、较低的氧化应激标志物水平、较多的肝脏转氨酶表达减少和星状细胞活化减少，这让人想起人类早期的NASH。TG组小鼠肝细胞凋亡也受到明显抑制。相比之下，WT小鼠的血清脂联素水平和肝脏脂联素受体的表达显著降低，这与周围肝脏组织中胰岛素抵抗的程度高于TG小鼠一致。创新和结论：我们的数据首次表明，PRDX4可能通过改善氧化应激诱导的损伤来预防NASH、T2 DM和代谢综合征。抗氧化剂。氧化还原信号。19,1983-1998。
Aims: Consumption of a high-fructose diet (HFrD) can induce the development of a metabolic syndrome, manifesting as nonalcoholic steatohepatitis (NASH) and/or type 2 diabetes mellitus (T2DM), via a process in which oxidative stress plays a critical role. Peroxiredoxin 4 (PRDX4) is a unique and only known secretory member of the PRDX antioxidant family. However, its putative roles in the development of NASH and/or T2DM have not been investigated. Results: To elucidate the functions of PRDX4 in a metabolic syndrome, we established a nongenetic mouse model of T2DM by feeding mice a HFrD after injecting a relatively low dose of streptozotocin. Compared with wild-type (WT), human PRDX4 transgenic (Tg) mice exhibited significant improvements in insulin resistance, characterized by a lower glucose and insulin concentration and faster responses in glucose tolerance tests. The liver of Tg also showed less severe vesicular steatosis, inflammation, and fibrosis, along with lower lipid concentrations, lower levels of oxidative stress markers, more decreased expression of hepatic aminotransferase, and more reduced stellate cell activation than those in the WT liver, reminiscent of human early NASH. Hepatocyte apoptosis was also significantly repressed in Tg mice. By contrast, serum adiponectin levels and hepatic adiponectin receptor expression were significantly lower in WT mice, consistent with greater insulin resistance in the peripheral liver tissue compared with Tg mice. Innovation and Conclusion: Our data for the first time show that PRDX4 may protect against NASH, T2DM, and the metabolic syndrome by ameliorating oxidative stress-induced injury. Antioxid. Redox Signal. 19, 1983-1998.