Peroxiredoxin 6 Is a Key Antioxidant Enzyme in Modulating the Link between Glycemic and Lipogenic Metabolism
Peroxiredoxin 6 Is a Key Antioxidant Enzyme in Modulating the Link between Glycemic and Lipogenic Metabolism
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DOI：
10.1155/2019/9685607
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发表时间：
2019-12-20
影响因子：
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通讯作者：
Lauro, Davide
中科院分区：
文献类型：
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作者：
Arriga, Roberto;Pacifici, Francesca;Lauro, Davide
肥胖者的胰岛素作用和葡萄糖刺激的胰岛素分泌减少。此外，过量摄入脂质会增加氧化应激，导致明显的2型糖尿病(T2 DM)。在抗氧化防御系统中，过氧化还蛋白6(PRDX6)能还原H_2O_2、短链和磷脂过氧化产物。越来越多的证据表明，PRDX6参与了动脉粥样硬化和2型糖尿病的发病机制，但其在肥胖及其并发症的发病机制中的作用尚不清楚。因此，在本研究中，我们试图通过使用PRDX6基因敲除小鼠(PRDX6(-/-))来研究这种关联。利用代谢笼测定代谢参数，如二氧化碳(VCO2)产生、氧气消耗(VO2)和呼吸交换率(RER)。分别进行腹膜腔胰岛素试验和糖耐量试验评价胰岛素敏感性和糖耐量。肝和胰腺的组织化学分析也进行了评估。实时荧光定量聚合酶链式反应(Real-Time-PCR)分析脂、糖代谢相关酶的表达。在高脂饮食(HFD)24周后，与对照组相比，PRDX6(-/-)小鼠体重增加，食物和饮料摄入量增加。PRDX6(-/-)小鼠的VO2消耗和VCO2产生减少，而RER低于0.7，表明存在普遍的脂代谢。喂食HFD的PRDX6(-/-)小鼠表现出胰岛素敏感性和葡萄糖刺激的胰岛素分泌的进一步恶化。此外，在PRDX6(-/-)小鼠中，胰岛素没有抑制脂肪组织的脂肪分解，从而导致肝脏脂肪过载和血清ALT、胆固醇和甘油三酯水平升高。有趣的是，在PRDX6(-/-)小鼠中，肝脏和脂肪组织与促炎基因上调有关。最后，与对照组相比，PRDX6(-/-)小鼠显示出更高的非酒精性脂肪性肝炎(NASH)发生率。我们的结果表明，PRDX6在肥胖相关代谢紊乱的发生发展中可能具有功能和保护作用，如肝脏疾病和T2 DM，并可能被认为是治疗这些疾病的潜在靶点。
Insulin action and often glucose-stimulated insulin secretion are reduced in obesity. In addition, the excessive intake of lipids increases oxidative stress leading to overt type 2 diabetes mellitus (T2DM). Among the antioxidative defense systems, peroxiredoxin 6 (PRDX6) is able to reduce H2O2 and short chain and phospholipid hydroperoxides. Increasing evidences suggest that PRDX6 is involved in the pathogenesis of atherosclerosis and T2DM, but its role in the etiopathology of obesity and its complications is still not known. Therefore, in the present study, we sought to investigate this association by using PRDX6 knockout mice (PRDX6(-/-)). Metabolic parameters, like carbon dioxide (VCO2) production, oxygen consumption (VO2), and the respiratory exchange ratio (RER), were determined using metabolic cages. Intraperitoneal insulin and glucose tolerance tests were performed to evaluate insulin sensitivity and glucose tolerance, respectively. Liver and pancreas histochemical analyses were also evaluated. The expression of enzymes involved in lipid and glucose metabolism was analyzed by real-time PCR. Following 24 weeks of high-fat-diet (HFD), PRDX6(-/-) mice showed weight gain and higher food and drink intake compared to controls. VO2 consumption and VCO2 production decreased in PRDX6(-/-) mice, while the RER was lower than 0.7 indicating a prevalent lipid metabolism. PRDX6(-/-) mice fed with HFD showed a further deterioration on insulin sensitivity and glucose-stimulated insulin secretion. Furthermore, in PRDX6(-/-) mice, insulin did not suppress adipose tissue lipolysis with consequent hepatic lipid overload and higher serum levels of ALT, cholesterol, and triglycerides. Interestingly, in PRDX6(-/-) mice, liver and adipose tissue were associated with proinflammatory gene upregulation. Finally, PRDX6(-/-) mice showed a higher rate of nonalcoholic steatohepatitis (NASH) compared to control. Our results suggest that PRDX6 may have a functional and protective role in the development of obesity-related metabolic disorders such as liver diseases and T2DM and may be considered a potential therapeutic target against these illnesses.