8-Oxoguanine DNA glycosylase (OGG1) deficiency increases susceptibility to obesity and metabolic dysfunction.
8-Oxoguanine DNA glycosylase (OGG1) deficiency increases susceptibility to obesity and metabolic dysfunction.
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DOI：
10.1371/journal.pone.0051697
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Lloyd RS
中科院分区：
文献类型：
--
作者：
Sampath H;Vartanian V;Rollins MR;Sakumi K;Nakabeppu Y;Lloyd RS
DNA的氧化损伤主要通过碱基切除修复来修复，这是一种由8-氧鸟嘌呤DNA糖基酶(OGG1)等DNA糖基酶催化的途径。虽然OGG1与维持基因组完整性和预防肿瘤发生有关，但我们报告了OGG1在改变细胞和全身能量动态平衡方面的新作用。与野生型(WT)动物相比，OGG1基因缺陷(OGG1−/−)小鼠在暴露于高脂饮食后肥胖和肝脏脂肪变性增加。与WT同龄人相比，Ogg1−/−动物在喂养高脂饲料时也有更高的血浆胰岛素水平和糖耐量受损。能量消耗分析显示，喂食高脂饲料的Ogg1−/−小鼠的静息二氧化碳浓度更高，因此在静息阶段呼吸商增加，这表明这些小鼠更喜欢碳水化合物代谢而不是脂肪氧化。此外，基因芯片和定量聚合酶链式反应分析表明，脂肪酸氧化的关键基因，包括肉碱棕榈酰转移酶-1和完整转录共激活因子pGC-1α在Ogg1−/−肝脏中显著下调。参与三氯乙酸循环代谢的多个基因在Ogg1−/−小鼠肝脏中也显著减少。此外，Ogg1−/−小鼠的肝糖原储备减少，空腹血酮显著降低。总而言之，这些数据表明，OGG1缺陷改变了细胞底物代谢，有利于脂肪节约型，导致Ogg1−/−小鼠肥胖和相关病理的易感性增加。
Oxidative damage to DNA is mainly repaired via base excision repair, a pathway that is catalyzed by DNA glycosylases such as 8-oxoguanine DNA glycosylase (OGG1). While OGG1 has been implicated in maintaining genomic integrity and preventing tumorigenesis, we report a novel role for OGG1 in altering cellular and whole body energy homeostasis. OGG1-deficient (Ogg1−/−) mice have increased adiposity and hepatic steatosis following exposure to a high-fat diet (HFD), compared to wild-type (WT) animals. Ogg1−/− animals also have higher plasma insulin levels and impaired glucose tolerance upon HFD feeding, relative to WT counterparts. Analysis of energy expenditure revealed that HFD-fed Ogg1−/− mice have a higher resting VCO2 and consequently, an increased respiratory quotient during the resting phase, indicating a preference for carbohydrate metabolism over fat oxidation in these mice. Additionally, microarray and quantitative PCR analyses revealed that key genes of fatty acid oxidation, including carnitine palmitoyl transferase-1, and the integral transcriptional co-activator Pgc-1α were significantly downregulated in Ogg1−/− livers. Multiple genes involved in TCA cycle metabolism were also significantly reduced in livers of Ogg1−/− mice. Furthermore, hepatic glycogen stores were diminished, and fasting plasma ketones were significantly reduced in Ogg1−/− mice. Collectively, these data indicate that OGG1 deficiency alters cellular substrate metabolism, favoring a fat sparing phenotype, that results in increased susceptibility to obesity and related pathologies in Ogg1−/− mice.
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影响因子：
14.5
作者：
Nemec AA;Wallace SS;Sweasy JB
通讯作者：
Sweasy JB
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作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
Verdine, GL