The Non-coding RNA gadd7 Is a Regulator of Lipid-induced Oxidative and Endoplasmic Reticulum Stress
The Non-coding RNA gadd7 Is a Regulator of Lipid-induced Oxidative and Endoplasmic Reticulum Stress
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DOI：
10.1074/jbc.m806209200
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发表时间：
2009-03-20
影响因子：
4.8
通讯作者：
Schaffer, Jean E.
中科院分区：
文献类型：
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作者：
Brookheart, Rita T.;Michel, Carlos I.;Schaffer, Jean E.
在肥胖和糖尿病中，脂肪酸摄取和利用的失衡导致非脂肪组织中脂肪的过度积累。这种脂质过载与细胞功能障碍和细胞死亡有关，这会导致器官衰竭，这种现象被称为脂毒性。为了阐明脂质介导的细胞死亡的分子机制，我们培育了一个突变的中国仓鼠卵巢细胞系，并对其进行了鉴定，该细胞系对棕榈酸酯诱导的细胞死亡具有抗性。在这个突变体中，随机插入逆转录病毒启动子陷阱已经扰乱了非编码RNA的基因，生长受阻的DNA损伤诱导基因7(Gadd7)。在这里，我们报告了Gadd7是由脂毒应激以一种依赖于活性氧物种(ROS)的方式诱导的，并且是脂质和一般氧化应激所介导的细胞死亡所必需的。通过突变或短发夹状RNA敲除gadd7可以显著降低脂类和非脂类诱导的ROS。此外，Gadd7的缺失可以延缓和减轻ROS诱导的内质网应激。总而言之，这些数据首次表明，在氧化应激及其诱导内质网应激反应的前馈环路中，存在一个非编码RNA。
In obesity and diabetes, an imbalance in fatty acid uptake and fatty acid utilization leads to excess accumulation of lipid in non-adipose tissues. This lipid overload is associated with cellular dysfunction and cell death, which contribute to organ failure, a phenomenon termed lipotoxicity. To elucidate the molecular mechanism of lipid-mediated cell death, we generated and characterized a mutant Chinese hamster ovary cell line that is resistant to palmitate-induced cell death. In this mutant, random insertion of a retroviral promoter trap has disrupted the gene for the non-coding RNA, growth arrested DNA-damage inducible gene 7 (gadd7). Here we report that gadd7 is induced by lipotoxic stress in a reactive oxygen species (ROS)-dependent fashion and is necessary for both lipid-and general oxidative stress-mediated cell death. Depletion of gadd7 by mutagenesis or short hairpin RNA knockdown significantly reduces lipid and nonlipid induced ROS. Furthermore, depletion of gadd7 delays and diminishes ROS-induced endoplasmic reticulum stress. Together these data are the first to implicate a non-coding RNA in a feed-forward loop with oxidative stress and its induction of the endoplasmic reticulum stress response.