The Non-coding RNA gadd7 Is a Regulator of Lipid-induced Oxidative and Endoplasmic Reticulum Stress

被引:71
作者
Brookheart, Rita T. [1 ]
Michel, Carlos I. [1 ]
Listenberger, Laura L. [1 ]
Ory, Daniel S. [1 ,2 ]
Schaffer, Jean E. [1 ,3 ]
机构
[1] Cardiovasc Res Ctr, Dept Internal Med, St Louis, MO 63110 USA
[2] Washington Univ, Sch Med, Dept Cell Biol & Physiol, St Louis, MO 63110 USA
[3] Washington Univ, Sch Med, Dept Dev Biol, St Louis, MO 63110 USA
基金
美国国家卫生研究院;
关键词
PALMITATE-INDUCED APOPTOSIS; UNFOLDED PROTEIN RESPONSE; FATTY-ACID OXIDATION; LIPOTOXIC CELL-DEATH; HEPATIC STEATOSIS; NAD(P)H OXIDASE; LIVER-INJURY; RAT-HEART; EXPRESSION; OBESITY;
D O I
10.1074/jbc.M806209200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:7446 / 7454
页数:9
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