The non-coding RNA gadd7 is a regulator of lipid-induced oxidative and endoplasmic reticulum stress.
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 non-lipid 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.
Brookheart
Rita T
RT
Center for Cardiovascular Research, Department of Internal Medicine, the Department of Cell Biology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Michel
Carlos I
CI
Listenberger
Laura L
LL
Ory
Daniel S
DS
Schaffer
Jean E
JE
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D003920:Diabetes Mellitus / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005227:Fatty Acids / Q000235:genetics / Q000378:metabolism*; D016296:Mutagenesis; D009154:Mutation; D009765:Obesity / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D022661:RNA, Untranslated / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*
D005227:Fatty Acids; D022661:RNA, Untranslated; D017382:Reactive Oxygen Species