A critical role for eukaryotic elongation factor 1A-1 in lipotoxic cell death.
The deleterious consequences of fatty acid (FA) and neutral lipid accumulation in nonadipose tissues, such as the heart, contribute to the pathogenesis of type 2 diabetes. To elucidate mechanisms of FA-induced cell death, or lipotoxicity, we generated Chinese hamster ovary (CHO) cell mutants resistant to palmitate-induced death and isolated a clone with disruption of eukaryotic elongation factor (eEF) 1A-1. eEF1A-1 involvement in lipotoxicity was confirmed in H9c2 cardiomyoblasts, in which small interfering RNA-mediated knockdown also conferred palmitate resistance. In wild-type CHO and H9c2 cells, palmitate increased reactive oxygen species and induced endoplasmic reticulum (ER) stress, changes accompanied by increased eEF1A-1 expression. Disruption of eEF1A-1 expression rendered these cells resistant to hydrogen peroxide- and ER stress-induced death, indicating that eEF1A-1 plays a critical role in the cell death response to these stressors downstream of lipid overload. Disruption of eEF1A-1 also resulted in actin cytoskeleton defects under basal conditions and in response to palmitate, suggesting that eEF1A-1 mediates lipotoxic cell death, secondary to oxidative and ER stress, by regulating cytoskeletal changes critical for this process. Furthermore, our observations of oxidative stress, ER stress, and induction of eEF1A-1 expression in a mouse model of lipotoxic cardiomyopathy implicate this cellular response in the pathophysiology of metabolic disease.
Borradaile
Nica M
NM
Center for Cardiovascular Research, Division of Cardiology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Buhman
Kimberly K
KK
Listenberger
Laura L
LL
Magee
Carolyn J
CJ
Morimoto
Emiko T A
ET
Ory
Daniel S
DS
Schaffer
Jean E
JE
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D009202:Cardiomyopathies / Q000139:chemically induced / Q000378:metabolism; D016923:Cell Death; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000502:physiology; D051379:Mice; D008954:Models, Biological; D016254:Mutagenesis, Insertional; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress; D010168:Palmitates / Q000633:toxicity*; D020648:Peptide Elongation Factor 1 / Q000378:metabolism / Q000502:physiology*; D034622:RNA Interference; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
D015415:Biomarkers; D010168:Palmitates; D020648:Peptide Elongation Factor 1; D017382:Reactive Oxygen Species