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MBC in Press, published online ahead of print November 30, 2005
Mol. Biol. Cell 10.1091/mbc.E05-08-0742

A more recent version of this article appeared on February 1, 2006
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Submitted on August 10, 2005
Revised on November 16, 2005
Accepted on November 18, 2005

A Critical Role for Eukaryotic Elongation Factor 1A-1 in Lipotoxic Cell Death

Nica M. Borradaile, Kimberly K. Buhman, Laura L. Listenberger, Carolyn J. Magee, Emiko T.A. Morimoto, Daniel S. Ory, and Jean E. Schaffer

Center for Cardiovascular Research, Division of Cardiology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110

Monitoring Editor: John York

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 CHO cell mutants resistant to palmitate-induced death, and isolated a clone with disruption of eukaroytic elongation factor (eEF) 1A-1. eEF1A-1 involvement in lipotoxicity was confirmed in H9c2 cardiomyoblasts, in which siRNA-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.

Address correspondence to: Jean E. Schaffer (jschaff{at}wustl.edu)




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