A critical role for eukaryotic elongation factor 1A-1 in lipotoxic cell death

• Published in: Molecular biology of the cell 2006-02, Vol.17 (2), p.770-778
• Main Authors: Borradaile, Nica M, Buhman, Kimberly K, Listenberger, Laura L, Magee, Carolyn J, Morimoto, Emiko T A, Ory, Daniel S, Schaffer, Jean E
• Format: Article
• Language: English
• Subjects: Animals; Biomarkers - metabolism; Cardiomyopathies - chemically induced; Cardiomyopathies - metabolism; Cell Death; Cell Line; Cricetinae; Cricetulus; Disease Models, Animal; Endoplasmic Reticulum - physiology; Mice; Models, Biological; Mutagenesis, Insertional; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Oxidative Stress; Palmitates - toxicity; Peptide Elongation Factor 1 - metabolism; Peptide Elongation Factor 1 - physiology; Rats; Reactive Oxygen Species - metabolism; RNA Interference
• ISSN: 1059-1524; 1939-4586; 1059-1524
• DOI: 10.1091/mbc.e05-08-0742

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.