A Critical Role for Eukaryotic Elongation Factor 1A-1 in Lipotoxic Cell Death
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Published:2006-02
Issue:2
Volume:17
Page:770-778
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ISSN:1059-1524
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Container-title:Molecular Biology of the Cell
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language:en
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Short-container-title:MBoC
Author:
Borradaile Nica M.1, Buhman Kimberly K.1, Listenberger Laura L.1, Magee Carolyn J.1, Morimoto Emiko T.A.1, Ory Daniel S.1, Schaffer Jean E.1
Affiliation:
1. Center for Cardiovascular Research, Division of Cardiology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110
Abstract
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.
Publisher
American Society for Cell Biology (ASCB)
Subject
Cell Biology,Molecular Biology
Reference49 articles.
1. Aasum, E., Belke, D. D., Severson, D. L., Riemersma, R. A., Cooper, M., Andreassen, M., and Larsen, T. S. (2002). Cardiac function and metabolism in Type 2 diabetic mice after treatment with BM 17.0744, a novel PPAR-alpha activator.Am. J. Physiol.283, H949-H957. 2. Al-Maghrebi, M., Cojocel, C., and Thompson, M. (2004). Regulation of elongation factor-1 mRNA levels by vitamin E in diabetic rat kidneys.FASEB J.18, C46. 3. Browning, J. D., and Horton, J. D. (2004). Molecular mediators of hepatic steatosis and liver injury.J. Clin. Investig.114, 147-152. 4. Brownlee, M. (2003). A radical explanation for glucose-induced beta cell dysfunction.J. Clin. Investig.112, 1788-1790. 5. Cabrero, A., Alegret, M., Sanchez, R. M., Adzet, T., Laguna, J. C., and Carrera, M. V. (2002). Increased reactive oxygen species production down-regulates peroxisome proliferator-activated alpha pathway in C2C12 skeletal muscle cells.J. Biol. Chem.277, 10100-10107.
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