QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

Vol. 17, Issue 2, 770-778, February 2006

This Article Full Text Full Text (PDF) Supplemental Material All Versions of this Article: E05-08-0742v1 17/2/770    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Borradaile, N. M. Articles by Schaffer, J. E. Search for Related Content PubMed PubMed Citation Articles by Borradaile, N. M. Articles by Schaffer, J. E.

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

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

Submitted August 10, 2005; Revised November 16, 2005; Accepted November 18, 2005
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 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.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

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

This article has been cited by other articles:

				Y. Zhang, K. Larade, Z.-g. Jiang, S. Ito, W. Wang, H. Zhu, and H. F. Bunn The flavoheme reductase Ncb5or protects cells against endoplasmic reticulum stress-induced lipotoxicity J. Lipid Res., January 1, 2010; 51(1): 53 - 62. [Abstract] [Full Text] [PDF]

				R. T. Brookheart, C. I. Michel, L. L. Listenberger, D. S. Ory, and J. E. Schaffer The Non-coding RNA gadd7 Is a Regulator of Lipid-induced Oxidative and Endoplasmic Reticulum Stress J. Biol. Chem., March 20, 2009; 284(12): 7446 - 7454. [Abstract] [Full Text] [PDF]

				D. Zhong, J. Zhang, S. Yang, U. J. K. Soh, J. P. Buschdorf, Y. T. Zhou, D. Yang, and B. C. Low The SAM domain of the RhoGAP DLC1 binds EF1A1 to regulate cell migration J. Cell Sci., February 1, 2009; 122(3): 414 - 424. [Abstract] [Full Text] [PDF]

				T.-S. Park, Y. Hu, H.-L. Noh, K. Drosatos, K. Okajima, J. Buchanan, J. Tuinei, S. Homma, X.-C. Jiang, E. D. Abel, et al. Ceramide is a cardiotoxin in lipotoxic cardiomyopathy J. Lipid Res., October 1, 2008; 49(10): 2101 - 2112. [Abstract] [Full Text] [PDF]

				N. Anderson and J. Borlak Molecular Mechanisms and Therapeutic Targets in Steatosis and Steatohepatitis Pharmacol. Rev., September 1, 2008; 60(3): 311 - 357. [Abstract] [Full Text] [PDF]

				L. R. Peterson, P. Herrero, J. McGill, K. B. Schechtman, Z. Kisrieva-Ware, D. Lesniak, and R. J. Gropler Fatty Acids and Insulin Modulate Myocardial Substrate Metabolism in Humans With Type 1 Diabetes Diabetes, January 1, 2008; 57(1): 32 - 40. [Abstract] [Full Text] [PDF]

				Y. Xie, J. Luo, S. Kennedy, and N. O. Davidson Conditional Intestinal Lipotoxicity in Apobec-1-/- Mttp-IKO Mice: A SURVIVAL ADVANTAGE FOR MAMMALIAN INTESTINAL APOLIPOPROTEIN B mRNA EDITING J. Biol. Chem., November 9, 2007; 282(45): 33043 - 33051. [Abstract] [Full Text] [PDF]

				M. F. Gregor and G. S. Hotamisligil Thematic review series: Adipocyte Biology. Adipocyte stress: the endoplasmic reticulum and metabolic disease J. Lipid Res., September 1, 2007; 48(9): 1905 - 1914. [Abstract] [Full Text] [PDF]

				W. Guo, S. Wong, W. Xie, T. Lei, and Z. Luo Palmitate modulates intracellular signaling, induces endoplasmic reticulum stress, and causes apoptosis in mouse 3T3-L1 and rat primary preadipocytes Am J Physiol Endocrinol Metab, August 1, 2007; 293(2): E576 - E586. [Abstract] [Full Text] [PDF]

				S. Horke, I. Witte, P. Wilgenbus, M. Kruger, D. Strand, and U. Forstermann Paraoxonase-2 Reduces Oxidative Stress in Vascular Cells and Decreases Endoplasmic Reticulum Stress-Induced Caspase Activation Circulation, April 17, 2007; 115(15): 2055 - 2064. [Abstract] [Full Text] [PDF]

				P. A. Grimsrud, M. J. Picklo Sr., T. J. Griffin, and D. A. Bernlohr Carbonylation of Adipose Proteins in Obesity and Insulin Resistance: Identification of Adipocyte Fatty Acid-binding Protein as a Cellular Target of 4-Hydroxynonenal Mol. Cell. Proteomics, April 1, 2007; 6(4): 624 - 637. [Abstract] [Full Text] [PDF]

				N. M. Borradaile, X. Han, J. D. Harp, S. E. Gale, D. S. Ory, and J. E. Schaffer Disruption of endoplasmic reticulum structure and integrity in lipotoxic cell death J. Lipid Res., December 1, 2006; 47(12): 2726 - 2737. [Abstract] [Full Text] [PDF]