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Journal of Lipid Research, Vol. 47, 2726-2737, December 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology
Disruption of endoplasmic reticulum structure and integrity in lipotoxic cell death
* Center for Cardiovascular Research, Division of Cardiology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110
Division of Bioorganic Chemistry, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110
Published, JLR Papers in Press, September 7, 2006.
1 To whom correspondence should be addressed. e-mail: jschaff{at}wustl.edu
Cell dysfunction and death induced by lipid accumulation in nonadipose tissues, or lipotoxicity, may contribute to the pathogenesis of obesity and type 2 diabetes. However, the mechanisms leading to lipotoxic cell death are poorly understood. We recently reported that, in Chinese hamster ovary (CHO) cells and in H9c2 cardiomyoblasts, lipid overload induced by incubation with 500 µM palmitate leads to intracellular accumulation of reactive oxygen species, which subsequently induce endoplasmic reticulum (ER) stress and cell death. Here, we show that palmitate also impairs ER function through a more direct mechanism. Palmitate was rapidly incorporated into saturated phospholipid and triglyceride species in microsomal membranes of CHO cells. The resulting membrane remodeling was associated with dramatic dilatation of the ER and redistribution of protein-folding chaperones to the cytosol within 5 h, indicating compromised ER membrane integrity. Increasing ß-oxidation, through the activation of AMP-activated protein kinase, decreased palmitate incorporation into microsomes, decreased the escape of chaperones to the cytosol, and decreased subsequent caspase activation and cell death. Thus, palmitate rapidly increases the saturated lipid content of the ER, leading to compromised ER morphology and integrity, suggesting that impairment of the structure and function of this organelle is involved in the cellular response to fatty acid overload.
Supplementary key words palmitate • fatty acid • lipotoxicity • lipid synthesis
Abbreviations: AICAr, 5-aminoimidazole-4-carboxamide-1-ß-4-ribofuranoside; AMPK, AMP-activated protein kinase; ER, endoplasmic reticulum; GRP78, glucose-regulated protein 78; PC, phosphatidylcholine; PDI, protein disulfide isomerase; ROS, reactive oxygen species; SCD1, stearoyl-coenzyme A desaturase 1; TAG, triacylglycerol
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