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J. Biol. Chem., Vol. 276, Issue 18, 14890-14895, May 4, 2001
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From the Center for Cardiovascular Research, Departments of
Internal Medicine, Molecular Biology, and Pharmacology, Washington
University School of Medicine, St. Louis, Missouri 63110-1010
Cytotoxic accumulation of long chain fatty acids has
been proposed to play an important role in the pathogenesis of diabetes mellitus and heart disease. To explore the mechanism of cellular lipotoxicity, we cultured Chinese hamster ovary cells in the
presence of media supplemented with fatty acid. The saturated fatty
acid palmitate, but not the monounsaturated fatty acid oleate, induced programmed cell death as determined by annexin V positivity, caspase 3 activity, and DNA laddering. De novo ceramide synthesis
increased 2.4-fold with palmitate supplementation; however, this was
not required for palmitate-induced apoptosis. Neither biochemical nor
genetic inhibition of de novo ceramide synthesis arrested apoptosis in Chinese hamster ovary cells in response to palmitate supplementation. Rather, our data suggest that palmitate-induced apoptosis occurs through the generation of reactive oxygen species. Fluorescence of an oxidant-sensitive probe was increased 3.5-fold with
palmitate supplementation indicating that production of reactive intermediates increased. In addition, palmitate-induced apoptosis was
blocked by pyrrolidine dithiocarbamate and
4,5-dihydroxy-1,3-benzene-disulfonic acid, two compounds that scavenge
reactive intermediates. These studies suggest that generation of
reactive oxygen species, independent of ceramide synthesis, is
important for the lipotoxic response and may contribute to the
pathogenesis of diseases involving intracellular lipid accumulation.
Palmitate-induced Apoptosis Can Occur through a
Ceramide-independent Pathway*
*
This work was supported by a National Science Foundation
graduate research fellowship (to L. L. L.), National
Institutes of Health Grant DK54268 (to J. E. S.), and
American Heart Association Grant 0040040N (to J. E. S.).The costs of publication of this article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Center for
Cardiovascular Research, Washington University School of Medicine, 660 South Euclid Ave., Box 8086, St. Louis, MO 63110-1010. Tel.: 314-362-8717; Fax: 314-362-0186;
E-mail:jschaff@imgate.wustl.edu.
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