Palmitate-induced Apoptosis Can Occur through a Ceramide-independent Pathway*

By Laura L. Listenberger, D. Ory, J. Schaffer. Journal of Biological Chemistry, 2001

612 citations recorded by the source corpus.

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.

Subfields: Cell Biology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/b233b4cac837a3a542d9c96e80b401b4002861be

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Citations in the corpus

Serine palmitoyltransferase, a key enzyme of sphingolipid metabolism. (2003, background): “For most cell types, enhanced de novo synthesis of ceramide via SPT is required for palmitateinduced apoptosis [85,86,88,89], whereas palmitate-induced apoptosis of CHO cells is suggested to occur through a ceramide-independent, but reactive oxygen species-dependent, pathway [88].”
Molecular mechanisms of diabetic cardiomyopathy (2014, neutral): “An important underlying mechanism for lipotoxic damagemay be increased rates of apoptotic cell death, which may be due to increased ceramide biosynthesis, increased ROS production, remodelling of the mitochondrial membrane phospholipid composition, including a decrease in cardiolipin content, and in”
Saturated fatty acids induce endoplasmic reticulum stress and apoptosis independently of ceramide in liver cells. (2006, methodology): “Previous studies (7, 13, 22, 24, 32, 36) in Chinese hamster ovary (CHO) cells, cardiac myocytes, pancreatic -cells, breast cancer cell lines, and hematopoietic precursor cell lines have demonstrated that toxicity from accumulation of long-chain fatty acids is specific to or made more severe by satur”
Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: The central role of nontriglyceride fatty acid metabolites (2010, background): “For example, blocking the final step of ceramide synthesis with the fumonisin B1 did not prevent palmitate lipotoxicity in liver-derived cell lines,(51,56) and ceramides did not seem to be involved in palmitate-induced lipotoxic cell death in Chinese hamster ovary cells despite their levels being el”
Cardiac remodeling in obesity. (2008, background): “Evidence exists that increased palmitate may mediate apoptosis via ceramideindependent mechanisms despite the associated increase in ceramide content, suggesting the existence of other lipid mediators of lipoapoptosis (184, 213).”
Diabetic cardiomyopathy, causes and effects (2010, background): “Since palmitate-induced cell death in CHO was not completely prevented by inhibition of ceramide biosynthesis [27], additional mechanisms by which FA induced-cell death were proposed.”