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How fat kills heart cells

Droplets of stored lipids accumulate in the cytoplasm of cardiac myocytes in a variety of cardiomyopathies, ranging from such chronic conditions as diabetes and obesity to the pathology that leads to sudden death in otherwise healthy young people. Still, it has been difficult to judge whether excess lipid storage reflects some other underlying pathology or whether it contributes directly to the death of heart muscle. Chiu and coworkers have tested this matter by forcing the overproduction of long-chain fatty acyl CoA in cardiac myocytes, using an enzyme that helps retain fatty acids in the cell following uptake. As a consequence of overexpressing the acyl-CoA synthetase (ACS1), long-chain fatty acids accumulate more rapidly than the cell can consume them or dispose of them, and they are stored in the form of triglycerides and other lipids. Chiu et al. show that ACS1 transgenic lines die prematurely, at a rate proportional to the level of enzyme overexpression. In these animals, cardiac myocytes die through apoptosis and necrosis, and those cells with with large lipid inclusions are lost preferentially. Interestingly, ceramide, a lipid mediator of apoptosis, is one of the species that accumulates in the hearts of these animals. While inhibition of ceramide signaling might therefore be protective, the authors note other quantitative and qualitative features of cellular lipids — differences that could also contribute to the pathology seen in this model and, presumably, in humans with certain forms of cardiomyopathy.

Journal of Clinical Investigation. March 2001.

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