The two Cs: ceramide and cardiomyopathy

Abstract

The paper published in this issue of the Journal (1) highlights the great importance of lipid metabolism, fatty acid metabolism, and, particularly, ceramide homeostasis in cardiac function. While fatty acid is a preferred fuel for the energy of cardiac contractility, an imbalance between fatty acid and glucose metabolism may result in the generation of lipotoxic metabolites that disturb the function in the heart, in severe cases leading to cardiomyopathy, especially dilated cardiomyopathy. Rodent models of this pathology and altered metabolic homeostasis include obesity, often associated with diabetes and increases in the expression of fatty acid transport protein; of fatty acyl CoA synthase; and of either PPARa or PPARg nuclear hormone receptors regulating fatty acid metabolism. The precise mechanism of cardiac dysfunction is not fully established. The paper by Park et al. (1) represents a further probing of the model established in Goldbergʼs laboratory about 5 years ago (2). In an effort to determine the possible role of an extravascular pool of lipoprotein lipase (LPL), they developed a mouse in which LPL was expressed in and tethered to cardiomyocyte plasma membrane by a glycosylphosphatidyl inositol anchoring sequence (LPLgpi). This transgene was driven by a myosin heavy chain promoter. These mice exhibited increased lipid uptake and oxidation, ceramide accumulation, and a dilated cardiomyopathy, with decreased functional cardiomyocyte shortening. The mechanism of this cardiac dysfunction was not clear.