Diabetes and obesity are both associated with lipotoxic cardiomyopathy, independent of coronary artery disease and hypertension. The role of ceramide metabolism and accumulation in the development of cardiomyopathy has been investigated in Drosophila. Systemic, adipose-specific, or heart-specific attenuation of ceramide degradative gene expression was sufficient to induce symptoms of lipotoxic cardiomyopathy, as was direct ceramide feeding. Inhibition of ceramide biosynthesis gene expression caused heart dysfunction in the opposite direction (leading to cardiac constriction as opposed to dilation), suggesting that ceramide homeostasis in cardiomyocytes is critical for optimal heart function.
Loss-of-function genotypes for the following genes have been assessed: CDase (orthologous to human ASAH2, involved in ceramide catabolism) Sk1 and Sk2 (orthologous to human SPHK1 and SPHK2, sphingosine kinases involved in regulation of sphingosine degradation); lace (orthologous to human SPTLC2 and SPTLC3, required for de novo sphingolipid synthesis); schlank (orthologous to human CERS5, CERS6, CERS2 and other ceramide synthases); ifc (orthologous to human DEGS2 and DEGS1, involved in sphingolipid biosynthesis).
For several of the orthologous human genes, including Hsap\CERS6, Hsap\CERS2, Hsap\CERS3, and Hsap\DEGS1, a construct of a tagged the wild-type gene has been introduced into flies, but none has been characterized in the context of this disease model. For Hsap\DEGS1, heterologous rescue (functional complementation) of the amorphic ifc larval lethal phenotype has been demonstrated.
[updated Nov. 2020 by FlyBase; FBrf0222196]
Studies in humans have related cardiac lipid content with disturbance of cardiac function. Diabetes and obesity are both associated with lipotoxic cardiomyopathy, exclusive of coronary artery disease and hypertension (Drosatos and Schulze, 2013, pubmed:23508767; Park and Goldberg, 2012, pubmed:22999245).
Ceramide is a major molecule in sphingolipid metabolism and has been studied extensively. In addition to its structural role in plasma membranes and lipoproteins, ceramide and its metabolites have profound effects on cellular signaling, such as apoptosis and insulin response (Park and Goldberg, 2012, pubmed:22999245).
Moderate-scoring ortholog of human ASAH2 (1 Drosophila to 1 human). Dmel\CDase shares 44% identity and 61% similarity with the human gene.
Moderate- to high-scoring ortholog of human SPTLC2 and SPTLC3 (1 Drosophila to 2 human). Dmel\lace shares 50-57% identity and 68-77% similarity with the human genes.
High-scoring ortholog of human CERS5 and CERS6; moderate-scoring ortholog of human CERS2, CERS3, CERS4 (1 Drosophila to 5 human). Dmel\schlank shares 38-42% identity and 59-62% similarity with the human genes.
High-scoring ortholog of human DEGS1 and DEGS2 (1 Drosophila to 2 human). Dmel\ifc shares 58-62% identity and 72-76% similarity with the human genes.
