The Role of Sphingolipid Metabolism in Obesity-Related Lipotoxic Cardiomyopathy

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DESCRIPTION (provided by applicant): Obesity and Type II Diabetes have been shown to adversely affect cardiac function. A signature set of cardiac defects arising from these conditions is generally referred to as lipotoxic cardiomyopathy (LCM). Common functional defects of LCM generally include cardiac hypertrophy, diastolic dysfunction, arrhythmia and loss of pumping power. Metabolic features of LCM include abnormal accumulation of various lipids in the heart including triglycerides, fatty acids and the bioactive sphingolipid (SL) ceramide. However, there is still a wide gap in our knowledge regarding whether ceramides and related SLs play a direct, active role in the induction or progression of lipotoxic cardiomyopathies. These questions have been difficult to answer due to the lack of a suitable genetic model. Additionally, reliable high-throughput techniques to identify and quantitate all SL subspecies (the sphingolipidome) have only recently emerged. Ceramide is well established for its role in promoting cell death (apoptosis). The SL sphingosine 1- phosphate (S1P) has been shown to play an opposing role, promoting cell survival. In this respect, the levels of ceramide and S1P act as a rheostat in regulating cell fate as well as a variety of other processes. Interestingly, preliminary data suggests that ceramide accumulation in flies induces classic hallmarks of LCM, while flies that also accumulate S1P are protected from LCM. Thus, this suggests that the ceramide: S1P rheostat may have a novel regulatory role in determining heart size, structure and function in LCM. Here, Drosophila will be used as a model organism to determine if direct accumulation of ceramide in the heart is sufficient to induce classic hallmarks of LCM. The first specific aim is to characterize the role of ceramide in induction of lipotoxic cardiomyopathy. The second specific aim is to characterize the role of sphingosine 1-phosphate (S1P) in mitigating lipotoxic cardiomyopathy. These studies will use both genetic and pharmacological approaches to manipulate the ceramide: S1P rheostat, and directly assess its effects in vivo on cardiac size, structure and function.