Abstract 1386: Inhibition Of Ceramide Biosynthesis Decreases Cardiomyopathy In Lipoprotein Lipase (LpL) Lipotoxicity
Cardiac specific overexpression of glycosylphosphatidylinositol (GPI)-anchored human LpL (hLpLGPI) leads to lipid-induced cardiomyopathy. Fatty acid (FA) oxidation was increased and glucose oxidation was decreased in isolated perfused hLpLGPI hearts. We hypothesized that excess FA uptake into the hearts increases ceramide and this alters glucose utilization and increases myocellular apoptosis, and causes dilated cardiomyopathy in hLpLGPI mice. To test this hypothesis, we inhibited cardiac ceramide by two methods: treatment with myriocin, a specific inhibitor of serine palmitoyltransferase (SPT) a rate-limiting enzyme in ceramide biosynthesis, and by genetic deletion. Myrioicn treatment reduced cardiac ceramide levels, ANP/BNP mRNA expression, and some, but not all, apoptosis markers. Myriocin-treated LpLGPI mice had improved systolic function and survival compared to untreated hLpLGPI controls, however, survival was still reduced compared to control mice. 2-deoxyglucose, which was increased in lipotoxic hLpLGPI hearts, was normalized by myriocin. Glycogen accumulation in hLpLGPI hearts was reduced. Heterozygous deletion of LCB1, a SPT subunit, reduced cardiac ceramide levels in LpLGPI to the levels in wild type mice and improved systolic function. Our results suggest a critical role for ceramide accumulation in the pathogenesis of the hLpLGPI mouse cardiomyopathy. Pharmacological and genetic inhibition of ceramide biosynthesis may also improve heart function in other lipid-driven cardiomyopathies.