Abstract
Ceramide is among a number of potential lipotoxic molecules that are thought to modulate cellular energy metabolism. The heart is one of the tissues thought to become dysfunctional due to excess lipid accumulation. Dilated lipotoxic cardiomyopathy, thought to be the result of diabetes and severe obesity, has been modeled in several genetically altered mice, including animals with cardiac-specific overexpression of glycosylphosphatidylinositol (GPI)-anchored human lipoprotein lipase (LpL(GPI)). To test whether excess ceramide was implicated in cardiac lipotoxicity, de novo ceramide biosynthesis was inhibited pharmacologically by myriocin and genetically by heterozygous deletion of LCB1, a subunit of serine palmitoyltransferase (SPT). Inhibition of SPT, a rate-limiting enzyme in ceramide biosynthesis, reduced fatty acid and increased glucose oxidation in isolated perfused LpL(GPI) hearts, improved systolic function, and prolonged survival rates. Our results suggest a critical role for ceramide accumulation in the pathogenesis of lipotoxic cardiomyopathy.
Highlights
Ceramide is among a number of potential lipotoxic molecules that are thought to modulate cellular energy metabolism
DAG was elevated in LpLGPI hearts, but myriocin had no effect on cardiac DAG levels (Table 2)
Acyl CoAs were reduced in LpLGPI hearts, and myriocin treatment restored them to WT levels (Table 2)
Summary
Ceramide is among a number of potential lipotoxic molecules that are thought to modulate cellular energy metabolism. The heart is one of the tissues thought to become dysfunctional due to excess lipid accumulation. Thought to be the result of diabetes and severe obesity, has been modeled in several genetically altered mice, including animals with cardiac-specific overexpression of glycosylphosphatidylinositol (GPI)-anchored human lipoprotein lipase (LpLGPI). In addition to triglyceride (TG), these tissues have increased levels of FAs, fatty acyl CoA, diacylglycerol (DAG), and ceramide [3, 4]. We have previously studied mice with cardiomyocyte overexpression of a glycosylphosphatidylinositol (GPI) membrane-anchored form of lipoprotein lipase, denoted LpLGPI, that develop dilated cardiomyopathy [19]. These hearts have an accumulation of ceramide. We show that ceramide accumulation plays a significant role
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