Effects of Hormone-Sensitive Lipase Overexpression on Lipotoxic Cardiomyopathy in Mice Lacking Adipose Triglyceride Lipase

Lipotoxic cardiomyopathy, which is associated with obesity and diabetes, is characterized by intracellular triacylglycerol (TAG) droplet accumulation (steatosis). The first step of TAG hydrolysis is catalyzed by adipose triglyceride lipase (ATGL), and its deficiency results in extreme cardiac steatosis in mice and humans. Although hormone-sensitive lipase (HSL) functions as a diacylglycerol (DAG) lipase in the heart, we hypothesized that activated HSL might catalyze cardiac TAG hydrolysis. To test this hypothesis we generated transgenic mice with cardiac-specific HSL-overexpression (cHSL) and crossed them with ATGL-knockout (KO) mice. By crossing ATGL-KO and cHSL lines, we generated homozygous ATGL-KO (AKO) mice, AKO mice with cardiac HSL-overexpression (AKO/cHSL), and wild type (Wt) mice. Cardiac lipid content was measured and its function was assessed by ultrasonography. Histological investigation was performed by transmission electron microscopy. Cardiac TAG content of AKO mice was 160-fold greater than that of Wt mice, whereas that of AKO/cHSL mice was as low as that of Wt hearts. Cardiac systolic function (fractional shortening; FS) was markedly reduced in AKO mice compared to that of Wt mice (28% vs. 49%), while AKO/cHSL mice showed comparable FS to that of Wt mice (48% vs. 49%). Electron microscopy showed accumulation of huge lipid droplets, damaged mitochondria with destroyed cristae and vacuole degeneration, and disrupted intercalated discs (where gap junctions and desmosomes are localized) in the cardiomyocytes of AKO mice. In contrast, the cardiomyocytes of AKO/cHSL mice showed no such morphological characteristics. These results indicate that cardiac overexpression of HSL normalizes lipotoxic cardiomyopathy in AKO mice and suggest that activation of cardiac HSL could be a potent strategy to regulate the lipotoxic cardiomyopathies that occur in metabolic disorders.