Abstract
Intracellular lipid accumulation in the heart is associated with cardiomyopathy, yet the precise role of triglyceride (TG) remains unclear. With exercise, wild type hearts develop physiologic hypertrophy. This was associated with greater TG stores and a marked induction of the TG-synthesizing enzyme diacylglycerol (DAG) acyltransferase 1 (DGAT1). Transgenic overexpression of DGAT1 in the heart using the cardiomyocyte- specific alpha-myosin heavy chain (MHC) promoter led to approximately a doubling of DGAT activity and TG content and reductions of approximately 35% in cardiac ceramide, 26% in DAG, and 20% in free fatty acid levels. Cardiac function assessed by echocardiography and cardiac catheterization was unaffected. These mice were then crossed with animals expressing long-chain acyl-CoA synthetase via the MHC promoter (MHC-ACS), which develop lipotoxic cardiomyopathy. MHC-DGAT1XMHC-ACS double transgenic male mice had improved heart function; fractional shortening increased by 74%, and diastolic function improved compared with MHC-ACS mice. The improvement of heart function correlated with a reduction in cardiac DAG and ceramide and reduced cardiomyocyte apoptosis but increased fatty acid oxidation. In addition, the survival of the mice was improved. Our study indicates that TG is not likely to be a toxic lipid species directly, but rather it is a feature of physiologic hypertrophy and may serve a cytoprotective role in lipid overload states. Moreover, induction of DGAT1 could be beneficial in the setting of excess heart accumulation of toxic lipids.
Highlights
Glycerol (DAG) to TG, is catalyzed by diacylglycerol acyltransferase (DGAT) enzymes
Mice—Because the myosin heavy chain (MHC)-DGAT1 transgene reduced ceramide and DAG, we studied whether the MHC-DGAT1 transgene would affect heart lipids, gene expression, or function in a model of lipotoxicity because of increased heart trapping of fatty acids
We studied how cardiac TG is modulated during exercise and whether overexpression of DGAT1 affects heart function in normal and lipotoxic hearts
Summary
The reaction was carried out at 37 °C for 5 min and stopped by adding 0.75 ml of lipid extraction solvents (chloroform/methanol in a ratio of 2:1). Lipid Extraction, TG, and Free Fatty Acid (FFA) Measurements—Lipids were assessed in hearts isolated from mice fasted for 12 h and perfused with phosphate-buffered saline. To measure TG, DAG, FFA, and ceramide, lipids were first extracted from muscles using chloroform/methanol/HCl [21]. Isolated heart muscles were first washed for 1 h at 37 °C in Krebs-Henseleit bicarbonate buffer (10 mM HEPES, pH 7.35, 24 mM NaHCO3, 114 mM NaCl, 5 mM KCl, 1 mM MgCl2, and 2.2 mM CaCl2) containing 8 mM glucose, 32 mM mannitol, and 0.1% bovine serum albumin. After washing with three times icecold phosphate-buffered saline, the tissue was homogenized, and trapped radioactivity plus total produced 3H2O were counted as fatty acid uptake.
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