Myocardial ATGL Overexpression Decreases the Reliance on Fatty Acid Oxidation and Protects against Pressure Overload-Induced Cardiac Dysfunction

Abstract

Alterations in myocardial triacylglycerol content have been associated with poor left ventricular function, suggesting that enzymes involved in myocardial triacylglycerol metabolism play an important role in regulating contractile function. Myocardial triacylglycerol catabolism is mediated by adipose triglyceride lipase (ATGL), which is rate limiting for triacylglycerol hydrolysis. To address the influence of triacylglycerol hydrolysis on myocardial energy metabolism and function, we utilized mice with cardiomyocyte-specific ATGL overexpression (MHC-ATGL). Biochemical examination of MHC-ATGL hearts revealed chronically reduced myocardial triacylglycerol content but unchanged levels of long-chain acyl coenzyme A esters, ceramides, and diacylglycerols. Surprisingly, fatty acid oxidation rates were decreased in ex vivo perfused working hearts from MHC-ATGL mice, which was compensated by increased rates of glucose oxidation. Interestingly, reduced myocardial triacylglycerol content was associated with moderately enhanced in vivo systolic function in MHC-ATGL mice and increased isoproterenol-induced cell shortening of isolated primary cardiomyocytes. Most importantly, MHC-ATGL mice were protected from pressure overloadinduced systolic dysfunction and detrimental structural remodeling following transverse aortic constriction. Overall, this study shows that ATGL overexpression is sufficient to alter myocardial energy metabolism and improve cardiac function. Myocardial triacylglycerol (TG) is stored in cytosolic lipid droplets within cardiomyocytes and constitutes a critical fatty acid (FA) and energy reserve for the heart. Metabolism of cardiac TG is highly dynamic (2, 29), which likely evolved as a means to ensure continuous FA supply for mitochondrial oxidation independent of short-term fluctuations in plasma FA availability. Previous studies have shown that FAs released by intracellular TG hydrolysis contribute significantly to the generation of ATP necessary for contractile function (2, 34, 39), suggesting that TG hydrolysis plays a critical role in regulating cardiac function. In agreement with this finding, dysregulation of myocardial TG metabolism and either increased or reduced TG content have been associated with cardiac dysfunction and/or heart failure induced by obesity, diabetes, aging, ischemia, and hemodynamic pressure overload (3,5,8,22,26,(31)(32)(33)(34). Moreover, a clear correlation between increased myocardial TG content and decreased cardiac function has been established in rodents and humans (7,12,22,24), supporting the concept that excessive TG accumulation in the heart is detrimental. On the other hand, it has also been postulated that increasing TG content and sequestration of potentially lipotoxic FA metabolites in the myocardial TG pool can be beneficial for heart function (28, 42). As such, the physiological consequences of preventing myocardial TG accumulation with regard to normal physiology and disease remain to be elucidated.As the enzymes that control TG lipolysis may have an as yet und...

Multiphasic triacylglycerol dynamics in the intact heart during acute in vivo overexpression of CD36

“…This concept was recently demonstrated in the ATGL overexpressing mouse, in which protection from pressure overload-induced heart failure was conferred without an increase in LCFA oxidation, possibly due to a maintenance of normal PPAR ␣ activity ( 26 ). Interestingly, in so-called physiological or exercise-induced cardiac hypertrophy, there is an increase in CD36 expression levels ( 49 ).…”

“…The total long chain fatty acyl CoA concentration was determined as described previously by HPLC ( 25,26 ). The data was normalized to milligrams of protein by converting wet weight to milligrams of protein using the average value determined when isolating DAG.…”

Cardiac-specific overexpression of perilipin 5 provokes severe cardiac steatosis via the formation of a lipolytic barrier

“…Considering that Plin5 expression is induced by peroxisome proliferator-activated receptor (PPAR) ␣ ( 16, 28 ), a nuclear hormone receptor that regulates the expression of numerous oxidative phosphorylation genes, it may suggest that Plin5 couples LD FA release to mitochondrial FAO. However, the global deletion of Plin5 provoked a relatively mild phenotype in mice ( 29 ), although LDs were virtually absent in cardiac muscle (CM), similar to the lack of LDs in transgenic mice with cardiac-specifi c ATGL overexpression ( 30 ). Thus, it appears feasible that Plin5 primarily shields LDs from uncontrolled TG mobilization but is not critical for ATGL-mediated lipolysis and FA channeling to mitochondria.…”

The role of triacylglycerol in cardiac energy provision

“…Heart-specific ATGL overexpression decreased mTAG, and surprisingly, decreased cardiac FA oxidation, supporting a role for a mTAG pool to facilitate FA flux to mitochondria. In addition, improved cardiac systolic function and protection from pressure-overload stress remodelling was seen in older mice overexpressing ATGL [114]. ATGL overexpression maintained cardiac energetics (ATP; PCr:ATP) and function in high fat fed mice, but exogenous NEFA oxidation was halved, suggesting preferential utilisation of endogenous lipids from the mTAG pool [139].…”

“…1). mTAG buffers excess, potentially toxic FAs (especially at times of increased NEFA flux-uptake and/or limited FA oxidation), hence its putative role in lipotoxicity [113,114]. However, its utilisation for ATP synthesis depends on oxidative metabolism, and the oxygen required for this must be derived from the coronary blood this raises a paradox, since if blood flow is sufficient to provide oxygen for mTAG-FA oxidative metabolism, then it should also be able to provide blood-borne substrates.…”