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Project ATGL

Role of adipose triglyceride lipase in vascular function

Funded by FWF grants F3003 and 24005


In 2006, adipose triglyceride lipase (ATGL) has been identified as key enzyme of mammalian lipolysis, i.e. the hydrolytic cleavage of triglycerides into free fatty acids and diacylglycerols. The lipolytic cascade is completed by the action of hormone sensitive lipase (HSL) and monoglyceride lipase (MGL) which catalyze the breakdown of diacylglycerols and monoacylglycerols, respectively.

ATGL is predominantly expressed in adipose tissues but found to a lesser extent in a variety of other tissues and organs, including kidney, skeletal muscle, and heart. Systemic deletion of the ATGL gene resulted in a phenotype with massive neutral lipid accumulation in multiple tissues and cell types.

Cardiac phenotype of ATGL-/- mice

In cardiac muscle, ATGL deficiency caused an age-dependent increase of myocyte lipid droplets in number and size. Langendorff perfusion of isolated hearts demonstrated that ATGL-/- mice suffer from prominent systolic and diastolic dysfunction. Left-ventricular developed pressure as function of cardiac preload (Frank Starling relation) was significantly reduced in ATGL deficiency (A). Pharmacological challenge with increasing concentrations of the ß-adrenergic agonist norepinephrine induced a positive inotropic response in WT hearts, while ATGL-/- hearts were much less sensitive (B). (Wölkart et al. BJP 2012; 16:380-89)

Cardiac dysfunction in ATGL deficiency is associated with oxidative stress

NADPH oxidase-mediated superoxide production (measured as gp91ds-tat-inhibited chemiluminescence) was significantly increased in hearts of ATGL-/- mice. In parallel, cardiac protein expression of NADPH oxidase 2 and its cytosolic subunits gp47phox and gp91phox was upregulated indicating that ATGL-/- mice suffer from cardiac oxidative stress. (Schrammel et al. BBA 2013; 1831(11):1600-08)

Endothelium-dependent relaxation is impaired in ATGL deficiency

Vasomotor studies with aortas isolated from WT and ATGL-/- mice showed that acetylcholine-dependent relaxation was completely blunted in ATGL deficiency (A). Relaxation to the NO donor DEA/NO, a compound that directly targets smooth muscle cells, was fully preserved (B).


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