Vascular ATGL-dependent lipolysis protects endothelial function against exogenous lipids overload; involvement of endogenous cPLA2–PGI2 pathway

Abstract

Abstract Adipose triglyceride lipase (ATGL) is involved in lipolysis and displays detrimental pathophysiological role in cardio-metabolic diseases. However, the organo-protective effects of ATGL-induced lipolysis were also suggested. The aim of this work was to characterize the function of lipid droplets (LDs) and ATGL-induced lipolysis in the regulation of endothelial function. ATGL-dependent LDs hydrolysis and cytosolic phospholipase A2 (cPLA2)-derived eicosanoids production were studied in the aorta, endothelial and smooth muscle cells exposed to exogenous oleic acid (OA) or arachidonic acid (AA). Functional effects of ATGL-dependent lipolysis was studied in vitro in endothelial barrier integrity assay and in vivo in relation to postprandial endothelial dysfunction. The formation of LDs was invariably associated with elevated production of endogenous AA-derived prostacyclin (PGI2). In the presence of the inhibitor of ATGL or the inhibitor of cytosolic phospholipase A2,, production of eicosanoids was reduced, with concomitant increase in the number of LDs. OA administration impaired endothelial barrier integrity in vitro that was further impaired if OA was given together with atglistatin. In vivo, olive oil induced postprandial endothelial dysfunction that was significantly deteriorated by ATGL inhibition. In summary, vascular lipid droplets formation was associated with ATGL- and cPLA2-dependent PGI2 production from endogenous AA. The inhibition of ATGL resulted in an impairment of endothelial barrier function in vitro and deterioration of endothelial function upon exposure to olive oil in vivo. These results demonstrate that vascular ATGL-cPLA2-PGI2−dependent pathway activated by lipid overload and linked to LDs formation in endothelium and smooth muscle cells has a vasoprotective role and counterbalances detrimental vascular effects of lipid overload.