Vascular ATGL-dependent lipolysis and the activation of cPLA2-PGI2 pathway protect against postprandial endothelial dysfunction

Adipose triglyceride lipase (ATGL) plays a key role in lipolysis and is implicated in the pathophysiology of cardio-metabolic diseases. However, it has also been suggested that ATGL-induced lipolysis may have protective effects on organs. This study aimed to investigate the role of lipid droplets (LDs) and ATGL-induced lipolysis in regulating endothelial function. Researchers examined ATGL-dependent hydrolysis of LDs and the production of cytosolic phospholipase A2 (cPLA2)-derived eicosanoids in the aorta, as well as in endothelial and smooth muscle cells, which were exposed to exogenous oleic acid (OA) or arachidonic acid (AA). They also explored the functional effects of ATGL-dependent lipolysis and the activation of the cPLA2/PGI2 pathway in vivo, particularly in relation to postprandial endothelial dysfunction.

The study found that LD formation was consistently linked with Atglistatin increased production of endogenous AA-derived prostacyclin (PGI2). Inhibition of ATGL or cPLA2 led to reduced eicosanoid production and a corresponding increase in LDs. In vitro, OA administration compromised endothelial barrier integrity, and this effect was exacerbated when OA was combined with an ATGL inhibitor. Importantly, in vivo, postprandial endothelial dysfunction induced by olive oil was significantly worsened by the inhibition of ATGL, cPLA2, or the prostacyclin (IP) receptor.

In summary, the formation of vascular LDs induced by exogenous AA or OA was associated with ATGL- and cPLA2-dependent PGI2 production from endogenous AA. Inhibiting ATGL impaired endothelial barrier function in vitro, while the disruption of the ATGL-cPLA2-PGI2 pathway exacerbated endothelial dysfunction in response to olive oil in vivo. The findings suggest that the vascular ATGL-cPLA2-PGI2 pathway, activated by lipid overload and linked to LD formation in endothelial and smooth muscle cells, plays a protective role by mitigating the harmful effects of lipid overload on endothelial function.