Understanding the Contribution of Endothelial Lipid Droplet Metabolism in Cardiovascular Diseases

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Project Summary/Abstract Components of the metabolic syndrome are interconnected in a way that remains poorly understood. Obesity and hypertension are, for example, highly correlated. However, how obesity or fat intake increases blood pressure is unclear. The presence of lipid droplets (LDs) has been observed in endothelial cells (ECs) under pathological conditions. Surprisingly, however, LD biology in ECs is little studied and how altered endothelial LD metabolism affects health is entirely unknown. We now find, in preliminary data, that endothelial LDs likely contribute significantly to the progression of cardiovascular disease. To test the role of LDs in the endothelium, we have generated EC-specific adipose triglyceride lipase (ATGL) (the rate-limiting enzyme in TG hydrolysis) knockout (KO) mice. The ATGL ECKO mice had LD accumulation in numerous vascular beds and were predisposed to multiple cardiovascular diseases including hypertension and atherosclerosis. Strikingly, expression of endothelial nitric oxide synthase (eNOS), a dominant vasodilator that protects against hypertension and atherosclerosis, was suppressed in ATGL-deficient ECs both in cell culture and in vivo. eNOS expression was restored by reducing LD contents, either by increasing lipolysis or decreasing TG synthesis. These data strongly suggest that LDs are causal to the compromised eNOS expression, and led us to hypothesize that endothelial LD accumulation causes vascular dysfunction and cardiovascular disease and propose the following two aims: Aim1. To test in vivo whether LDs are responsible for impaired vasoreactivity, hypertension and atherosclerosis seen in ATGL ECKO mice by using genetic ablation of enzymes that promote TG synthesis, which we have shown to be sufficient to rescue LD content in vitro. Aim2. To investigate the mechanism by which LD accumulation leads to endothelial dysfunction. We hypothesize the existence of a LD – NF-kB – MCP1 axis as a novel mechanism for impaired eNOS expression and endothelial dysfunction in ATGL-deficient ECs. This study will elucidate largely unknown endothelial LD biology in the context of cardiovascular and metabolic disease and provide fundamental insight into the poorly understood relationship between metabolic syndrome and vascular complications of cardiovascular disease.