Understanding the Contribution of Endothelial Lipid Droplet Metabolism in Cardiovascular Diseases

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.