Lipid droplets in the endothelium: The missing link between metabolic syndrome and cardiovascular disease? (original) (raw)

What is the importance of these findings? In addition to confirming the known link between high-fat diet and TG-rich endothelial LDs (2, 6), the data provided in Kim et al. (7) and Boutagy, Gamez-Mendez, et al. (8) reveal a mechanistic link between high-circulating, TG-rich lipoproteins and common vascular diseases that is mediated by induction of LDs in the endothelium. Specifically, the observation that endothelial LDs suppress NO synthesis and induce a proinflammatory state provides a mechanistic link between endothelial LDs and both hypertension and atherosclerosis. Further, these papers highlight a pathogenic role of TG-rich LD in the context of ATGL deletion, in contrast to the more traditionally accepted view where TG synthesis is thought to buffer against lipid-induced ER stress. A direct role of TG levels in cardiovascular disease has been controversial, as mechanistic studies have been lacking. While high circulating LDL cholesterol is causally linked with atherosclerosis, there is still residual risk for cardiovascular disease in patients taking statins, which effectively lower LDL cholesterol. Recent data in humans with well-treated LDL but high TGs have shown that TG lowering itself with icosapent ethyl reduced acute cardiovascular ischemic events, suggesting that additional cardiovascular protection may occur from lowering TGs (9). Since acute cardiovascular events, such as unstable angina, ischemic stroke, and acute myocardial infarction, are caused by rupture of inflamed atherosclerotic plaques, both these manuscripts now provide mechanisms for how a high-fat diet and high TGs can contribute directly to hypertension and vascular inflammation via LD toxicity in the endothelium. However, there are still several unanswered questions. Interestingly, humans with ATGL mutations have been described, and these patients present with hepatomegaly, myopathy, and cardiomyopathy, but not specifically with hypertension and/or excess atherosclerosis (4). Whether this outcome is related to maintenance of some residual functional activity for the enzyme in the endothelium or some counter effect of ATGL deficiency in other tissues is not known. Interestingly, global knockout of Atgl in mice phenocopies aspects of the human syndrome, including cardiac steatosis and severe heart failure; moreover, global _Atg–_deficient mice suffered from pronounced vascular endothelial dysfunction that was rescued by PPARα agonists, which restored NO synthase enzyme activity (10).

Although both manuscripts showed that LD accumulation in the endothelium associated with decreased eNOS expression, NO production, and impaired endothelium-dependent relaxation, the direct mechanisms remain to be determined (7, 8). In addition, Kim et al. (7) further shows that these characteristics are associated with increased systemic blood pressure. However, both groups measured endothelial vasodilation in conduit vessels (aorta, carotid), which do not contribute to regulation of blood flow or blood pressure control. Examination of endothelial function in resistance vessels, which contribute to peripheral vascular resistance and hence blood pressure, would provide stronger evidence that impaired endothelial NO production mediates the blood pressure response in these models. A more substantial limitation is that both manuscripts studied the impact of LDs in endothelial cells using exclusively male animals. As such, whether these mechanisms are relevant in females cannot be inferred from either study. Obesity disproportionately affects women (11) and, when associated with metabolic syndrome, has a greater negative impact on cardiovascular outcomes in women (12). Hence, understanding molecular mechanisms linking dyslipidemia to cardiovascular disease in females is particularly important.

In sum, TG-rich LDs that form in the endothelium as a consequence of high-fat diet or due to loss of ATGL may contribute directly to cardiovascular disease by inducing vascular inflammation and promoting atherosclerosis and by suppressing NO formation to contribute to hypertension (Figure 1). The metabolic syndrome that consists of lipid changes, including raised TGs, low HDL cholesterol, and hypertension and insulin resistance, is very common in the adult population throughout the world (5). The treatment of metabolic syndrome currently requires separate agents for treating dyslipidemia and hypertension. These data suggest that enhancing TG breakdown in the endothelium could be a therapeutic target for patients with metabolic syndrome that may provide multiple benefits, and hence, warrants further exploration.