In the United States, atherosclerosis is an underlying cause of endothelial dysfunction, chronic peripheral vascular disease, and subsequent heart attack or stroke, thereby increasing morbidity and mortality (10). Obesity aggravates the progress of atherosclerosis by providing a consistent low-grade chronic inflammation that worsens cardiovascular health. Fundamentally, calorie intake (primarily from fat)-dependent inflammation is a key transition from initial atherogenesis to further advancement, leading to thrombosis as a final complication of atherosclerosis (4). Atheromas contain a yellow fatty substance that was first discovered by Virchow more than 100 years ago. Later, Windaus identified the yellow substance as cholesterol and proposed the role of lipids in the pathogenesis of atherosclerosis (8). Lipoproteins transport cholesterol and triglycer-ides in plasma to maintain homeostasis. Lipoproteins can efficiently cross the protective endothelial layer and penetrate into the intima of the artery wall and, depending on particle size, plasma concentration, blood pressure, and arterial injury, defines their affinity and ability to bind proteoglycans and to enter or leave subendothelial space. The aggregation of trig-lyceride-rich lipoproteins, including intermediate-density lipo-protein, chylomicron remnants, and very-low-density lipopro-tein (VLDL), drive the activation of leukocytes (foam cell macrophages) by enzymatic modification leading to an aggravated inflammatory response. Foam cell macrophages provoke maladaptive responses, such as activation of Toll-like receptors, the NLRP3 inflammasome and interleukin-l3, apoptosis, and other prothrombotic pathways (9). In this issue of the American Journal of Physiology-Heart and Circulatory Physiology, Fan et al. (2) recently showed that gravin is critical for lipid metabolism via the reduction of sterol regulatory element-binding proteins-2 (SREBP-2) expression, and the absence of gravin-mediated signaling delays the high-fat diet (HFD)-induced hyperlipidemia and limits atherogenesis progression to atherosclerosis.
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