## 1 Introduction
### Cholesterol and Atherosclerosis  
Since atherosclerosis is an immuno-metabolic disorder involving chronic inflammation, oxidative stress, epigenetics, metabolic dysfunction, neovascularization, vascular proliferation, apoptosis, matrix degradation, and thrombosis, atherosclerotic plaque formation involves many metabolic pathways. The process of atherosclerotic plaque formation begins with the recruitment of monocytes. They are taken up and migrate across the endothelium by selectins, mainly P-selectin [13]. By binding integrins to the vascular cell adhesion molecule (VCAM-1) and the intercellular adhesion molecule (ICAM-1) in the endothelium, monocytes remain firmly attached to the endothelium. additionally, while rolling over the endothelial cells, chemokines derived from the endothelium, mostly CXCL1, CXCL2, CXCL4, and CCL5, activate monocytes [14]. The monocytes then migrate to the internal space; previously secreted chemokines maintain this process in response to signals that promote the inflammatory process. Monocyte chemoattractant protein-1 (MCP-1), produced mostly by endothelium, monocytes, macrophages, and smooth muscle cells, is the most involved in monocyte recruitment and transmigration [15]. Its expression increases after a pro-inflammatory stimulus or tissue damage [16; 17]. In the intima, depending on the microenvironment's nature, monocytes differentiate into macrophages with pro-inflammatory (M1) or anti-inflammatory (M2) phenotypes [18; 19]. M1 macrophages secrete inflammatory cytokines, chemokines, nitric oxide (NO), and reactive oxygen species (ROS), promote monocyte recruitment, and propagate inflammation. Additionally, macrophages are responsible for mediating both modified and unmodified LDL particles internalization. Lipoproteins retained in the intima are susceptible to modification, mostly oxidation, due to the inflammatory environment, which allows them to be internalized by the scavenger receptors CD36, type A scavenger receptor 1 (SRA-1), and low-density lipoprotein receptor-1 (LOX-1) [20]. It should be emphasized that the expression of these receptors does not depend on cholesterol uptake. Hence, in the atherosclerotic plaque, where oxidized LDL (oxLDL) concentration is greatly increased, cells internalize more significant oxLDL amounts [21]. In cells, oxLDL is broken down in lysosomes, and ACAT esterifies lipoprotein cholesterol in the ER. Hydrolysis of cholesterol esters stored as droplets generates free cholesterol, which is transferred from macrophages into apoA1 or HDL particles. This process is mediated by the ATP-binding cassettes A1 (ABCA1) and G1 (ABCG1) and type B scavenger receptor 1 (SR-B1), cholesterol transporters that play an essential role in mediating the efflux of cholesterol from cells and preventing the formation of foam cells [22]. The microenvironment of pro-inflammatory atherosclerotic lesions impairs the ABCA1 efflux system in M1 and M2 macrophages, favoring foam cell accumulation. Additionally, hyper uptake of lipids by macrophages sustains the inflammatory response, and oxLDL induce signaling cascades that activate NF-kB targets, promoting endothelial activation, monocytes recruitment, and formation of foam cells [23]. The differentiation of monocytes into macrophages enhances foam cell formations and enlarges the atherosclerotic lesion [24]. The accumulation of cholesterol in the subendothelial compartment promotes, inside and outside the cells, the cholesterol crystals formation and contributes to the development of atherosclerotic plaque. The plaque cholesterol crystals activate the NLRP3 inflammasome in macrophages, promoting pro-inflammatory pathways [25]. Although NLRP3 activation and assembly are not completely understood, its activation is known to lead to the activation of caspase-1, which cleaves the pro-inflammatory cytokine family interleukin 1 (IL-1) into their bioactive forms, contributing to inflammation, see [26]. CD36 receptor-mediated oxLDL uptake is believed to be responsible for NLRP3 activation.