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  • br Author Contributions br Funding Canadian


    Author Contributions
    Funding Canadian Institutes of Health Research, operating grant NMD-83126 and the internal funding from the National Research Council Canada, Charlottetown, PE, Canada.
    Disclosure Statement
    Introduction Cholesterol is an essential structural component of the plasma membrane, where it maintains a barrier between Beta-Lapachone and the environment, regulates permeability and fluidity and creates “lipid rafts” by gathering a variety of signaling molecules. In mammals, it also serves as the substrates for synthesis of steroid hormones, vitamin D and bile acids. An insufficient supply of cholesterol produces detrimental effects on cell function, tissue development and whole-body physiology. However, excessive cholesterol or hypercholesterolemia has pathological consequences. Atherosclerosis is the pathological basis of most cardiovascular disease (CVD), including myocardial infarction, stroke, and peripheral artery disease [1]. The formation of atherosclerotic lesions is a chronic process characterized by excessive cholesterol deposition in the arterial intima. Clinical trials and animal studies have established a direct correlation between plasma cholesterol levels and the incidence of CVD, which is the leading cause of death and disability worldwide [[2], [3], [4]]. Due to the importance of cholesterol in cell biology, the mammals have evolved several cellular and systemic mechanisms for maintaining cholesterol homeostasis in the body. Reverse cholesterol transport (RCT), originally proposed by Glomset et al. in 1973 [5], is a physiological process in which excess peripheral cholesterol is transported by high-density lipoprotein (HDL) to the liver for excretion into the bile and feces. It has been believed as a critical mechanism by which HDL protects against atherosclerosis [6]. However, knockout of ATP-binding cassette transporter A1 (ABCA1), lecithin:cholesterol acyltransferase (LCAT) or apolipoprotein A-I (apoA-I) in mice has no effects on fecal neutral sterol content despite extremely low plasma levels of HDL cholesterol (HDL-C), suggesting the existence of an HDL-independent pathway for the body to eliminate excess cholesterol [[7], [8], [9]]. RCT reveals only a small portion of cholesterol transport and metabolism. Other pathways including intestinal cholesterol absorption, modified lipoprotein influx into peripheral cells, and hepatic low-density lipoprotein (LDL) particle uptake are also essential for maintaining overall cholesterol homeostasis [[10], [11], [12]]. Currently, to the best of our knowledge, there is no model available to describe the process from the initial intestinal cholesterol absorption to the final fecal excretion. Thus, we propose a working model named cholesterol transport system (CTS), as shown in Fig. 1. This model not only includes the traditional RCT pathway but also refers to additional steps, such as cholesterol absorption in the small intestine, cholesterol influx and esterification in peripheral cells, LDL uptake by the liver, and transintestinal cholesterol excretion (TICE). Extensive studies have shown that dysregulation of the CTS is a primary cause for hypercholesterolemia and atherogenesis [[13], [14], [15]]. A variety of drugs targeting the CTS are currently under development, some of which have shown promise for decreasing major cardiovascular events in CVD patients [16,17]. In this review, we describe the biological processes of the CTS and summarize the current knowledge about its role and therapeutic implications in atherosclerosis.
    Dietary and biliary cholesterol absorption Humans obtain cholesterol mainly through two pathways: de novo biosynthesis and absorption from daily diet and bile. Since de novo biosynthesis of cholesterol consumes abundant energy, the body has evolved to take up readily available cholesterol molecules from the gut lumen and bile. Niemann-Pick C1-Like 1 (NPC1L1), a homolog of NPC1 protein, has been proven to be responsible for this process [10]. NPC1L1 contains three large extracellular loops, an N-terminal domain (NTD), 13 transmembrane helices, seven small cytoplasmic loops and a less conserved C-terminal cytoplasmic tail [18]. Five of the 13 transmembrane helices form a sterol-sensing domain (SSD) that is also present in several other proteins involved in cholesterol metabolism including NPC1, 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase and Patched [19]. The SSD is sensitive to intracellular cholesterol content and thus directs NPC1L1 shuttling between the endocytic recycling compartment (ERC) and plasma membrane [20]. When cells are rich in cholesterol, NPC1L1 translocates to the ERC, leading to inhibition of cholesterol absorption. In the presence of low intracellular cholesterol concentrations, NPC1L1 returns to the cell surface for cholesterol uptake. In addition, sterol binding pocket within the NTD of NPC1L1 can directly interact with cholesterol, leading to the conformation change of NPC1L1 and subsequent cholesterol entry [21].