This method involves intravenous delivery of 3H-cholesterol nanoparticles, followed by blood and sample collection to quantify tracer counts in plasma, non-HDL, and HDL fractions, as well as fecal fractions. While RCT from macrophage foam cells requires the cholesterol pumps ABCA1 and ABCG1 (ATP-binding cassette proteins A1 and G1), mechanisms regulating RCT from intimal vascular smooth muscle cells that have transdifferentiated to macrophage-like foam cells (V-mac) are not well understood, though cholesterol efflux from V-macs appears defective relative to macrophage foam cells. Smooth muscle cell phenotypic switching in atherosclerosis. x�%�A�0����/5A:m��=�\�H��1c�=6o�nB�aQCzb�,,�Q�sYW�H�FiR߅}ֈa��Wc��G���O����Mh�3�6d�K�>��2�v2v��.� }� Enhanced atheroprotection and lesion remodelling by targeting the foam cell and increasing plasma cholesterol acceptors. Early steps in reverse cholesterol transport: cholesteryl ester hydrolase and other hydrolases. Defects in bile acid synthesis due to mutations in bile acid biosynthetic genes caused both abnormal cholesterol metabolism and bile acid metabolism, which led to cholesterol gallstone disease, dyslipidemia, and cardiovascular diseases in humans [9]. <>stream Diminished rate of mouse peritoneal macrophage cholesterol efflux is not related to the degree of HDL glycation in diabetes mellitus. Update on cardiovascular outcomes at 30 years of the diabetes control and complications trial/epidemiology of diabetes interventions and complications study. <>stream Therapeutic inhibition of miR-33 rromotes fatty acid oxidation but does not ameliorate metabolic dysfunction in diet-induced obesity. 39 0 obj In this review, we will summarize some of the potential reasons for this inconsistency, update the mechanisms of RCT, and highlight conditions in which impaired HDL function or RCT contributes to vascular disease. The nuclear hormone receptors LXR and FXR (farnesoid X receptor) are important regulators of cholesterol excretion, by controlling the transcription and activity of numerous cholesterol transporters and bile synthesis enzymes.105–107. 2 RCT is defined as the process by … microRNA-33 regulates macrophage autophagy in atherosclerosis. <>>>/BBox[0 0 595.44 841.68]/Length 116>>stream Nuclear receptors as potential targets for modulating reverse cholesterol transport. Study to Investigate CSL112 in Subjects With Acute Coronary Syndrome (AEGIS-II). The aim of this study was to investigate macrophage reverse cholesterol transport (RCT) in hamster, a CETP-expressing species, fed omega 3 fatty acids (ω3PUFA) supplemented high fat diet (HFD). LXR-mediated ABCA1 expression and function are modulated by high glucose and PRMT2. endstream ABCG1 redistributes cell cholesterol to domains removable by high density lipoprotein but not by lipid-depleted apolipoproteins. synthesis, and reverse cholesterol transport. Division of Cardiology, Department of Medicine, New York University School of Medicine, New York (T.J.B., E.A.F.). Cholesterol efflux capacity, high-density lipoprotein particle number, and incident cardiovascular events: an analysis from the JUPITER trial (justification for the use of statins in prevention: an intervention trial evaluating rosuvastatin). Role of hepatic lipase and endothelial lipase in high-density lipoprotein-mediated reverse cholesterol transport. x�+� � | Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. These results have also been replicated in studies examining the clonality of VSMC in atherosclerotic plaques in mice.70,71 The percent of the macrophage-marker positive cells of VSMC origin varied among the studies, but it was substantial in all, ranging from 30% to 70% (increasing with the stage of disease). <>stream It should be noted that in none of the studies mentioned above and in many similar ones has HDL function been ascertained, leaving open the possibility that HDL function is the key attribute for CVD risk reduction.113 HDL function as a clinically important factor has found traction not only in the aforementioned CEC studies, but also finds some support from some but not all (eg, Nicholls et al192) infusion studies of recombinant HDL and HDL-like particles. Exploiting macrophage autophagy-lysosomal biogenesis as a therapy for atherosclerosis. Paraoxonase-1 (PON1); Reverse Cholesterol Transport (RCTr). Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. The enzymes, regulation, and genetics of bile acid synthesis. 35 0 obj Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease. HDL’s cardiovascular protective effect has conventionally been attributed to its ability to act as both the acceptor of cholesterol from cells and as the cholesterol carrier in the RCT pathway, including delivery to the liver. The amount of free cholesterol is maintained in a relatively narrow range, making cellular cholesterol homeostasis essential for normal cell function. Cellular cholesterol flux studies: methodological considerations. 12 0 obj Hypoxia in murine atherosclerotic plaques and its adverse effects on macrophages. In the liver, the CE is hydrolyzed and the free cholesterol is either converted to bile acids or transported by ABCG5 and ABCG8 into the bile for excretion into the feces. Retroendocytosis pathway of ABCA1/apoA-I contributes to HDL formation. Abstract. endobj Herein, we will focus on the roles of macrophages and vascular smooth muscle cells (VSMCs) in the early steps of the RCT process, given their crucial role in the development of cardiovascular diseases (CVDs), especially atherosclerosis. Effects of cholesteryl ester transfer protein inhibition on high-density lipoprotein subspecies, apolipoprotein A-I metabolism, and fecal sterol excretion. MicroRNA-33-dependent regulation of macrophage metabolism directs immune cell polarization in atherosclerosis. Autophagy in the cellular energetic balance. Background: Cholesterol efflux as a key event in reverse cholesterol transport (RCT) is considered now as both diagnostic tool and a promising target for the treatment of atherosclerosis. The primary end point is the first occurrence of a major adverse cardiovascular event, cardiovascular death, myocardial infarction, or stroke within 90 days, and the expected completion date is 2022.187. Arteriosclerosis, Thrombosis, and Vascular Biology, https://clinicaltrials.gov/ct2/show/NCT03473223, Controversial Role of Lecithin:Cholesterol Acyltransferase in the Development of Atherosclerosis, Novel LCAT (Lecithin:Cholesterol Acyltransferase) Activator DS-8190a Prevents the Progression of Plaque Accumulation in Atherosclerosis Models, Metabolic Regulators of Vascular Inflammation, LDL Receptor Regulates the Reverse Transport of Macrophage-Derived Unesterified Cholesterol via Concerted Action of the HDL-LDL Axis, Vascular Health and Biology/Thrombosis (Clinical). Mechanisms and consequences of cellular cholesterol exchange and transfer. For example, these lymphoid aggregates secrete chemokines that may promote foam cell retention, which may in turn increase plaque lipid burden.141. endstream endobj Among blood plasma lipoproteins that transport lipids in the organism, a significant role belongs to high-density lipoproteins (HDL). receptor class B, type I (SR-BI): membrane protein that promotes cellular uptake of cholesteryl esters. HDL cholesterol efflux capacity and incident cardiovascular events. endobj endobj Lymphatic capillaries have been localized in the adventitia of atherosclerotic plaques, where they play an important role in the drainage of local inflammatory cells and cytokines and protect against atherosclerosis development.135 The lymphatic vasculature is also critical for the removal of cholesterol from macrophages in RCT, accounting for 50% of cholesterol delivery from cholesterol-loaded macrophages into the plasma compartment.136 Moreover, lymphatic insufficiency in mice disrupts proper lipoprotein metabolism (eg, elevated cholesterol and triglyceride levels in VLDL and LDL fractions) and vascular homeostasis, leading to accelerated atherosclerosis.137 These findings are in agreement with previous studies showing that interstitial fluid supports RCT; whereas plasma mainly contains α-HDL particles that are the predominant carriers of CE to hepatocytes, interstitial fluid provides a metabolic environment that drives the conversion of α-HDL to pre-β-HDL, the main acceptor of free cholesterol from peripheral tissues.138. endobj We will also discuss other aspects of the RCT pathway, including its quantitative assessment in vitro and in vivo. <>stream Development of the smooth muscle foam cell: uptake of macrophage lipid inclusions. RCT describes a mechanism by which excess cholesterol from peripheral tissues is transported to the liver for hepatobiliary excretion, thereby inhibiting foam … endstream The Framingham Heart Study in the 1960s was the first study to report inverse associations between cardiovascular risk and plasma HDL-C (high-density lipoprotein cholesterol). The cholesteryl ester cycle in macrophage foam cells. HDL particles can be partitioned into several subclasses according to the specific isolation or separation technique applied.139 By ultracentrifugation, 2 HDL subclasses can be obtained: HDL2 (1.063–1.125 g/mL) and HDL3 (1.125–1.21 g/mL). x�+� � | Contribution of intimal smooth muscle cells to cholesterol accumulation and macrophage-like cells in human atherosclerosis. Four prospective American studies. Advanced glycation end-products (AGEs) and functionality of reverse cholesterol transport in patients with type 2 diabetes and in mouse models. <>stream endstream endobj This can occur through biliary cholesterol excretion or transintestinal cholesterol efflux (TICE) that mediate ≈25% and 33% of total fecal neutral sterol loss, respectively. Human paraoxonase 1 overexpression in mice stimulates HDL cholesterol efflux and reverse cholesterol transport. <>stream Structure of the human lipid exporter ABCA1. Ablation of neutral cholesterol ester hydrolase 1 accelerates atherosclerosis. <>>>/BBox[0 0 595.44 841.68]/Length 116>>stream Reverse cholesterol transport (RCT) is a complex process ensuring the efflux of cholesterol from peripheral cells and its transport back in the liver for its metabolism and biliary excretion. <>>>/BBox[0 0 595.44 841.68]/Length 116>>stream Reverse cholesterol transport and atherosclerosis. Therefore, RCT to the liver of cholesterol derived from peripheral cells in humans involves 2 routes; (1) direct (HDL-SR-B1) and (2) indirect (HDL-LDL/VLDL-liver LDLR). In particular, atherosclerosis development is associated with a progressive defect in autophagy in cells positive for macrophage markers MOMA-2 (monocyte/macrophage antibody) and CD11b in the plaque,49 and defective clearance of cargo tagged by the autophagy marker p62/SQSTM1 is readily observed by detection of its accumulation in whole aortic protein lysates.49,50 Further, inhibition of autophagy pathways in mice promotes atherosclerosis development by reduced lipophagy and lysosome-mediated cholesterol cellular efflux, which contributes to inflammasome hyperactivation, elevated cell death, and defective efferocytosis within plaques.36,49,51 A critical role for autophagy and lysosomal biogenesis to suppress atherosclerosis development is supported by studies showing that systemic miR-33 inhibition or macrophage overexpression of the master transcriptional regulator of autophagy and lysosomal genes, TFEB (transcription factor EB), restores plaque macrophage autophagy, improves efferocytosis and inflammation, and ultimately reduces atherosclerosis burden.50,52, The routes by which free cholesterol generated at the site of lipid lipolysis (within lysosomes or at the LD surface) reaches the ABCA1 and ABCG1 cholesterol transporters on the plasma membrane depends on both vesicular and nonvesicular trafficking pathways, although the precise mechanisms are poorly characterized.53,54 The general working hypothesis is that cholesterol transporters sit at the plasma membrane and await delivery of cholesterol to be effluxed; but, this is an oversimplification as these can be motile, as exemplified by ABCA1 that continuously shuttles between the plasma membrane and endolysosomal compartments.55 This shuttling is a regulated process that is impeded by hypoxia.56,57 ABCG1 relocalizes from the Golgi and ER to the plasma membrane following LXR activation to stimulate efflux to HDL.58 This involves ABCG1 concentrating on intracellular endocytic vesicles (eg, recycling endosomes) to apparently redistribute sterols to the plasma membrane outer leaflet on fusion, so that cholesterol desorbs to exogenous lipid acceptors such as HDL.59 Transporters that possess distinct subcellular localizations likely preferentially efflux cholesterol from specific intracellular pools; for instance, apoA-I/ABCA1 retroendocytosis is required for efficient cholesterol efflux under lipid-loaded conditions60 and conversely, ABCA1-mediated cholesterol efflux is primarily dependent on autophagy for its cholesterol source.45, Another cholesterol trafficking pathway is mediated by OSBP (oxysterol-binding)-ORPs (related proteins). 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