A combination of this methodology along with HDL CEC quantification and advanced modalities in imaging, such as intravascular ultrasonography, optical coherence tomography, and near-infrared spectroscopy to facilitate in situ plaque imaging may together provide a better assessment of whole-body RCT capacities in humans and allow for clinical testing of new drugs for the treatment of CAD.128. 32 0 obj The enzymes, regulation, and genetics of bile acid synthesis. MiR-33 contributes to the regulation of cholesterol homeostasis. Proteomic diversity of high density lipoproteins: our emerging understanding of its importance in lipid transport and beyond. To prevent toxicity, surplus cholesterol is effluxed from the cells to extracellular acceptors or converted to cholesteryl ester (CE) and stored in cytosolic lipid droplets (LDs). Nuclear receptors as potential targets for modulating reverse cholesterol transport. endobj Artery tertiary lymphoid organs: powerhouses of atherosclerosis immunity. All mammalian cells require cholesterol, with the highest concentration in the plasma membrane and the lowest in the endoplasmic reticulum (ER) membrane. x�+� � | RAGE suppresses ABCG1-mediated macrophage cholesterol efflux in diabetes. endstream x�+� � | Subendothelial lipoprotein retention as the initiating process in atherosclerosis: update and therapeutic implications. <>>>/BBox[0 0 595.44 841.68]/Length 116>>stream 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. Plasma apolipoproteins AI, AII, B, CI, and E are glucosylated in hyperglycemic diabetic subjects. Diabetes-mediated myelopoiesis and the relationship to cardiovascular risk. [1][2][3] The protective functions of HDL are due to its role in reverse cholesterol transport (RCT) but also may be related to antioxidant and anti-inflammatory activities. 38 0 obj Macrophage reverse cholesterol transport: key to the regression of atherosclerosis? 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).1 This landmark discovery inspired investigations into the mechanisms by which HDL confers atheroprotection, leading to the identification of the reverse cholesterol transport (RCT) pathway.2 RCT is defined as the process by which cholesterol moves out of cells in peripheral tissues (including foam cells in atherosclerotic plaques), enters the circulation, and is excreted in the feces. Ablation of neutral cholesterol ester hydrolase 1 accelerates atherosclerosis. ATP binding cassette A1 (ABCA1) mediates microparticle formation during high-density lipoprotein (HDL) biogenesis. <>stream 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). endstream HDL-mimetic PLGA nanoparticle to target atherosclerosis plaque macrophages. <>>>/BBox[0 0 595.44 841.68]/Length 116>>stream This process is essential to RCT given that just 5% of plasma apoA-I exists as pre-β-HDL, the principal acceptors of cholesterol from peripheral cells.138,179,180 Proteomic analyses reveal that the composition of HDL is more complex than anticipated, containing ≈200 diverse proteins distributed among various HDL subclasses. endobj Increased phospholipid transfer protein activity associated with the impaired cellular cholesterol efflux in type 2 diabetic subjects with coronary artery disease. 19 0 obj x�S�*�*T0T0 B�����i������ yA$ High-density lipoproteins: biology, epidemiology, and clinical management. endstream x�%�A�0����/5A:m��=�\�H��1c�=6o�nB�aQCzb�,,�Q�sYW�H�FiR߅}ֈa��Wc��G���O����Mh�3�6d�K�>��2�v2v��.� }� Krüppel-like factor 4 regulates macrophage polarization. <>stream 6 0 obj �}��=$�6��ޓ�O�O���{�P"�N)�u͂�۪��`�Bp\�!���Zn��ۯ�߫��[�����A�xA���8|CwM��4A� �){���y8���ҵ�O���%���xޞ����������_�i+��.Ƈ_��M�|���G ����zD����H}���_����ۃ�)�I'�\t|�.7�.�'�N�鯖���Ysԉ��ZYĭ�_l�����A4�o�~�zMĐ���������~�n]e���}Xkf�a.A5���6x��\�Au��}<=�v�_�����Xa+�1P�>Cg�K�?�<0�}��z���z_���ׯ_���-4��?���x6���������~�߯�k�����a�/�������"�o������������I9�����P�&�`�+����� �x�1п�/y��[l}�������~���>���>���q�� � 27 0 obj Extensive proliferation of a subset of differentiated, yet plastic, medial vascular smooth muscle cells contributes to neointimal formation in mouse injury and atherosclerosis models. Inhibition of miR-33a/b in non-human primates raises plasma HDL and lowers VLDL triglycerides. x�S�*�*T0T0 B�����i������ ye( Cholesterol and phospholipid efflux from cultured cells. x�S�*�*T0T0 B�����i������ yJ% <>stream Reverse cholesterol transport is a multi-step process resulting in the net movement of cholesterol from peripheral tissues back to the liver first via entering the lymphatic system, then the bloodstream. Lipoprotein remodeling generates lipid-poor apolipoprotein A-I particles in human interstitial fluid. endstream Mechanisms and consequences of cellular cholesterol exchange and transfer. Mireille Ouimet, University of Ottawa Heart Institute, 40 Ruskin St, Room H4229, Ottawa, ON K1Y 4L7, Canada, Email, Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa Heart Institute, University of Ottawa, Canada (M.O.). 24 0 obj Lipid incorporation inhibits Src-dependent assembly of fibronectin and type I collagen by vascular smooth muscle cells. VSMC plasticity in atherosclerosis is well recognized; for example, in the media of atherosclerotic arteries, they are considered to be contractile and can become proliferative, migrate to the intima, where they are synthetic, and exhibit the loss of many markers of the VSMC in the contractile state, such as smooth muscle cell actin and myosin heavy chain.30 Though it has been long appreciated that VSMC in the intima can also take up cholesterol through a variety of pathways,29,65,66 phenotypic changes in these VSMC-foam cells at the molecular level had not been systematically studied. MicroRNAs are transported in plasma and delivered to recipient cells by high-density lipoproteins. x�+� � | 13 0 obj x�S�*�*T0T0 B�����i������ yw* Whether foam cells of VSMC origin can also emigrate from plaques and the extent to which they may do so relative to classical macrophage foam cells remains to be determined. endstream Dallas, TX 75231 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. Preclinical reversal of atherosclerosis by FDA-Approved compound that transforms cholesterol into an anti-inflammatory “Prodrug”. Macrophage cholesterol efflux is a central step in reverse cholesterol transport, which helps to maintain cholesterol homeostasis and to reduce atherosclerosis. endstream 33 0 obj LIPA variants in genome-wide association studies of coronary artery diseases: loss-of-function or gain-of-function? The not-so-simple HDL story: is it time to revise the HDL cholesterol hypothesis? 3 0 obj Red blood cells play a role in reverse cholesterol transport. Three conceptual approaches to enhancing RCT have been proposed: (1) improve macrophage cholesterol efflux, (2) improve HDL functionality (ie, its capacity to accept or transport cholesterol), and (3) improve hepatic cholesterol uptake and biliary/intestinal excretion.88 As research has continued, this third possibility has been informed by mounting evidence that several HDL-independent routes can promote RCT and that cholesterol removal from the body may not require hepatobiliary cholesterol excretion.89 Thus, the term RCT currently encompasses all potential routes of net cholesterol flux from peripheral tissues into the feces,90 including artificial ones that have therapeutic potential. 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. endobj It is well established that cholesterol ester-enriched foam cells are the hallmark of atherosclerotic plaques. 1-800-242-8721 Effect of serial infusions of CER-001, a pre-β high-density lipoprotein mimetic, on coronary atherosclerosis in patients following acute coronary syndromes in the CER-001 atherosclerosis regression acute coronary syndrome trial: a randomized clinical trial. This controversy, however, should not negate the strong experimental evidence that a major function of HDL particles is to mediate RCT and that an increased understanding of the mechanisms by which this is accomplished represents a chance to revise and refine the HDL hypothesis. 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). endobj endobj This is the process whereby, as the HDL particles move through the circulation, they extract free cholesterol from less-dense particles throughout the circulatory tree, thereby reducing the overall level of total cholesterol. On balance, the evidence still argues for further research to better understand how HDL functionality contributes to RCT to develop prevention and treatment strategies to reduce the risk of cardiovascular disease. 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). Factors to consider about the functionality of HDL include its pleiotropic actions besides cholesterol efflux. endobj This consists of injecting macrophages loaded with radiolabeled cholesterol into the peritoneal cavity of mice, and measuring the appearance of the radiolabel into the plasma, liver, and feces over time.124 The major limitation of this assay is that it does not consider the bidirectional movement of cholesterol in and out of macrophages, and thus one cannot draw conclusions about the net outward flux of cholesterol mass. Reductions in the expression levels of these receptors resulted in decreased cholesterol efflux to apoA-I and HDL.163 Further, consistent with other studies,165–169 it was found that diabetes mellitus enhanced both atherosclerosis progression and impaired regression and that global deletion of RAGE overcame these defects by restoration of ABCA1 and ABCG1, promoting macrophage CEC despite ongoing hyperglycemia.163,170. In addition to being essential for the removal of cholesterol from plaque macrophages,28 ABCA1 and ABCG1 regulate the proliferation of hematopoietic stem and progenitor cells to control the abundance of blood monocytes.27 Given the link between myelopoiesis and CVD risk,130,171 suppression of this process is likely to directly inhibit the progression of atherosclerotic lesions and promote lesion regression.166 Diabetes mellitus can suppress hematopoietic precursor cell ABCA1 and ABCG1 levels, promoting myelopoiesis and atherosclerosis.165 Furthermore, inhibition of miR-33, a negative regulator of cellular ABCA1 and ABCG1, suppresses leukocytosis and reduces plaque macrophage inflammation in diabetic mice.165 Despite persisant hyperglycemia, suppression of miR-33 not only restored essential cholesterol transporters and reduced myelopoiesis, but it also promoted inflammation resolution in established plaques. HDL-C is considered "good cholesterol" because of the physiologic function it performs in "reverse cholesterol transport." Literature Review. Isolation of high-density lipoproteins for non-coding small RNA quantification. Retroendocytosis pathway of ABCA1/apoA-I contributes to HDL formation. Keywords HDL , HDL receptor , reverse cholesterol transport , selective cholesterol uptake Free cholesterol in nascent HDL is then esterified by the enzyme lecithin-cholesterol acyl transferase (LCAT), producing mature HDL. LXR-induced redistribution of ABCG1 to plasma membrane in macrophages enhances cholesterol mass efflux to HDL. Association between blood glucose variability and coronary plaque instability in patients with acute coronary syndromes. The human ABCA1 transporter nuclear receptors as potential targets for modulating reverse cholesterol transport traditionally referred as. 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In ApoE-deficient mice more effect than low intensity exercise on RCTr elements vivo method for measuring cholesterol efflux! Phosphatidylcholine therapy story: is it time to revise the HDL proteome: a in.

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