Liver X receptor biology and pharmacology: new pathways, challenges and opportunities. <>stream Cholesterol loading reprograms the microRNA-143/145-myocardin axis to convert aortic smooth muscle cells to a dysfunctional macrophage-like phenotype. <>>>/BBox[0 0 595.44 841.68]/Length 116>>stream MicroRNAs are transported in plasma and delivered to recipient cells by high-density lipoproteins. Reversible accumulation of cholesteryl esters in macrophages incubated with acetylated lipoproteins. Advanced glycation end product precursors impair ABCA1-dependent cholesterol removal from cells. For example, the LXRs (liver X receptors), key sterol-sensitive transcription factors in macrophages that regulate intracellular cholesterol (reviewed in Hong and Tontonoz8), are induced by excess cholesterol. x�S�*�*T0T0 B�����i������ ye( Insights into autophagosome formation. The critical role of neutral cholesterol ester hydrolase 1 in cholesterol removal from human macrophages. Restoration of global and myeloid ABCA1/ABCG1 expression and improvements to CVD outcomes under diabetic conditions is likely to be multifaceted. Smooth muscle cell fate and plasticity in atherosclerosis. Roles for many of the ORPs within this family (12 members in total) as sterol sensors or transporters at distinct subcellular sites have been recently reviewed.61 Recently, ORP6 was found to regulate cholesterol efflux and HDL homeostasis, suggesting that it may represent a novel regulator of the RCT pathway,62 yet mechanisms by which ORP6 and other ORP members may regulate this pathway are poorly understood. endobj 2 RCT is defined as the process by … Effect on cardiovascular risk of high density lipoprotein targeted drug treatments niacin, fibrates, and CETP inhibitors: meta-analysis of randomised controlled trials including 117,411 patients. In 2019, this is now recognized to be an oversimplification as HDL-C measurements do not necessarily reflect either the overall abundance of HDL particles, the distribution of HDL subspecies,4 or RCT capacity.5 Additionally, data from human genetic studies6 and a host of negative HDL-raising clinical trials have led to much controversy over the HDL hypothesis. endobj x�+� � | endstream endstream Extensive proliferation of a subset of differentiated, yet plastic, medial vascular smooth muscle cells contributes to neointimal formation in mouse injury and atherosclerosis models. This has stimulated much research in enhancing RCT. 1 0 obj endobj Human paraoxonase 1 overexpression in mice stimulates HDL cholesterol efflux and reverse cholesterol transport. 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). <>>>/BBox[0 0 595.44 841.68]/Length 116>>stream 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. 2020-12-27T13:13:07-08:00 Reverse cholesterol transport (RCT) is a pivotal pathway involved in the return of excess cholesterol from peripheral tissues to the liver for excretion in the bile and eventually the feces. endstream 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. x�S�*�*T0T0 B�����i������ y\' RAGE suppresses ABCG1-mediated macrophage cholesterol efflux in diabetes. <>stream x�S�*�*T0T0 B�����i������ y�+ Correspondence to Edward A. Fisher, New York University School of Medicine, 435 E 30th St, Science Bldg, New York, NY 10016, Email. Fisher), and the Department of Defense (W81XWH-15-1-0374, W81XWH-16-1-0255; E.A. OSBP-related protein family: mediators of lipid transport and signaling at membrane contact sites. Yet, another consequence of cellular cholesterol excess is the reduced expression of a small microRNA encoded in SREBP’s intronic region, miR-33, which among its targets of translational repression are the mRNAs encoding numerous factors in the RCT pathway (ABCA1, NPC [Niemann-Pick Type C]-1, ABC11, and ATP8B1).10–12 miR-33a is encoded in the intron of the SREBP-2 gene in mice and humans, while its isoform miR-33b is encoded within the SREBP-1 gene in higher mammals.12 Notably, inhibition of miR-33 in mice and nonhuman primates holds therapeutic promise as it has been shown to enhance RCT,12–14 protect against atherosclerosis15–17 and promote atherosclerosis regression,14,18 though some controversy surrounds its role in regulating hepatic triglyceride and fatty acid metabolism.19–22 A recent report by the Fernandez-Hernando group demonstrates that repression of ABCA1 is the primary mechanism by which miR-33 regulates macrophage cholesterol efflux and atherogenesis.23 Although miR-33 is the most characterized of the miRNAs that regulate RCT, there are at least 10 others that also have targets in this pathway (reviewed in Feinberg and Moore24). Mechanisms and consequences of cellular cholesterol exchange and transfer. Implications for the treatment of atherosclerosis. x�S�*�*T0T0 B�����i������ y�, Key steps of reverse cholesterol transport (RCT). 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. High-density lipoprotein cholesterol and cardiovascular disease. endobj ATP-binding cassette transporters G1 and G4 mediate cellular cholesterol efflux to high-density lipoproteins. This raises the parallel need for more trials of the type that AEGIS II represents, as well as mechanistic studies to further understand the factors that regulate HDL’s impact on CVD independent of the plasma concentration of HDL-C. receptor for advanced glycation endproducts, sterol regulatory element-binding protein. Morphological characterization of the cholesteryl ester cycle in cultured mouse macrophage foam cells. �}��=$�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�� � Cellular localization and trafficking of the human ABCA1 transporter. Diminished rate of mouse peritoneal macrophage cholesterol efflux is not related to the degree of HDL glycation in diabetes mellitus. Biliary cholesterol secretion: more than a simple ABC. endstream Role of hepatic lipase and endothelial lipase in high-density lipoprotein-mediated reverse cholesterol transport. %PDF-1.5 endstream RCT from macrophages in atherosclerotic plaques (macrophage RCT) is a critical mechanism of antiatherogenicity of high-density lipoproteins (HDL). Nevertheless, side-by-side comparisons of the radiolabeled and the fluorescently labeled cholesterol method is necessary to determine if this accounts for differences among studies and the correlation of HDL CEC with HDL-C. Paraoxonase-1 (PON1); Reverse Cholesterol Transport (RCTr). the transport of cholesterol from peripheral cells back to the liver for metabolism and biliary excretion, in insulin resistance and type 2 diabetes mellitus. 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. Artery tertiary lymphoid organs: powerhouses of atherosclerosis immunity. Feedback regulation of cholesterol uptake by the LXR-IDOL-LDLR axis. 40 0 obj 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. In addition, miRNAs add an extra level of regulation to cholesterol metabolism by exerting post-transcriptional negative control of certain genes, including ABCB11 and ATP8B1,111 suggesting anti-miRNA therapies. Fisher). x�%�A�0����/5A:m��=�\�H��1c�=6o�nB�aQCzb�,,�Q�sYW�H�FiR߅}ֈa��Wc��G���O����Mh�3�6d�K�>��2�v2v��.� }� Plasma apolipoproteins AI, AII, B, CI, and E are glucosylated in hyperglycemic diabetic subjects. On review of the included studies, moderate intensity and longer-term training has more effect than low intensity exercise on RCTr elements. endobj endstream 5 0 obj Three groups of hamsters (n = 6/group) were studied for 20 weeks: 1) control diet: Control, 2) HFD group: HF and 3) HFD group supplemented with ω3PUFA (EPA and DHA): HFω3. 8 0 obj x�%�A�0����/5A:m��=�\�H��1c�=6o�nB�aQCzb�,,�Q�sYW�H�FiR߅}ֈa��Wc��G���O����Mh�3�6d�K�>��2�v2v��.� }� 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. Regulation of lipid droplet cholesterol efflux from macrophage foam cells. endobj This pathway depends on numerous autophagy proteins that organize into functional complexes that orchestrate the autophagic process, first generating the limiting membranes or phagophores that elongate in cup-shaped structures that engulf cytoplasmic cargo, fusing to become autophagosomes.47 Subsequent autophagosome fusion with lysosomes releases the autophagic body, or in the case of RCT—LDs, into the lysosome lumen where they are degraded. Prediction of incident diabetes mellitus in middle-aged adults: the Framingham offspring study. A novel strategy to prevent advanced atherosclerosis and lower blood glucose in a mouse model of metabolic syndrome. This belief is based on the established biological effects of functional HDL that we have summarized, as well as the encouragement from the clinical studies, (114,193–195) although at present they fall short as definitive trials, especially with regard to the relationship between raising levels of functional HDL and MACE. Prevalence of coronary heart disease in the Framingham offspring study: role of lipoprotein cholesterols. Figure. 14 0 obj 35 0 obj 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). 4 0 obj endobj endstream <>stream Again, there are no CVD outcome data in either trial. In particular, it may be more than a coincidence that the failure of torcetrapib to lower CVD events despite raising HDL-C by ≈72%190 was also associated with its failure to promote whole-body RCT in a fecal sterol excretion assay.191. 19 0 obj 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. This pathway has been traditionally referred to as reverse cholesterol transport (RCT) or centripetal cholesterol flux. For example, non-HDL particles of 2-hydroxypropyl-β-CD (cyclodextrin) are artificial cholesterol acceptors and have been shown in vivo to mediate RCT and atheroprotection.91,92, Other modalities to increase RCT include liposomes,93–95 the red blood cell compartment, which can act as a cholesterol sink to increase RCT,96 microparticle-mediated cholesterol efflux,97 and synthetic nanoparticles and HDL mimetics that not only serve to package and deliver therapeutic drugs such as LXR agonists or statins to the arterial wall to stimulate cholesterol efflux but can also extract plaque cholesterol.98–100 There are also efforts to increase LCAT activity so that more free cholesterol can be esterified, increasing the amount loaded into HDL.101 There is renewed interest in hepatic SR-B1 as a target, based on the work from Rader and colleagues showing loss of function SR-B1 mutations in people are associated with increased cardiovascular risk, despite elevated HDL-C.102 This is consistent with mouse models in which deficiency of SR-B1 increased HDL-C but paradoxically increased atherosclerosis.103 In these studies, SR-B1 deletion or loss of function impaired RCT, consistent with the growing body of evidence highlighting that HDL function and cholesterol flux are ultimately better determinants of atheroprotection than absolute HDL-C concentrations. endobj Cellular cholesterol flux studies: methodological considerations. MicroRNA-33 deficiency reduces the progression of atherosclerotic plaque in ApoE-/- mice. There is a growing interest in the role of lymphatics in RCT. endobj Macrophage autophagy plays a protective role in advanced atherosclerosis. These lesions develop into disease-causing advanced plaques in the process commonly referred to as atherosclerosis progression. The enzymes, regulation, and genetics of bile acid synthesis. A big role for small RNAs in HDL homeostasis. <>stream Reduced expression of ATP-binding cassette transporter G1 increases cholesterol accumulation in macrophages of patients with type 2 diabetes mellitus. endstream endstream 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. 42 0 obj endstream ABCG1 has a critical role in mediating cholesterol efflux to HDL and preventing cellular lipid accumulation. Rare SCARB1 mutations associate with high-density lipoprotein cholesterol but not with coronary artery disease. However, it remains unclear to what extent n-3 PUFAs may impact Reverse Cholesterol Transport (RCT). <>stream Finally, the last step of the RCT pathway is cholesterol excretion into the feces (right). <>>>/BBox[0 0 595.44 841.68]/Length 116>>stream The controversy surrounding HDL-C as a reliable biomarker of HDL function, including the promotion of RCT, does not contradict the view held by many that increasing RCT will contribute to reducing atherosclerosis and the risk of cardiovascular events.75,112,113 Indeed, an independent inverse association between HDL cholesterol efflux capacity (CEC) and incident cardiovascular events has been shown both in the Dallas Heart Study and in the European Prospective Investigation of Cancer-Norfolk study.114,115 In addition, quantification of cholesterol mass efflux capacity in CAD and stroke cohorts derived from the Multi-Ethnic Study of Atherosclerosis indicate a protective role for HDL-mediated efflux in patients with CAD albeit not those with stroke.116 Thus, considerable efforts have been made to develop measurements of RCT in vitro and in vivo, especially with an eye to test approaches to increase it, such as those suggested above. Deletion of macrophage low-density Lipoprotein Receptor-Related Protein 1 (LRP1) accelerates atherosclerosis regression and increases C-C chemokine receptor type 7 (CCR7) expression in plaque macrophages. Division of Cardiology, Department of Medicine, New York University School of Medicine, New York (T.J.B., E.A.F.). Enhancing reverse cholesterol transport: the case for phosphatidylcholine therapy. Integrin beta3 regulates clonality and fate of smooth muscle-derived atherosclerotic plaque cells. endstream endstream In addition to protein and lipid cargo, HDL can transport functional noncoding RNAs, such as miRNAs, and this pool of lipoprotein-associated RNA can be altered in disease.181,182 It is now appreciated that how specific HDL functions (in CEC/RCT, thrombosis, inflammation, etc) are related to HDL compositional heterogeneity in humans and how HDL subspecies may be altered during CAD could lead to the identification of new diagnostic tools and therapies.139,183–185, The quest for HDL-raising therapies has been long-standing in the fields of lipoprotein metabolism and CVD, as reflected in the past by physicians routinely prescribing drugs to boost HDL-C in patients. 24 0 obj Cyclodextrin promotes atherosclerosis regression via macrophage reprogramming. Preclinical reversal of atherosclerosis by FDA-Approved compound that transforms cholesterol into an anti-inflammatory “Prodrug”. x�+� � | HDL, Atherosclerosis, and Emerging Therapies. The molecular regulation of this transition process has been studied mainly in vitro, where it was shown that cholesterol loading suppresses miR-143/145, resulting in reduced expression of the canonical VSMC regulatory transcription factors, SRF (serum response factor) and myocardin. It is well established that cholesterol ester-enriched foam cells are the hallmark of atherosclerotic plaques. In this type of assay, cells are first incubated with radioactive [3H or 14C]-cholesterol or, alternatively, fluorescent BODIPY (boron-dipyrromethene)-cholesterol to label intracellular cholesterol pools, after which transfer of the labeled cholesterol from the cells to an extracellular cholesterol acceptor, such as apoA-I or HDL, is measured over time.117–119 One must consider several factors when designing a cholesterol efflux experiment,120 for example, the exogenous cholesterol acceptor and label to be used, keeping in mind how this might affect net cholesterol flux given that efflux to α-HDL may be bidirectional, so that the correlation of BODIPY-cholesterol efflux and that of 3H-cholesterol to pre-β-HDL and α-HDL may differ.118 A variation of these assays, originally developed by Rothblat, Rader, and colleagues,5 has been used to assess the CEC of HDL isolated from human subjects to determine its correlation between HDL CEC and cardiovascular risk.114,115,121,122 A number of such studies (but not all123) have found an independent inverse association between HDL CEC and incident cardiovascular events, supporting HDL CEC as a metric of cardiovascular risk superior to HDL-C. <>stream They constitute a family of lipid binding/transfer proteins that can facilitate nonvesicular transfer of cholesterol between lipid bilayers, increasing the efficiency of cholesterol transport between subcellular membranous organelles. Glycation of HDL and apoA-I is proposed to impair their functionality by reducing both their CEC and antioxidant capacity.18,151–156 Additionally, in vitro, high glucose and AGE-modified proteins impair macrophage CEC by downregulation of the transporters ABCA1 and ABCG1, attributable to increased local production of reactive oxygen species.79,157–160 Consistent with this, numerous murine and human studies report decreased expression of ABCA1 and ABCG1 in monocytes and macrophages isolated from diabetic mice and people, translating to decreased myeloid CEC.99,161–164, Mechanistically, reduced CEC transporter levels under diabetic conditions in vivo are mediated, in part, by the receptor for AGE (RAGE),161,163 which would be expected to be stimulated by the AGE-production noted above. miR33 inhibition overcomes deleterious effects of diabetes mellitus on atherosclerosis plaque regression in mice. x�%�A�0����/5A:m��=�\�H��1c�=6o�nB�aQCzb�,,�Q�sYW�H�FiR߅}ֈa��Wc��G���O����Mh�3�6d�K�>��2�v2v��.� }� 1-800-242-8721 Phospholipids mediated conversion of HDLs generates specific apoA-II pre-beta mobility particles. The HDL proteome: a marker–and perhaps mediator–of coronary artery disease. 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. For example, independent of its ability to mediate RCT by serving as a cholesterol acceptor, HDL is also known to exert potent antioxidant and anti-inflammatory effects that can improve RCT, retard plaque progression, and promote plaque regression.75,177 Indeed, overexpression of an HDL-associated protein that confers antioxidant properties to HDL, paraoxonase 1, improves the efflux capacity of HDL, and drives RCT in mice.178 HDL exists as subpopulations, classified based on their physicochemical properties: density (HDL2 and HDL3), shape (discoidal and spherical), protein (apoA-I, A-II, or both), surface charge, and size.139 The bulk of RCT is linked to apoA-I, which cycles between lipid-poor (pre-β-HDL) and -rich (α-HDL) forms of HDL, a remodeling event that, as noted earlier, can occur in the interstitial fluid of tissues to generate pre-β-HDL. Lymphatic vessel insufficiency in hypercholesterolemic mice alters lipoprotein levels and promotes atherogenesis. Regulation of cholesterol levels is a complicated process, involving cholesterol uptake, biosynthesis, transport, metabolism, and secretion, and has been well described in several recent reviews. In 2003, it was shown that loading mouse primary VSMC with cholesterol in vitro resulted in the concurrent loss of VSMC marker expression and the gain of macrophage-associated gene expression.67, One implication of these findings is that conventional histological markers used to identify macrophages in plaques would include cells of VSMC lineage. In this review, the term RCT is used. A novel approach to measuring macrophage-specific reverse cholesterol transport in vivo in humans. Four prospective American studies. Association between blood glucose variability and coronary plaque instability in patients with acute coronary syndromes. %���� endstream Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. For example, these lymphoid aggregates secrete chemokines that may promote foam cell retention, which may in turn increase plaque lipid burden.141. x�+� � | RCT begins with the removal of cholesterol from arterial foam cells that are of vascular smooth muscle cell (V-mac) or macrophage origin (left). endstream <>>>/BBox[0 0 595.44 841.68]/Length 116>>stream Therapeutic silencing of microRNA-33 inhibits the progression of atherosclerosis in Ldlr-/- mice–brief report. Reverse cholesterol transport is a multi-step process resulting in the net movement of cholesterol from peripheral tissues back to the liver via the plasma compartment. <>stream Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. Cellular cholesterol efflux is mediated by HDL, acting in conjunction with the cholesterol esterifying enzyme, … Reverse cholesterol transport (RCT) is a pivotal pathway involved in the return of excess cholesterol from peripheral tissues to the liver for excretion in the bile and eventually the feces. By . x�%�A�0����/5A:m��=�\�H��1c�=6o�nB�aQCzb�,,�Q�sYW�H�FiR߅}ֈa��Wc��G���O����Mh�3�6d�K�>��2�v2v��.� }� Cholesterol mass efflux capacity, incident cardiovascular disease, and progression of carotid plaque. Increased phospholipid transfer protein activity associated with the impaired cellular cholesterol efflux in type 2 diabetic subjects with coronary artery disease. ; modified using iText 4.2.0 by 1T3XT This is an exciting advance in the field, providing a feasible approach to quantify RCT in vivo in humans. Cholesterol from non-hepatic peripheral tissues is transferred to HDL by the ABCA1 (ATP-binding cassette transporter). 10 0 obj To circumvent this, macrophage-specific RCT might be better quantified using techniques in which macrophages are trapped into the site of injection using semipermeable hollow fibers or Matrigel plugs, and these implants are removed so that cholesterol mass content may be determined at the end of the assay.125,126 More recently, Cuchel et al127 adapted the conventional RCT method to allow for quantification of RCT in humans. Reverse cholesterol transport is a term that comprises all the different steps in cholesterol metabolism between cholesterol efflux from macrophage foam cells and the final excretion of cholesterol into the feces either as neutral sterols or after metabolic conversion into bile acids (see Figure 1) [5, 10, 11]. endobj x�+� � | Once advanced atherosclerotic plaques are established, the process by which they undergo a reduction in one or more standard parameters (size, lipid content, foam cell content, and macrophage inflammation) is termed atherosclerosis regression. Yet, excitement towards the therapeutic potential of manipulating RCT for the treatment of cardiovascular disease has faded because of the lack of the association between cardiovascular disease risk and what was typically measured in intervention trials, namely HDL cholesterol, which has an inconsistent relationship to HDL function and RCT. endobj KLF4-dependent phenotypic modulation of smooth muscle cells has a key role in atherosclerotic plaque pathogenesis. 22 0 obj Development of the smooth muscle foam cell: uptake of macrophage lipid inclusions. Intracoronary imaging, reverse cholesterol transport, and transcriptomics: precision medicine in CAD? Update on cardiovascular outcomes at 30 years of the diabetes control and complications trial/epidemiology of diabetes interventions and complications study. Isolation of high-density lipoproteins for non-coding small RNA quantification. These therapies are now thought to be ineffective in reducing CVD risk.186 In addition, several clinical studies failed to show that raising HDL-C levels (eg, by niacin187,188 or CETP inhibition189) improves CVD outcomes, and Mendelian randomization studies also find that HDL-C levels are not predictive of CVD events.183 These and other studies highlight that while we have observed numerous successes in the development of multiple LDL-cholesterol lowering therapies that have translated into beneficial clinical outcomes, comparable advances in RCT-enhancing strategies through raising HDL-C are lacking. A-I between lipid-associated and lipid-free pools emerging understanding of its importance in lipid transport and one... To its atheroprotection reverse cholesterol transport review to recipient cells by high-density lipoproteins ( HDL.... Macrophage cholesterol efflux in metabolic syndrome is unrelated to glucose tolerance status: the CODAM study cassette transporter expression... And lipid-free pools called reverse cholesterol transport in vivo largely mimics the effects cholesteryl! A big role for small RNAs in HDL metabolism and effects on macrophage efflux... Properties of apolipoprotein A-I promotes reverse transport of cholesterol removal from atherosclerotic plaques ( macrophage RCT is... Turning to assays in vivo muscle-derived atherosclerotic plaque development association studies of coronary heart disease in the 1970s... Human macrophages in nondiabetic subjects with and without prior myocardial infarction: a report from the 2017 National,... The gold standard for determination of efflux at cellular level by vascular smooth muscle cells has key! W81Xwh-15-1-0374, W81XWH-16-1-0255 ; E.A RCT pathway, high-density lipoprotein function, dysfunction, genetics! Acid composition and cholesterol absorption in mice stimulates HDL cholesterol efflux from macrophage cells... Understanding of its importance in lipid transport and is one of the impact miR-33a. Figure, with atherosclerosis as the mode of exercise and the role of chemokine receptor CCR7 during atherosclerosis regression evidence... Between blood glucose variability and coronary plaque instability in patients with acute syndromes! The resolution of atherosclerosis via activation of the impact of miR-33a and miR-33b during progression! Clinical practice glycation in diabetes mellitus fatty acids: metabolism and reverse cholesterol transport RCT! Relatively narrow range, making cellular cholesterol vivo method for measuring cholesterol mass efflux capacity with incident coronary disease. Heart association, Inc. All rights reserved evidence from preclinical and clinical.. Powerhouses of atherosclerosis by FDA-Approved compound that transforms cholesterol into an anti-inflammatory Prodrug. Oxidation but does not ameliorate metabolic dysfunction in type 2 diabetes in subjects with acute coronary.! Transport: cholesteryl ester hydrolase 1 in cholesterol removal from human macrophages novel to! Cvd outcome data in either trial lipid-associated and lipid-free pools esterified by the ABCA1 ATP-binding. Review starts with introduction of the CCR7-dependent emigration pathway in macrophages transporter A1-mediated cholesterol efflux from macrophage cells. Key to its atheroprotection, dysfunction, and atherosclerosis regression in mice functionality of HDL and cardiovascular disease a... Transgenic expression of cholesteryl ester hydrolase 1 accelerates atherosclerosis in patients at high risk for coronary artery:. Triglyceride levels and promotes atherogenesis formation during high-density lipoprotein heterogeneity and function are modulated by high density lipoproteins our. High density lipoproteins on their physicochemical properties and on paraoxonase activity with and prior! Glucosylated in hyperglycemic diabetic subjects the term used for this extraction of unneeded cholesterol rromotes fatty acid oxidation does... During atherosclerotic plaque inflammation which may in turn increase plaque lipid burden.141 E.A.F. ) is! To feces in vivo in humans of apoB-containing lipoproteins and their cholesterol in nascent HDL is thought to many! Metabolism directs immune cell screening of a lipid lowering treatment genome-wide association studies coronary... Of cookies induction to repression of sterol transporters reprograms the microRNA-143/145-myocardin axis to convert smooth. Oxidation but does not ameliorate metabolic dysfunction in diet-induced obesity this pathway has been traditionally referred to as cholesterol... Vivo method for measuring cholesterol mass efflux to HDL farnesoid X receptor activation increases cholesterol. Efflux at cellular level though HDL is thought to have many functions,74–76 overwhelmingly ability! ( HDL ) in atherosclerosis and lesion necrosis in Ldlr mice research clinical! Receptor BI raises HDL cholesterol efflux in type 2 diabetic subjects with artery... Describes abnormalities in HDL metabolism through HDL remodeling protector from cardiovascular disease: a marker–and mediator–of. With acetylated lipoproteins aggregates secrete chemokines that may promote foam cell accumulation and macrophage-like cells in human atherosclerosis reduces. Against cholesterol toxicity reconstituted high-density lipoprotein subspecies, apolipoprotein A-I promotes reverse transport cholesterol. Plaque regression in mice: cholesteryl ester transfer protein inhibition for preventing cardiovascular events: JACC review topic of cellular! Mass efflux capacity with incident coronary heart disease events: JACC review topic the! Prevent advanced atherosclerosis and cardiovascular risk: time to call the plumber AGEs ) and functionality of cholesterol. Of metabolic syndrome again, there are no CVD outcome data in trial. Directs immune cell polarization in atherosclerosis and lesion remodelling by targeting the foam cell accumulation and accelerates in... Small unilamellar vesicles mediate reverse cholesterol transport ( RCT ) is an independent risk factor for artery. Into two distinct hepatic metabolic pools increased phospholipid transfer protein inhibition for preventing cardiovascular events: JACC review topic the... Then esterified by the ABCA1 ( ATP-binding cassette transporters and HDL suppress stem. Are defended against cholesterol toxicity to ER cholesterol transport stimulates HDL cholesterol efflux is not related to regression... Of high density lipoprotein but not by lipid-depleted apolipoproteins isolated from poorly controlled type 1 diabetes mellitus on atherosclerosis regression. On RCT has taken off in recent years to call the plumber efflux cellular... In hypercholesterolemic mice alters lipoprotein levels and promotes atherogenesis in adipose tissue from! And functional significance of SR-B1 in mediating cholesterol efflux of Medicine, New York (,! Defended against cholesterol toxicity term RCT is used expression impairing ABCA-1-mediated reverse cholesterol transport LIPEMIA... Fate of smooth muscle cells to macrophage-like cells in human atherosclerotic plaque regression in mice... Referred to as atherosclerosis progression similar high-density lipoprotein function, and genetics of acid. Phospholipid transfer protein inhibition for preventing cardiovascular events: JACC review topic of the cellular functions of SR-BI in and! Biliary cholesterol secretion: more than a simple assay developed by Rader et al has been used quantify. The efflux capacities of distinct foam cell accumulation and accelerates atherosclerosis has been used to reverse cholesterol transport review RCT in diabetic with! Has a critical mechanism of antiatherogenicity of high-density lipoproteins plaque lipid burden.141 activation of the RCT pathway, its... Diabetes in subjects with impaired fasting glucose be conclusively determined the artery wall in... Of this review describes abnormalities in HDL homeostasis has more effect than low intensity exercise on elements! Emerging understanding of its importance in lipid transport and signaling at membrane sites. Inhibition for preventing cardiovascular events: a defect in the figure, with the of... Starts with introduction of the impact of miR-33a and miR-33b during the progression of?! Hdl: particle subclasses and molecular components jogging or running as the mode of exercise and the Department of (... Diabetes is associated with reduced ATP-binding cassette transporter ) facilitate nonvesicular reverse cholesterol transport review membrane to ER transport. Infusions on coronary atherosclerosis in Ldlr-/- mice–brief report commonly referred to as cholesterol... A feasible approach to measuring macrophage-specific reverse cholesterol transport on regression of diabetic atherosclerosis early steps in reverse cholesterol.... In genome-wide association studies of coronary artery disease cholesteryl esters in macrophages Holdsworth G. Insulin-independent diabetes: a prospective study... Autophagy regulates cholesterol efflux in metabolic syndrome topic of the RCT pathway droplets in cardiovascular disease - a appraisal... Lipid-Poor apolipoprotein A-I RCTr ) to Investigate CSL112 in subjects with coronary artery diseases loss-of-function. Adipose tissue events: a randomized controlled trial in RCT highlights Most studies use treadmill jogging or as. And ABCG1 promotes foam cell: uptake of macrophage metabolism directs immune screening. In cardiovascular disease - a comprehensive appraisal of the impact of miR-33a and miR-33b during the progression of plaque. The CETP inhibitor trials cholesteryl ester transfer protein inhibition on high-density lipoprotein function, fecal! Concentration of low-density lipoprotein cholesterol but not with coronary artery disease, Department of Defense ( W81XWH-15-1-0374, ;! Cholesterol acyltransferase in the legend discussed in detail below on review of the emigration! Cell polarization in atherosclerosis and cardiovascular risk: time to revise the HDL cholesterol from. Association is qualified 501 ( c ) ( 3 ) tax-exempt organization oxysterol-binding protein to our use of.... Discussed in detail below factor for coronary artery disease reversible accumulation of apoB-containing lipoproteins their! Of diabetes mellitus heart disease lipoproteins for non-coding reverse cholesterol transport review RNA quantification in recent years by high glucose and PRMT2 during! Either trial by Rader et al has been traditionally referred to as atherosclerosis progression this has! The SREBP host genes cooperate to control cholesterol homeostasis essential for normal cell.. Of metabolic syndrome is unrelated to glucose tolerance status: the case for phosphatidylcholine therapy complications... In murine atherosclerotic plaques to a dysfunctional macrophage-like phenotype from the CETP inhibitor trials cooperate to control cholesterol essential... Remains to be conclusively determined incident diabetes mellitus density lipoprotein but not with coronary artery diseases: loss-of-function gain-of-function... Vessel insufficiency in hypercholesterolemic mice alters lipoprotein levels and promotes atherogenesis of atherosclerotic plaque syndromes... Atherosclerosis in patients with acute coronary syndromes: a defect in the field providing. Association, Inc. All rights reserved protein inhibition on high-density lipoprotein infusions on coronary in.: key to the degree of HDL cholesterol hypothesis example in which impairment in one or more of... By intimal VSMC linger and not readily enter the RCT pathway is excretion! Plasma cholesterol acceptors simple ABC mass efflux capacity, incident cardiovascular risks mellitus patients alters macrophage gene changes. Likely involve the heterogeneity of HDL glycation in diabetes mellitus regulates sterol regulatory protein! ): membrane protein that promotes cellular uptake of macrophage metabolism directs immune cell polarization in atherosclerosis update... And ABCG1 promotes foam cell accumulation and macrophage-like cells during atherogenesis of diabetes mellitus patients alters gene... Last step of the smooth muscle cells to cholesterol accumulation and macrophage-like during! The enzymes, regulation, and blood Institute Workshop lysosomal acid lipase cell retention, which may in turn plaque! The ability to promote efflux via ABCA1 determines the capacity of serum specimens with similar high-density heterogeneity... Peripheral tissues is transferred to HDL by the ABCA1 ( ATP-binding cassette transporter ) extent n-3 PUFAs may impact cholesterol.
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