Is Low-Density Lipoprotein Cholesterol the Key to Interpret the Role of Lecithin:Cholesterol Acyltransferase in Atherosclerosis?
2018; Lippincott Williams & Wilkins; Volume: 138; Issue: 10 Linguagem: Inglês
10.1161/circulationaha.118.035358
ISSN1524-4539
AutoresCecilia Vitali, Alan T. Remaley, Marina Cuchel,
Tópico(s)Cancer, Lipids, and Metabolism
ResumoHomeCirculationVol. 138, No. 10Is Low-Density Lipoprotein Cholesterol the Key to Interpret the Role of Lecithin:Cholesterol Acyltransferase in Atherosclerosis? Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBIs Low-Density Lipoprotein Cholesterol the Key to Interpret the Role of Lecithin:Cholesterol Acyltransferase in Atherosclerosis? Cecilia Vitali, PhD, Alan T. Remaley, MD, PhD and Marina Cuchel, MD, PhD Cecilia VitaliCecilia Vitali Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia (C.V., M.C.) , Alan T. RemaleyAlan T. Remaley Lipoprotein Metabolism Section, Translational Vascular Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (A.T.R.). and Marina CuchelMarina Cuchel Marina Cuchel, MD, PhD, Perelman School of Medicine at the University of Pennsylvania, Translational Medicine and Human Genetics, 8th Floor, Maloney Building, Room 8039, 3600 Spruce Street, Philadelphia, PA 19104. Email E-mail Address: [email protected] Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia (C.V., M.C.) Originally published4 Sep 2018https://doi.org/10.1161/CIRCULATIONAHA.118.035358Circulation. 2018;138:1008–1011Article, see p 1000Lecithin:cholesterol acyltransferase (LCAT) is the only enzyme able to esterify cholesterol on plasma lipoproteins.1 LCAT catalyzes the transfer of fatty acids from phosphatidylcholine to unesterified cholesterol, thus generating lyso-phosphatidylcholine and cholesterol esters.1 Although LCAT displays both α and β activity (toward high-density lipoprotein [HDL] and apolipoprotein B–containing lipoproteins, respectively), it is widely believed that its preferred substrates are nascent discoidal HDL, which mainly consists of unesterified cholesterol, phospholipids, and apolipoprotein A-I, the main activator of LCAT.1 The result of LCAT activity on nascent HDL particles has profound metabolic consequences. First, the conversion of unesterified cholesterol into the more hydrophobic esterified cholesterol promotes the migration of cholesterol esters to the core of spherical HDL particles, thus generating a gradient of unesterified cholesterol between the lipoprotein surface and the peripheral cell membrane.1 Furthermore, the maturation of HDL into cholesterol ester–enriched particles facilitates their further remodeling and catabolism by promoting the interaction with circulating proteins, such as cholesteryl ester transfer protein and others, and liver cell receptors such as scavenger receptor class B type I.1 Given these findings, LCAT has been proposed to play a crucial role in raising high-density lipoprotein cholesterol (HDL-C) levels in vivo and in promoting reverse cholesterol transport; however, its role in the pathogenesis of atherosclerosis remains controversial.1Reverse cholesterol transport is believed to be one of the main mechanisms through which HDL exerts a cardio-protective effect.2 LCAT activity, therefore, would be expected to be associated with protection from atherosclerosis and cardiovascular risk; however, data from human and animal studies have provided conflicting results.1 LCAT overexpression in different mouse models has been associated with either increased or decreased atherosclerosis, whereas LCAT deficiency, in general, has been associated with atheroprotection.1 In rabbits and monkeys, which, like humans, express cholesteryl ester transfer protein, increased LCAT expression improves the lipoprotein profile and may reduce atherosclerosis.1 Genome-wide association studies and mendelian randomization studies in humans confirmed the link between LCAT variants and HDL-C levels, but it did not appear to alter cardiovascular risk.3 Data from carriers of LCAT loss-of-function mutations are similarly contradictory.1,3LCAT deficiency is a rare condition associated with 2 clinically distinct syndromes: familial LCAT deficiency (FLD) and fish-eye disease (FED).1 From a biochemical point of view, FLD-causing mutations induce a complete loss of both α and β LCAT enzymatic function, whereas FED-causing mutations decrease esterification on HDL but not on apolipoprotein B–containing lipoproteins.1 Both syndromes are characterized by extremely low HDL-C levels and corneal opacity. Patients with FLD, however, manifest a more severe phenotype, which includes anemia and proteinuria that eventually progresses to renal failure, as a result of an abnormal lipoprotein, LpX, that is not present in patients with FED.1 Because of its rarity, most data reported in the literature are case reports of isolated cases and their families. Two larger cohorts have been published to date, reporting data from both homozygous and heterozygous carriers of LCAT mutations and their noncarrier family members or healthy controls. Cross-sectional analysis conducted on these 2 cohorts to assess the association with subclinical atherosclerosis has provided conflicting findings. In the Dutch cohort, mainly composed of subjects carrying FED-causing mutations, a positive association was observed between LCAT deficiency and carotid intima-media thickness.4 The opposite was found in the Italian cohort, mainly composed by subjects carrying FLD-causing mutations, in which LCAT deficiency was associated with significantly lower carotid intima-media thickness.5In the current issue of Circulation, the article by Oldoni and colleagues6 provides a key insight into the previous conflicting results. The authors reassessed the contribution of LCAT on subclinical atherosclerosis in heterozygotes from both cohorts that carried either FED- or FLD-causing mutations. Homozygous or compound heterozygous were excluded, and carriers of mutations lacking the biochemical characterization, as well. An appropriate number of controls included either noncarrier family members or healthy blood donors. Consistent with previous data, subjects carrying either FED or FLD mutations display similar significantly reduced HDL-C levels in comparison with controls. It is noteworthy that carriers of FLD mutations had a significant 20% decrease in low-density lipoprotein (LDL) cholesterol levels in comparison with both carriers of FED mutations and controls (whose LDL cholesterol levels were similar).6 Carriers of FLD mutations displayed a lower burden of subclinical atherosclerosis, with overall lower average and maximum carotid intima-media thickness that remained significant in the fully adjusted model in comparison with both controls and carriers of FED mutations.6 Carriers of FED mutations displayed a trend toward increased common carotid intima-media thickness in comparison with controls that lost its significance in the fully adjusted model.6These findings suggest that LDL cholesterol levels may drive the association between LCAT and atherosclerosis and highlight the previously unappreciated physiological role of LCAT in the metabolism of apolipoprotein B–containing lipoproteins. Although the preferred substrate for the LCAT reaction is probably nascent HDL, LCAT activity may also modulate the levels and composition of these lipoproteins. In patients with FLD, the absence of direct LCAT-mediated esterification markedly affects LDL composition, leading to the generation of particles with relatively higher phospholipid, triglyceride, and cholesterol content and predisposing to the formation of LpX.1,7 A kinetic study demonstrated that LDL clearance is accelerated in patients with FLD in comparison with controls, which is explained in part by both an increase in the clearance of abnormal LDL particles and an upregulation of LDL receptor expression in FLD subjects.7 The data presented by Oldoni et al6 support the concept that, in heterozygous subjects carrying FLD-associated mutations, the reduced LCAT β activity results in a reduction in LDL cholesterol, possibly because of altered composition and accelerated catabolism (Figure). On the contrary, in subjects carrying FED-associated mutations the LCAT residual activity ensures the formation of normally distributed cholesterol ester–enriched LDL, with atherogenic potential comparable to control subjects (Figure). These data reaffirm the central role that LDL has in driving the atherosclerotic process.Download figureDownload PowerPointFigure. Impact of complete and partial loss of LCAT function on lipoprotein metabolism and atherosclerosis.A, Normal LCAT activity: HDL particles acquire unesterified cholesterol from peripheral cells. LCAT esterifies cholesterol in HDL particles (α activity), thus promoting their conversion to spherical mature particles that can be further remodeled by circulating enzymes such as CETP that facilitates the transfer of TG from apoB-containing lipoproteins to HDL in exchange for CE. Mature HDL can transport cholesterol to the liver for excretion. In addition, LCAT esterifies cholesterol to a lesser extent in apoB-containing lipoproteins (β activity). LDL particles can be cleared by the liver through LDLR-mediated pathway or be taken up by peripheral cells. Accumulation of LDL in the arterial wall contributes to atherogenesis. B, In subjects carrying FLD-causing mutations both α and β activity are lost. Nascent HDL particles preserve their ability to promote unesterified cholesterol efflux from peripheral cells but fail to convert to mature HDL and are rapidly cleared. CE-poor LDL particles are cleared faster by the liver and may display a less atherogenic potential. C, In subjects carrying FED-causing mutations α activity is lost and HDL fate is similar to that of FLD-causing mutations. However, β activity is preserved, thus leading to the formation of CE-rich LDL particles with atherogenic potential comparable to that of control subjects. apoB indicates apolipoprotein B; CE, cholesterol ester; CETP, cholesteryl ester transfer protein; FC, free, unesterified cholesterol; FED, fish eye disease; FLD, familial LCAT deficiency; HDL, high-density lipoprotein; LCAT, lecithin:cholesterol acyltransferase; LDL, low-density lipoprotein; LDLR, low-density lipoprotein receptor; SR-BI, scavenger receptor class B type I; TG, triglyceride; and VLDL, very low-density lipoprotein.This article, however, still leaves open the question of whether the activation or inhibition of LCAT would be beneficial for the prevention of cardiovascular disease in the general population, even though it clearly elevates HDL-C.1 Since the failure of many pharmacological interventions aimed at raising HDL-C levels to improve cardiovascular outcomes,2,8 focus has shifted to the assessment of HDL function to evaluate the atheroprotective potential of HDL. What role, if any, LCAT has in modulating HDL composition and therefore determining the atheroprotective potential of HDL still remains to be carefully examined. LCAT deficiency does not seem to be associated with impaired cholesterol efflux capacity, possibly because of a relative accumulation of discoidal particles that represent an excellent substrate for the ABCA1 transporter.9 Furthermore, although HDL from LCAT-deficient patients is cleared faster from the circulation,10 it seems to display an increased atheroprotective potential.11 In healthy volunteers, a significant increase in cholesterol esterification rate and LCAT concentration is consistently observed after the administration of reconstituted HDL (apolipoprotein A-I/phosphatidylcholine discs) and following a transient increase in plasma unesterified cholesterol.12 Finally, because a growing number of studies are highlighting the incredible compositional diversity of HDL in terms of proteins, lipid, and microRNA and the realization that most of the proteins carried by HDL associate with specific HDL sizes,8 it will be important to better understand the role of LCAT in determining HDL functions, and consequently its atheroprotective potential.Despite the uncertainty about LCAT as a target for drug development, recombinant LCAT has been recently produced and shown to correct the abnormal lipoprotein phenotype in the LCAT-KO mouse,1 and, in a phase 1B study, it appeared to be safe and well tolerated.13 In a single patient with FLD treated with recombinant LCAT, it raised HDL to near-normal levels and corrected the anemia that occurs in this disorder.14 The development of an oral therapy to chronically activate LCAT may also be feasible in the future based on early success in identifying small-molecule activators of LCAT.15 A clinical trial will test the use of recombinant LCAT in patients with acute coronary syndrome as an alternative to reconstituted HDL for rapidly raising HDL. Results from this and future clinical trials will likely clarify many of the long-standing mysteries related to LCAT and whether therapies aimed at modulating its activity will translate into improved HDL function or will beneficially alter LDL particles in such a way to reduce atherosclerosis.Sources of FundingResearch by Dr Remaley is supported by intramural research funds from the National Heart, Blood, Lung Institute, National Institutes of Health. Research by Dr Vitali is supported by grants HL055323 and HL059407, and research by Dr Cuchel is supported by grant HL059407 from the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official viewpoints of the National Institutes of Health.DisclosuresDr Vitali is a former trainee in Dr Calabresi's laboratory. Dr Remaley is supported by a research grant from MedImmune.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.https://www.ahajournals.org/journal/circMarina Cuchel, MD, PhD, Perelman School of Medicine at the University of Pennsylvania, Translational Medicine and Human Genetics, 8th Floor, Maloney Building, Room 8039, 3600 Spruce Street, Philadelphia, PA 19104. Email [email protected]upenn.eduReferences1. Rousset X, Shamburek R, Vaisman B, Amar M, Remaley AT. Lecithin cholesterol acyltransferase: an anti- or pro-atherogenic factor?Curr Atheroscler Rep. 2011; 13:249–256. doi: 10.1007/s11883-011-0171-6CrossrefMedlineGoogle Scholar2. Cuchel M, Rader DJ. Macrophage reverse cholesterol transport: key to the regression of atherosclerosis?Circulation. 2006; 113:2548–2555. doi: 10.1161/CIRCULATIONAHA.104.475715LinkGoogle Scholar3. 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Lecithin:cholesterol acyltransferase activation by sulfhydryl-reactive small molecules: role of cysteine-31.J Pharmacol Exp Ther. 2017; 362:306–318. doi: 10.1124/jpet.117.240457CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Darabi M and Kontush A (2022) High-density lipoproteins (HDL): Novel function and therapeutic applications, Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, 10.1016/j.bbalip.2021.159058, 1867:1, (159058), Online publication date: 1-Jan-2022. Ding J, Zhang W, Xue F, Sun Y, Yan Q, Chen Y and Shan G (2022) Highly dispersive AuNCs/[email protected]/PEI nanocomplexes for fluorescent detection of cholesterol in human serum, Microchimica Acta, 10.1007/s00604-022-05306-5, 189:5, Online publication date: 1-May-2022. Vitali C and Cuchel M (2020) Controversial Role of Lecithin:Cholesterol Acyltransferase in the Development of Atherosclerosis, Arteriosclerosis, Thrombosis, and Vascular Biology, 41:1, (377-379), Online publication date: 1-Jan-2021.Guo M, Ma S, Xu Y, Huang W, Gao M, Wu X, Dong X, Wang Y, Liu G and Xian X (2021) Correction of Familial LCAT Deficiency by AAV-hLCAT Prevents Renal Injury and Atherosclerosis in Hamsters—Brief Report, Arteriosclerosis, Thrombosis, and Vascular Biology, 41:7, (2141-2148), Online publication date: 1-Jul-2021. September 4, 2018Vol 138, Issue 10 Advertisement Article InformationMetrics © 2018 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.118.035358PMID: 30354544 Originally publishedSeptember 4, 2018 Keywordscholesterol esterscholesterol, LDLcholesterol, HDLatherosclerosisEditorialslecithin:cholesterol acyltransferase deficiencyPDF download Advertisement
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