High-density lipoprotein revisited: biological functions and clinical relevance

European Heart Journal, Год журнала: 2022, Номер 44(16), С. 1394 - 1407

Опубликована: Окт. 11, 2022

Abstract Previous interest in high-density lipoproteins (HDLs) focused on their possible protective role atherosclerotic cardiovascular disease (ASCVD). Evidence from genetic studies and randomized trials, however, questioned that the inverse association of HDL-cholesterol (HDL-C) is causal. This review aims to provide an update HDL health disease, also beyond ASCVD. Through evolution invertebrates, HDLs are principal lipoproteins, while apolipoprotein B-containing first developed vertebrates. transport cholesterol other lipids between different cells like a reusable ferry, but serve many functions including communication with inactivation biohazards bacterial lipopolysaccharides. These exerted by entire particles or distinct proteins carried rather than its cargo measured as HDL-C. Neither does HDL-C measurement reflect efficiency reverse transport. Recent indicate functional measures HDL, notably efflux capacity, numbers particles, better predictors ASCVD events Low levels related observationally, genetically, increased risks infectious diseases, death during sepsis, diabetes mellitus, chronic kidney disease. Additional, only observational, data associations low various autoimmune cancers, well all-cause mortality. Conversely, extremely high associated risk age-related macular degeneration (also genetically), encompasses dynamic multimolecular multifunctional likely emerged several physiological roles prevent heal pathologies For any clinical exploitation indirect marker must be replaced direct biomarkers reflecting causal respective

Язык: Английский

---

A Comparison of the Mouse and Human Lipoproteome: Suitability of the Mouse Model for Studies of Human Lipoproteins

Journal of Proteome Research, Год журнала: 2015, Номер 14(6), С. 2686 - 2695

Опубликована: Апрель 20, 2015

Plasma levels of low density lipoproteins (LDL) and high (HDL) exhibit opposing associations with cardiovascular disease in human populations mouse models have been heavily used to derive a mechanistic understanding these relationships. In humans, recent mass spectrometry studies revealed that the plasma lipoproteome is significantly more complex than originally appreciated. This particularly true for HDL which contains some 90 distinct proteins, majority play functional roles go beyond those expected simple lipid transport. Unfortunately, remains largely uncharacterized—a significant gap given heavy reliance on model. Using gel filtration chromatography analysis targets phospholipid-bound we compared its size distribution previous, identical analysis. We identified 113 associated proteins mouse. general, protein diversity LDL ranges was similar mice versus though differences were noted. For distributions, is, whether large small particles, example, also between species. Again, however, there clear exhibited by minority may reflect metabolic Finally, correlating profiles, five closely track major protein, apolipoprotein A-I across both Thus, most minor key inflammation, innate immunity, proteolysis inhibition, vitamin provides support continued use as model many aspects lipoprotein metabolism.

Язык: Английский

---

Leveraging knowledge of HDLs major protein ApoA1: Structure, function, mutations, and potential therapeutics

Biomedicine & Pharmacotherapy, Год журнала: 2022, Номер 154, С. 113634 - 113634

Опубликована: Сен. 2, 2022

Apolipoprotein A1 (ApoA1) is a member of the family proteins. It's vital protein that helps in production high-density lipoprotein (HDL) particles, which are crucial for reverse cholesterol transport (RCT). It also has anti-inflammatory, anti-atherogenic, anti-apoptotic, and anti-thrombotic properties. These functions interact to give HDL particles their cardioprotective characteristics. ApoA1 recently been investigated its potential role atherosclerosis, diabetes, neurological diseases, cancer, certain infectious diseases. Since ApoA1's discovery, numerous mutations have reported affect structural integrity alter function. Hence these insights led development clinically relevant peptides synthetic reconstituted (rHDL) mimics function ApoA1. As result, this review aimed provide an organized explanation our understanding structure various essential pathways. Furthermore, we comprehensively reviewed important (24 mutations) be involved Finally, we've focused on therapeutic potentials some beneficial mutations, small peptides, rHDL currently being researched or developed, since will aid novel therapeutics future.

Язык: Английский

---

HDL Functions—Current Status and Future Perspectives

Biomolecules, Год журнала: 2023, Номер 13(1), С. 105 - 105

Опубликована: Янв. 4, 2023

Cardiovascular disease (CVD) is the leading cause of death in Western countries. A low HDL-C associated with development CVD. However, recent epidemiology studies have shown U-shaped curves between and CVD mortality, paradoxically increased mortality patients extremely high levels. Furthermore, raising therapy using nicotinic acids or CETP inhibitors mostly failed to reduce events. Based on this background, HDL functions rather than could be a novel biomarker; research clinical utility functionality ongoing. In review, we summarize current status their future perspectives from findings basic trials.

Язык: Английский

---

Dyslipidemia in rheumatoid arthritis: the possible mechanisms

Frontiers in Immunology, Год журнала: 2023, Номер 14

Опубликована: Окт. 25, 2023

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease, of which the leading cause death cardiovascular disease (CVD). The levels total cholesterol (TC), low-density lipoprotein (LDL-c), and high-density (HDL-c) in RA decrease especially under hyperinflammatory conditions. It conflictive with increased risk CVD RA, called "lipid paradox". systemic inflammation may explain this apparent contradiction. proinflammatory cytokines mainly include interleukin-6(IL-6)、interleukin-1(IL-1)and tumor necrosis factor alpha(TNF-α). changes subcomponents structure HDL particles, to a weakened anti-atherosclerosis function promoting LDL oxidation plaque formation. Dysfunctional can further worsen abnormalities metabolism, increasing disease. However, specific mechanisms underlying lipid remain unclear. Therefore, article comprehensively integrates latest existing literature describe unique profile explore changes, investigate impact on

Язык: Английский

---

Preeclampsia Affects Lipid Metabolism and HDL Function in Mothers and Their Offspring

Antioxidants, Год журнала: 2023, Номер 12(4), С. 795 - 795

Опубликована: Март 24, 2023

Preeclampsia (PE) is linked to an overall increased cardiovascular risk for both the mother and child. Functional impairment of high-density lipoproteins (HDL) may contribute excess associated with PE. In this study, we investigated effects PE on maternal neonatal lipid metabolism, parameters HDL composition function. The study cohort included 32 normotensive pregnant women, 18 women diagnosed early-onset PE, 14 late-onset mothers, early- was atherogenic dyslipidemia, characterized by high plasma triglycerides low HDL-cholesterol levels. We observed a shift from large smaller subclasses in which antioxidant capacity mothers. further markedly levels HDL-associated apolipoprotein (apo) C-II triglyceride content HDL. neonates total cholesterol were increased, whereas efflux reduced conclusion, profoundly affect potentially contributing disease manifestation later life. also changes function, demonstrating that complications pregnancy lipoprotein metabolism.

Язык: Английский

---

Inverse relationship between circulating sphingosine-1-phosphate and precursor species and coronary artery calcification score in type 2 diabetes

Cardiovascular Diabetology, Год журнала: 2025, Номер 24(1)

Опубликована: Фев. 21, 2025

Abstract Background Sphingosine 1-phosphate (S1P) is a key mediator of lipid signaling with strong immunomodulatory and anti-inflammatory effects. Circulating S1P levels including in high-density lipoproteins (HDL) were demonstrated to be inversely associated cardiovascular diseases (CVD). However, no studies are available regarding potential implication on the risk CVD type 2 diabetes (T2D). The objective this study determine if increased T2D may involve an alteration circulating species as well their precursors. Methods A total 168 31 patients (154 men 45 women) Coronary artery calcification (CAC) score from DIACART CERABIAB cohorts, respectively, included study. Quantification precursors was carried out by LC–MS/MS plasma isolated HDL. CAC modeled binary variable (0/1 below or equal/above 100) using < 100 for reference. variables dichotomized at median (0/1: median). relationships between (below evaluated linear regression analyses. In vitro experiments conducted evaluate contribution HDL-S1P content properties HDL particles. Results Multivariate analysis revealed that levels, especially d18:1-S1P, sphingosine high (CAC > T2D. Clustering according concentration S1P-impoverished major feature 100. monocyte adhesion inflammation human umbilical vein endothelial cells inflammatory phenotype macrophages low exhibited impaired comparison HDL-S1P. Conclusion This unraveled biomarkers coronary atherosclerosis T2D, which underlie lower abundance activities Trial registration ClinicalTrials.gov number, NCT02431234. Graphical abstract

Язык: Английский

---

Rosuvastatin Alters the Proteome of High Density Lipoproteins: Generation of alpha-1-antitrypsin Enriched Particles with Anti-inflammatory Properties*

Molecular & Cellular Proteomics, Год журнала: 2015, Номер 14(12), С. 3247 - 3257

Опубликована: Окт. 20, 2015

Statins lower plasma cholesterol by as much 50%, thus reducing future cardiovascular events. However, the physiological effects of statins are diverse and not all related to low density lipoprotein (LDL-C) lowering. We performed a small clinical pilot study assess impact on lipoprotein-associated proteins in healthy individuals (n = 10) with normal LDL-C (<130 mg/dL), who were treated rosuvastatin (20 mg/day) for 28 days. Proteomic analysis size-exclusion chromatography isolated LDL, large high (HDL-L), HDL (HDL-S) fractions spectral counting was used compare relative protein detection before after statin therapy. Significant changes found each pool included both increases decreases several involved metabolism, complement regulation acute phase response. The most dramatic effect treatment an increase α-1-antirypsin (A1AT) counts associated HDL-L particles. Quantitative measurement ELISA confirmed average 5.7-fold A1AT. Molecular modeling predictions indicated that hydrophobic reactive center loop A1AT, functional domain responsible its protease inhibitor activity, is likely lipid binding association protect A1AT against oxidative inactivation. Cell culture experiments, using J774 macrophages, demonstrated enhances antiprotease preventing elastase induced production tumor necrosis factor α. In conclusion, we show can significantly alter composition LDL our studies reveal novel relationship between HDL. up-regulation anti-inflammatory functionality, which may contribute non-lipid lowering beneficial statins. Epidemiological have clearly identified elevated independent risk development disease (CVD) 1The abbreviations are:CVDCardiovascular diseaseA1ATα-1-antitrypsinFDRFalse discovery rateFPLCFast liquid chromatographyHDLHigh lipoproteinLDLLow lipoproteinNENeutrophil elastasenHDLNative HDLPPEPorcine pancreatic elastaseRCLReactive looprHDLReconstituted HDLSERPINSerine inhibitorTNF-αTumor (1.Kannel W.B. Castelli W.P. Gordon T. Cholesterol prediction atherosclerotic disease. New perspectives based Framingham study.Ann. Intern. Med. 1979; 90: 85-91Crossref PubMed Scopus (1000) Google Scholar). Plasma carried emulsions called lipoproteins. Lipoproteins exist polydisperse distribution distinct particle classes commonly classified very low, intermediate, high-density A perhaps overly simplistic but well accepted paradigm role lipoproteins CVD excess (LDL) promote CVD, depositing plaque, whereas (HDL) particles remove mediate other anti-atherogenic effects. This has been translated into setting terms diagnostic testing. primary metric assessment these largely content (i.e. HDL-C). Cardiovascular α-1-antitrypsin False rate Fast High Low Neutrophil Native Porcine Reactive Reconstituted Serine Tumor class compounds inhibit key enzyme synthesis liver, namely HMG-CoA reductase (3-hydroxy-3-methyl-glutaryl-CoA reductase). These also indirect metabolism upregulating hepatic expression receptor circulating 50% provide significant protection (2.Baigent C. Keech A. Kearney P.M. Blackwell L. Buck G. Pollicino Kirby Sourjina Peto R. Collins Simes Efficacy safety cholesterol-lowering treatment: prospective meta-analysis data from 90,056 participants 14 randomised trials statins.Lancet. 2005; 366: 1267-1278Abstract Full Text PDF (5760) There growing evidence mechanisms their effect, including anti-apoptotic activities improving endothelial cell function (3.Jain M.K. Ridker Anti-inflammatory statins: basic mechanisms.Nat. Rev. Drug. Discov. 4: 977-987Crossref (702) mechanisms, however, so pleiotropic atherosclerosis unknown. major contain subclasses, different physical chemical properties differ CVD. For example, total composed at least two subclasses: buoyant dense particularly proatherogenic (4.Chapman M.J. Guerin M. Bruckert E. Atherogenic, low-density Pathophysiology new therapeutic approaches.Eur. Heart J. 1998; 19: A24-30PubMed subclass more complex; it consists numerous subclasses varying compositions. Modern mass spectrometry (MS) techniques allowed thorough characterizations proteomes While typically contains only few prototypical proteins, such apoB, apoE, apoC's etc., many 90 among (5.Vaisar Pennathur S. Green P.S. Gharib S.A. Hoofnagle A.N. Cheung M.C. Byun Vuletic Kassim Singh P. Chea H. Knopp R.H. Brunzell Geary Chait Zhao X.Q. Elkon K. Marcovina Oram J.F. Heinecke J.W. Shotgun proteomics implicates inhibition activation antiinflammatory HDL.J. Clin. Invest. 2007; 117: 746-756Crossref (788) Scholar, 6.Karlsson Leanderson Tagesson Lindahl Lipoproteomics I: mapping two-dimensional gel electrophoresis spectrometry.Proteomics. 5: 551-565Crossref (118) 7.Karlsson II: 1431-1445Crossref (152) 8.Davidson W.S. proteome watch.www.davidsonlab.com. 2015; 9.Gordon S.M. Deng Lu L.J. Davidson characterization human fractionated filtration chromatography.J. Proteome Res. 2010; 9: 5239-5249Crossref (171) proteomic diversity accounts HDL, inflammation oxidation, anticoagulant pro-vasodilatory functions, name (10.Gordon Hofmann Askew D.S. lipoprotein: it's just about transport anymore.Trends Endocrinol. Metab. 2011; 22: 9-15Abstract (128) current study, tested hypothesis therapy, addition known effects, will this affect properties. shotgun patients during treatment. Our revealed elevation protein. addition, present enriched support property subfraction, could explain some Fasting blood samples obtained ten volunteers participating NIH Center Human Immunology, intended evaluate immune system. protocol approved institutional review board National Heart, Lung, Blood Institute (NHLBI) registered clinicaltrials.gov (NCT01200836); provided written informed consent. Three males 7 females enrolled, age 44.1 ± 11 years. Participants selected mg/dL) any modification therapy prior study. Recruited given collected venipuncture following time points: baseline, days treatment, stopping (washout). Samples stored −20° Because taken participant baseline on-treatment, subject acted own control. Lipid assays Siemens Dimension Vista analyzer, standard enzymatic assays. HDL-C measured direct assay (Siemens; Munich, Germany) determined Friedewald equation. Lipoprotein numbers sizes heparinized Vantera Clinical Analyzer (LipoScience; Raleigh, NC). Collected applied Superose 6 columns (GE Healthcare) arranged series Akta FPLC flow set 0.5 ml/min ml collected. Fractions assayed phosphatidylcholine, cholesterol, free triglyceride (Wako Diagnostics; Mountain View, CA) determine position elution subject, combined make (elution vol. 17.5 - 20 ml), HDL-large (HDL-L; 21 23 ml) HDL-small (HDL-S; 25 pools, generating 60 MS analysis. Pooled phospholipid resin washed isolate bound components, previously described (9.Gordon Resin then subjected overnight trypsin digestion 37 °C. Resulting peptides reduced dithiothreitol (200 mm; 30 min °C) carbamidomethylated iodoacetamide (800 °C). Digest solutions dried, reconstituted 100 μl water + 0.1% formic acid desalted ZipTips (Millipore; Billerica, MA), −20 °C until Desalted dried 10 analyzed Thermo Orbitrap Velos instrument. Blank runs sample prevent carry over. Peak lists generated Discoverer (version 1.3.0.339) resulting spectra searched SwissProt database 012214), Mascot 2.4.0) identify components (fragment ion tolerance 0.80 Da parent PPM). Search criteria included: taxonomy, fixed modification: carbamidomethylation (C), variable modifications: oxidation (M), deamidation (N, Q) up 2 missed cleavage sites allowed. Validation peptide identifications Scaffold software 4.1.1) 1.0% false (FDR) thresholds minimum required per Calculated decoy FDR 0.03% 0.7%, respectively. Spectral semi-quantitative comparison abundance on-treatment normalized spectrum count calculated software. Comparisons estimate same treatment; no comparisons made fractions. Data student's t test statistically (p < 0.05) counts. primarily screening purposes, candidates driven corrected multiple comparisons. All deposited ProteomeXchange Consortium (11.Vizcaino J.A. Deutsch E.W. Wang Csordas Reisinger F. Rios D. Dianes Sun Z. Farrah Bandeira N. Binz P.A. Xenarios I. Eisenacher Mayer Gatto Campos Chalkley R.J. Kraus H.J. Albar J.P. Martinez-Bartolome Apweiler Omenn G.S. Martens Jones A.R. Hermjakob provides globally coordinated submission dissemination.Nat. Biotechnol. 2014; 32: 223-226Crossref (2076) Scholar) via PRIDE partner repository dataset identifier PXD002633. prepared cholate dialysis method, purified apolipoprotein A-I 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (Avanti; Alabaster, AL) (12.Matz C.E. Jonas Micellar complexes phosphatidylcholines cholate-lipid dispersions.J. Biol. Chem. 1982; 257: 4535-4540Abstract sequential gradient ultracentrifugation (13.Chapman Goldstein Lagrange Laplaud ultracentrifugal procedure isolation serum.J. 1981; 339-358Abstract or native co-incubated (Human, Sigma Aldrich; St. Louis, MO) Unbound removed filtration, Amicon Ultra kDa centrifugal filter units (Millipore). Elastase activity EnzChek® kit (Life Technologies; Frederick, MD). mouse macrophages examine potential inflammation. cells plated 12-well plates 1 × 105 cells/well experiment. Cells twice PBS placed serum-free media h Treatments (PBS, nHDL, A1AT-HDL, A1AT) added media: matched nHDL A1AT-nHDL final concentration 200 μg/ml. μm. incubated (porcine pancreas, Aldrich, 500 nm) 4 centrifuged 3000 g 5 pellet loose debris supernatant transferred fresh tubes −80 further Elisa TNF-α (BioLegend; San Diego, media. Serum subjects lipids (Fig. 1A). As expected, resulted reductions (-28%; p 0.001), (-50%; 0.001) (-29%; 0.01) modest 3.6% significant, although larger (14.McTaggart Effects lipoproteins: contribution benefit.Cardiovasc. Drugs Ther. 2008; 321-338Crossref (121) mirrored levels. number (LDL-p) 51% predominantly due reduction 1B). HDL-p increased 6.2% 1C). separated size. triglycerides 2). Results analysis, indicate peak (Elution volume 17–20 ml). consistent measures presented Fig. 1. before, 21–25 observed. To alters proteome, pooled containing analyze rosuvastatin. divided halves, representing gain additional insight complexity screen whose changed because experimental approach validated previous 15.Gordon Urbina E.M. Dolan L.M. Heink Zang Shah A.S. type diabetes arterial stiffness male youth.Diabetes. 2013; 62: 2958-2967Crossref (59) validation approach, correlation B LDL-p. stoichiometry one molecule apoB linear would be expected quantitative measure number, observed 3 (R2 0.833, 0.0001) 3). 154 (supplemental Table S1). relatively size results correction comparisons; objective strictly focused studies, statistical without fraction, nine display result 4A). majority decreases, indicating Additionally, magnitude ranged −71%, similar degree achieved suggests It interesting, C3 (+71%) Ig κ chain V-II (+68%) despite apoB. nor importance known. Although had minimal caused 4B). Most notably, there marked (+2438%). ceruloplasmin showed (+27%). Reductions proteins: immunoglobulin chains (variable), N-acetylmuramoyl-l-alanine amidase (-69%), kallikrein (-26%), clusterin (-13%) lambda like polypeptide (-12%). Overall, fewer fraction: (α-1-antichymotrypsin (-89%), C2 (-44%), C-III (-13%), vitronectin (+23%). Of decided focus largest change understood. fact, greater than examined various diseases 16.Green Vaisar Kulstad J.J. Moore A.B. Combined niacin remodels proteome.Circulation. 118: 1259-1267Crossref (115) shown modulating inflammatory processes (17.Gilutz Siegel Y. Paran Cristal Quastel M.R. Alpha 1-antitrypsin myocardial infarction.Br. 1983; 49: 26-29Crossref (32) 18.Duckers J.M. Shale D.J. Stockley R.A. Gale N.S. Evans B.A. Cockcroft J.R. Bolton musculskeletal co-morbidities alpha antitrypsin deficiency.Respir. 11: 173Crossref (45) quantitatively levels data, subjects. noted segregation groups: responders (range: five- 18-fold) fraction response low-responders 36%) 5A 5B) did appear CRP (data shown). measuring plasma. clear trend increasing while return week washout, small, ∼10% 5C). correlate Based plasma, ∼4.54 1.73% 0.84 0.037% A1AT/HDL-particle ratio (mol:mol) 1:100 1:25 structural basis interaction lipoproteins, optimum thermodynamic orientation interact bilayer, 3D structures. crystal structure downloaded Protein Bank (http://www.rcsb.org; ID: 3NE4) input membranes server (http://opm.phar.umich.edu/) (19.Lomize M.A. Pogozheva I.D. Joo Mosberg H.I. Lomize A.L. OPM PPM web server: Resources positioning membranes.Nucleic Acids 2012; 40: D370-376Crossref (1031) From exposed random coil region predicted insert outer leaflet bilayer 6A). corresponds (RCL) active site ability proteolytic hydrophobic. noted, model, methionine residues critical (Met351 Met358) buried surface. highly susceptible sulfoxide. Previous either loss anti-elastase (20.Taggart Cervantes-Laurean Kim McElvaney N.G. Wehr Moss Levine R.L. Oxidation 351 358 causes anti-neutrophil activity.J. 2000; 275: 27258-27265Abstract If RCL (A1ATΔ346, 6B), markedly affinity surface, decreased insertion depth ΔGtransfer energy. model hypothesized burying surface capacity elastolytic activity. this, dialysis. seen profile, when discoidal apoA-I phospholipids, associates 7A). Similarly, became shown) (21.Moreno Ortega-Gomez Rubio-Navarro Louedec Ho-Tin-Noe B. Caligiuri Nicoletti Levoye Plantier Meilhac O. High-density potentia

Язык: Английский

---

High density lipoproteins are modulators of protease activity: Implications in inflammation, complement activation, and atherothrombosis

Atherosclerosis, Год журнала: 2016, Номер 259, С. 104 - 113

Опубликована: Ноя. 16, 2016

Язык: Английский

---

High density lipoprotein proteome is associated with cardiovascular risk factors and atherosclerosis burden as evaluated by coronary CT angiography

Atherosclerosis, Год журнала: 2018, Номер 278, С. 278 - 285

Опубликована: Сен. 25, 2018

Язык: Английский

---