HDL and Reverse Cholesterol Transport

Circulation Research, Journal Year: 2019, Volume and Issue: 124(10), P. 1505 - 1518

Published: May 9, 2019

Cardiovascular disease, with atherosclerosis as the major underlying factor, remains leading cause of death worldwide. It is well established that cholesterol ester-enriched foam cells are hallmark atherosclerotic plaques. Multiple lines evidence support enhancing cell efflux by HDL (high-density lipoprotein) particles, first step reverse transport (RCT), a promising antiatherogenic strategy. Yet, excitement towards therapeutic potential manipulating RCT for treatment cardiovascular disease has faded because lack association between risk and what was typically measured in intervention trials, namely cholesterol, which an inconsistent relationship to function RCT. In this review, we will summarize some reasons inconsistency, update mechanisms RCT, highlight conditions impaired or contributes vascular disease. On balance, still argues further research better understand how functionality develop prevention strategies reduce

Language: Английский

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Quantitative variability of 342 plasma proteins in a human twin population

Molecular Systems Biology, Journal Year: 2015, Volume and Issue: 11(2)

Published: Feb. 1, 2015

Article4 February 2015Open Access Quantitative variability of 342 plasma proteins in a human twin population Yansheng Liu Corresponding Author Department Biology, Institute Molecular Systems ETH Zurich, Switzerland Search for more papers by this author Alfonso Buil Genetic Medicine and Development, University Geneva Medical School, Geneva, Ben C Collins Ludovic CJ Gillet Lorenz Blum Lin-Yang Cheng Statistics Computer Science, Purdue University, West Lafayette, IN, USA Olga Vitek Jeppe Mouritsen Genevieve Lachance Twin Research Epidemiology, King's College London, St Tomas' Hospital Campus, UK Tim D Spector Emmanouil T Dermitzakis Ruedi Aebersold Faculty Information 1,‡, Buil2,‡, Collins1, Gillet1, Blum1, Cheng3, Vitek3, Mouritsen1, Lachance4, Spector4, Dermitzakis2 1,5 1Department 2Department 3Department 4Department 5Faculty ‡These authors contribute equally to study *Corresponding author. Tel: +41 44 633 2986; E-mail: [email protected] 3170; Fax: 1051; Biology (2015)11:786https://doi.org/10.15252/msb.20145728 PDFDownload PDF article text main figures. Peer ReviewDownload summary the editorial decision process including letters, reviewer comments responses feedback. ToolsAdd favoritesDownload CitationsTrack CitationsPermissions Figures & Info Abstract The degree origins quantitative most are largely unknown. Because design provides natural opportunity estimate relative contribution heritability environment different traits population, we applied here highly accurate reproducible SWATH mass spectrometry technique quantify 1,904 peptides defining unique 232 samples collected longitudinally from pairs monozygotic dizygotic twins at intervals 2–7 years, proportioned observed total its root causes, genes, environmental longitudinal factors. data indicate that show vastly patterns abundance among humans genetic control variation affect protein levels biological processes degrees. further strongly suggest concentrations clinical biomarkers need be calibrated against temporal Moreover, identified 13 cis-SNPs significantly influencing level specific proteins. These results therefore have immediate implications effective blood-based biomarker studies. Synopsis analyzed spectrometry. We used years. proteome is dissected roles heritable, determinants controlling functional clusters, suggesting as trait loci (pQTLs), five them associated with gene expression QTLs (eQTLs) tissues. Introduction effects genomic variation, modulated lifestyle environment, orchestrate extensive phenotypic found populations. quantification narrow-sense heritability, is, proportion variance attributable additive effects, important information basic disease biology (Lichtenstein et al, 2000; Stranger 2007; Emilsson 2008; Visscher 2008). Within can determined cohort Monozygotic (MZ) genetically identical thus provide extremely valuable importance genes benchmarking MZ phenotype discordances those (DZ) which, on average, share one half descent (Martin 1997). To date, such studies been performed organismal phenotype, transcript (Grundberg 2012; Wright 2014), epigenetic 2013) metabolic (Nicholson 2011; Shin respectively. Proteins predominantly determine biochemical state specimens proteomic thought closely adding complementary component corresponding nucleic acid-based indicators (Aebersold 2005; Picotti 2013; Wu 2013). quantitatively spectrometric measurement across DZ has technically challenging due high complexity large dynamic range samples, particularly proteome. Human blood prime source intensely studied because it obtained minimally invasive methods contains physiological pathological changes (Zhang 2007). However, spite an enormous number studies, clinically properties remain unexplored. Specifically, their stability over time Previous relevant population-based either not focused (Wu 2013), or had limited analytical depth (Melzer Kato Lourdusamy Johansson [from 10s 163 (Johansson 2013)] preference (Enroth 2014) and/or robustness outcome reproducibility 2011). Here, SWATH-MS, emerging high-throughput targeting method (Gillet 2014; Rost were 2- 7-year pairs. SWATH-MS essentially combines analyte throughput traditional shotgun discovery proteomics exquisite accuracy selected reaction monitoring (SRM), prototypical technique. inherent varies regulation under tight control. best our knowledge, first applies current, approaches analyzing (clinically relevant) sampling. Results proteins, newly developed 2012) cohort. consisted 72 Twins Adult Registry where drawn two points (Fig 1). average age 57.8 years visit, ranging 38 74 age. interval between samplings was 5.2 ± 1.4 63.1 second 78 (see Supplementary Fig S1 distribution actual visits). Fasted conditions 4 Table S1). Females chosen simplify experimental excluding gender variance. Figure 1. Experimental designThe survey providing reproducibility. overall partitioned into four contributing factors (heritable, common environmental, individual factors) unexplained using linear mixed model. Download figure PowerPoint data-independent acquisition (DIA) converts all ionized sample high-resolution, digital map fragment ion signals 2013a) In these maps, monitored via targeted analysis strategy, signal groups uniquely identifying peptide detected quantified each maps. parameters group peptide, masses, intensity chromatographic concordance, retention precursor range, constituted assay prepared priori spectral library 2A). generate library, deployed comprehensive sequencing digest sample, which firstly depleted 14 abundant then fractionated strong anion exchanger level, yielding assays 652 Further, included additional MS (Farrah 2011) in-house compendium (Rosenberger 2014). final combined contained than 43,000 peptides, representing 1,667 represents, largest SWATH-ready (freely provided raw data), maximized 2. Proteomic identification establishment comprehensive, ready analysis. reference spectra generated complemented known coefficient (CV) technical, whole-process levels. Heatmap hierarchical clustering vs. matrix indicates reproducibly fold intensities shown box plots. Antithrombin III (ANT3) vitamin D-binding (VTDB) examples stable whereas apolipoprotein(a) (APOA) serum amyloid A-1 (SAA1) variable red bars positions analytes whose cleared approved FDA blood. Using OpenSWATH software framework (Rost confidently 4,271 FDR 1%, 534 distinct unfractionated non-enriched 2A S2). Their estimated cover six orders magnitude according PeptideAtlas database 2011), reaching, some low several nanograms per milliliter (Supplementary S2A). On 3,520 425 sample. filtered select unambiguously UniProt (Mallick 2007) consistently samples. only 10.07% missing values approached 0% after applying re-quantification algorithm 4). dataset 42 (that about 40% of) US Food Drug Administration (FDA) purpose (hereafter, assayed proteins) (Anderson, 2010). It compares favorably prior multisample regarding considering mere 2.5 h consumed 0.015 μl injection, exceeds previous terms accuracy. next sought assess data. First, calculated protein. Overall, 84.5 76.0% technical replicates CVs < 25%. median CV 7.2% 2B) 14.2%. Second, compared SRM measurements spiked heavy isotope-labeled analyses established (Huttenhain 2012). As expected, ratios light versions 41 maps generally well correlated mean R = 0.85 S2B C). Third, unsupervised (HCA) 2C). HCA 137 (i.e. 59.1% 232) sampled individuals (96 144 88 twins) directly clustered adjacent nodes, indicating global similarity Substantial individuals. 174 50.8% 342) showed tenfold change extremes entire standard deviation ranged 0.1403 antithrombin 0.1465 1.1936 1.6871 protein, respectively 2D), protein-level feature within population. Variance decomposition took advantage utilized model systematically partition decomposed shared/individual 3A). Even though adult females who normally do live same household, they habits lifestyles non-twin siblings, reflected term “shared/ environment”. accounts 50% (e.g. short-term concentration fluctuations, diet etc.) technical/experimental variations. 13.6, 10.8, 11.6 13.6%, respectively, variance, 25.4, 20.8, 23.0 30.8%, biologically (the fraction explained design). (h2) good agreement correlations twins. Examples apolipoprotein(A), fibrinogen beta chain paraoxonase/arylesterase 1 illustrated 3B. Notably, sometimes “family component”, explains almost 46.2%) results. lists affected S3 proteins). For example, apolipoprotein(A) heritable (h2 0.6633), finding consistent reports (Boerwinkle 1992; Lopez Cenarro Top mostly components Swiss-Prot I.D. Protein name Gene Heritability Common Individual Longitudinal Unexplained Direct literature support P08519 Apolipoprotein(a) LPA 0.6633a (0.3734–0.9533) 0.1845 0.0000 0.1521 Yes P04220 Ig mu - 0.6542a (0.5297–0.7787) 0.1382 0.2077 O43866 CD5 antigen-like CD5L 0.6180a (0.2952–0.9408) 0.0409 0.1877 0.1534 Q03591 Complement factor H-related CFHR1 0.6149a (0.4902–0.7396) 0.0403 0.0099 0.3349 Q02985 3 CFHR3 0.6066a (0.4781–0.7352) 0.0249 0.3685 P01877 alpha-2 region IGHA2 0.0194 0.6688 0.2222 0.0082 0.0813 P00748 Coagulation XII F12 0.5862 0.1755 0.0764 0.1619 P31939 Bifunctional purine biosynthesis PURH ATIC 0.5605 0.1253 0.0065 0.3078 P01860 gamma-3 IGHG3 0.5531 0.2229 0.0364 0.1876 O75636 Ficolin-3 FCN3 0.5059 0.1081 0.0916 0.2944 Q99459 Cell division cycle 5-like CDC5L 0.0682 0.5295 0.1457 0.2566 P01861 gamma-4 0.4276 0.5185 0.0045 0.0495 P01777 V-III TEI 0.1278 0.0155 0.3881 0.0794 0.3892 P02749 Beta-2-glycoprotein APOH 0.1009 0.3807 0.1324 0.3861 P43490 Nicotinamide phosphoribosyltransferase NAMPT 0.0010 0.3594 0.2425 0.3970 Q562R1 Beta-actin-like 2 ACTBL2 0.5354 0.4646 P48681 Nestin NES 0.0938 0.4692 0.4371 Q16531 DNA damage-binding DDB1 0.1139 0.4560 0.4301 P19367 Hexokinase-1 HK1 0.1918 0.4510 0.3572 P60174 Triosephosphate isomerase TPI1 0.1137 0.4413 0.4450 Denotes 95% CIs estimates bold highlight significant respective cause. 3. Dissection Histograms percentage (red: heritability; blue: environment; dark yellow: effects; gray: fraction) based design. Selected names levels, APOA, protease C1 inhibitor (IC1), complement C4-A (CO4A), alpha (FIBA) pancreatic triacylglycerol lipase (LIPP), cohort, SAA1, pregnancy zone (PZP), trifunctional enzyme subunit (ECHA) C-reactive (CRP). Fibrinogen (FIBB), Serum (PON1). checked if possible modifications could 5% evidence possibly modified any type modification site reported S2 S3A). analysis, mapped achieved respect determining family (R 0.83, S3B). This suggests dominated naked forms peptide-level status undetectable negligible effect similar design, 58 also female but antibody bead-based technology (Kato yielded 284 extending scope six. Most importantly, applied, higher reproducibility, obviating remove outlying S4A–D) translating (P 5.19e-7, Wilcoxon rank-sum test, S4E–G). Intriguingly, result explain 13.6% 2.9% al (2011) conceptual used. discrepancy may mainly ascribed much shorter sampling (around months), aging together other unstable during ~5-year period tested present uncovered profound impact relatively long-term, dynamics. carefully existence besides 1.7% 116 cancer visits, least 6.9–17.2% changed menopausal visits. A 15 12.9% 116) confirmed II diabetes before visit one. No new According usage types medications (corticosteroids, thyroxine, statins antihypertensives), tended take (an 0.38 person versus 0.53 2, P 0.0125). report Enroth (2014) Spearman rho equals 0.29 correlation medications. summary, nature plus structure allowed us give causes plasma. Differential preferably regulated Statistically 80 23% 342, h2 > 0.25 0.01). close (2013) measured parent–children context thereby 19% heritable. 21 discovered (2013). Additionally, 60 changes, 52 familial 47 environment. Among these, 17 appeared both environments. discern biolog

Language: Английский

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High-density lipoproteins: A consensus statement from the National Lipid Association

Journal of clinical lipidology, Journal Year: 2013, Volume and Issue: 7(5), P. 484 - 525

Published: Aug. 11, 2013

Language: Английский

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High-Density Lipoproteins: Nature’s Multifunctional Nanoparticles

ACS Nano, Journal Year: 2016, Volume and Issue: 10(3), P. 3015 - 3041

Published: Feb. 18, 2016

High-density lipoproteins (HDL) are endogenous nanoparticles involved in the transport and metabolism of cholesterol, phospholipids, triglycerides. HDL is well-known as "good" cholesterol because it not only removes excess from atherosclerotic plaques but also has anti-inflammatory antioxidative properties, which protect cardiovascular system. Circulating transports proteins, vitamins, hormones, microRNA to various organs. Compared with other synthetic nanocarriers, such liposomes, micelles, inorganic polymeric nanoparticles, unique features that allow them deliver cargo specific targets more efficiently. These attributes include their ultrasmall size (8–12 nm diameter), high tolerability humans (up 8 g protein per infusion), long circulating half-life (12–24 h), intrinsic targeting properties different recipient cells. Various recombinant ApoA proteins mimetic peptides have been recently developed for preparation reconstituted exhibits similar those a potential industrial scale-up. In this review, we will summarize (a) clinical pharmacokinetics safety products, (b) comparison organic (c) rationale using drug delivery vehicles important therapeutic indications, (d) current state-of-the-art production, (e) HDL-based strategies small molecules, peptides/proteins, nucleic acids, imaging agents targeted

Language: Английский

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What Are We Looking At? Extracellular Vesicles, Lipoproteins, or Both?

Circulation Research, Journal Year: 2017, Volume and Issue: 121(8), P. 920 - 922

Published: Sept. 29, 2017

Language: Английский

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High-Density Lipoprotein

Circulation Research, Journal Year: 2014, Volume and Issue: 114(1), P. 171 - 182

Published: Jan. 2, 2014

High-density lipoprotein (HDL) is a complex mixture of lipoproteins that associated with many minor proteins and lipids influence the function HDL. Although HDL promising marker potential therapeutic target based on its epidemiological data effects healthy in vitro endothelial cells macrophages, as well infusion studies reconstituted patients hypercholesterolemia, it remains still uncertain whether or not cholesterol–raising drugs will improve outcomes. Recent suggest becomes modified coronary artery disease acute syndrome because oxidative processes result alterations proteome composition (proteome remodelling) leading to dysfunction.

Language: Английский

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Structure of HDL: Particle Subclasses and Molecular Components

Handbook of experimental pharmacology, Journal Year: 2014, Volume and Issue: unknown, P. 3 - 51

Published: Dec. 1, 2014

A molecular understanding of high-density lipoprotein (HDL) will allow a more complete grasp its interactions with key plasma remodelling factors and cell-surface proteins that mediate HDL assembly clearance. However, these particles are notoriously heterogeneous in terms almost every physical, chemical biological property. Furthermore, have not lent themselves to high-resolution structural study through mainstream techniques like nuclear magnetic resonance X-ray crystallography; investigators therefore had use series lower resolution methods derive general enigmatic particles. This chapter reviews current knowledge the composition, structure heterogeneity human HDL. The multifaceted composition proteome, multiple major protein isoforms involving translational posttranslational modifications, rapidly expanding lipidome, highly complex world subclasses putative models particle extensively discussed. brief history studies both plasma-derived recombinant forms is presented focus on detailed been derived from range spanning mass spectrometry dynamics.

Language: Английский

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What is the blood concentration of extracellular vesicles? Implications for the use of extracellular vesicles as blood-borne biomarkers of cancer

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Journal Year: 2018, Volume and Issue: 1871(1), P. 109 - 116

Published: Dec. 7, 2018

Language: Английский

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Mass-Spectrometry-Based Molecular Characterization of Extracellular Vesicles: Lipidomics and Proteomics

Journal of Proteome Research, Journal Year: 2015, Volume and Issue: 14(6), P. 2367 - 2384

Published: April 30, 2015

This review discusses extracellular vesicles (EVs), which are submicron-scale, anuclear, phospholipid bilayer membrane enclosed that contain lipids, metabolites, proteins, and RNA (micro messenger). They shed from many, if not all, cell types present in biological fluids conditioned culture media. The term EV, as coined by the International Society of Extracellular Vesicles (ISEV), encompasses exosomes (30–100 nm diameter), microparticles (100–1000 nm), apoptotic blebs, other EV subsets. EVs have been implicated cell–cell communication, coagulation, inflammation, immune response modulation, disease progression. Multiple studies report secretion disease-affected cells contributes to progression, e.g., tumor niche formation cancer metastasis. attractive sources biomarkers due their relevance relatively noninvasive accessibility a range physiological fluids. is focused on molecular profiling protein lipid constituents EVs, with emphasis mass-spectrometry-based "omic" analytical techniques. challenges purification characterization including contamination isolates limitations sample quantities, discussed along possible solutions. Finally, limited but growing investigation post-translational modifications proteins potential strategies for future in-depth EVs.

Language: Английский

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Translation of High-Density Lipoprotein Function Into Clinical Practice

Circulation, Journal Year: 2013, Volume and Issue: 128(11), P. 1256 - 1267

Published: Sept. 10, 2013

Language: Английский

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