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Journal ArticleDOI

The HDL Proteome Watch: Compilation of studies leads to new insights on HDL function.

01 Feb 2022-Biochimica et Biophysica Acta (Biochim Biophys Acta Mol Cell Biol Lipids)-Vol. 1867, Iss: 2, pp 159072
TL;DR: The HDL Proteome Watch Database as discussed by the authors is a collection of proteins associated with HDL, which is used to track proteomics studies from different laboratories across the world, and can offer interesting new insights into HDL function, such as immunity, inflammation, cell adhesion, hemostasis and protease regulation.
About: This article is published in Biochimica et Biophysica Acta.The article was published on 2022-02-01 and is currently open access. It has received 24 citations till now. The article focuses on the topics: Proteome & Proteomics.
Citations
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Journal ArticleDOI
TL;DR: In this paper , a U-shaped relationship between HDL-cholesterol (HDL-C) levels and several conditions have been reported, being both low and extremely high HDL-C levels associated with an increased risk of several pathologies and mortality.
Abstract: Graphical Abstract Graphical Abstract The great complexity of HDL. High-density lipoprotein (HDL) particles carry a large number of proteins and lipids, which contribute to define their compositional and functional complexity. HDLs exert multiple protective activities, essentially by three major mechanisms. HDLs, however, can lose their protective functions and even gain adverse functions in chronic diseases or during infections. U-shaped relationships between HDL-cholesterol (HDL-C) levels and several conditions have been reported, being both low and extremely high HDL-C levels associated with an increased risk of several pathologies and mortality. LCAT, lecithin:cholesterol acyltransferase; CETP, cholesteryl ester transfer protein; PONI, paraoxonase 1; S1P, sphingosine-1-phosphate; ASCVD, atherosclerotic cardiovascular disease; LDL, low-density lipoprotein; SAA, serum amyloid A; OxPL, oxidized phospholipids

18 citations

Journal ArticleDOI
TL;DR: The HDL hypothesis may need revision based on studies of HDL structure and function, but that the HDL hypothesis is not dead yet is concluded.
Abstract: High-density lipoprotein cholesterol (HDL-C) levels are inversely correlated with coronary heart disease (CHD) in multiple epidemiological studies, but whether HDL is causal or merely associated with CHD is unclear. Recent trials for HDL-raising drugs were either not effective in reducing CHD events or, if beneficial in reducing CHD events, were not conclusive as the findings could be attributed to the drugs’ LDL-reducing activity. Furthermore, the first large Mendelian randomization study did not causally relate HDL-C levels to decreased CHD. Thus, the hypothesis that HDL is protective against CHD has been rightfully challenged. However, subsequent Mendelian randomization studies found HDL characteristics that are causally related to decreased CHD. Many aspects of HDL structure and function, especially in reverse cholesterol transport, may be better indicators of HDL’s protective activity than simply measuring HDL-C. Cholesterol efflux capacity is associated with lower levels of prevalent and incident CHD, even after adjustment for HDL-C and apolipoprotein A-1 levels. Also, subjects with very high levels of HDL-C, including those with rare mutations that disrupt hepatic HDL uptake and reverse cholesterol transport, may be at higher risk for CHD than those with moderate levels. We describe here several cell-based and cell-free in vitro assays of HDL structure and function that may be used in clinical studies to determine which of HDL’s functions are best associated with protection against CHD. We conclude that the HDL hypothesis may need revision based on studies of HDL structure and function, but that the HDL hypothesis is not dead yet.

9 citations

Journal ArticleDOI
TL;DR: A current update of the pathophysiological consequences of MPO-induced changes in the structure and function of HDL is provided and possible therapeutic implications and options are discussed.
Abstract: Atherosclerosis is a disease of increased oxidative stress characterized by protein and lipid modifications in the vessel wall. One important oxidative pathway involves reactive intermediates generated by myeloperoxidase (MPO), an enzyme present mainly in neutrophils and monocytes. Tandem MS analysis identified MPO as a component of lesion derived high-density lipoprotein (HDL), showing that the two interact in the arterial wall. MPO modifies apolipoprotein A1 (apoA-I), paraoxonase 1 and certain HDL-associated phospholipids in human atheroma. HDL isolated from atherosclerotic plaques depicts extensive MPO mediated posttranslational modifications, including oxidation of tryptophan, tyrosine and methionine residues, and carbamylation of lysine residues. In addition, HDL associated plasmalogens are targeted by MPO, generating 2-chlorohexadecanal, a pro-inflammatory and endothelial barrier disrupting lipid that suppresses endothelial nitric oxide formation. Lesion derived HDL is predominantly lipid-depleted and cross-linked and exhibits a nearly 90% reduction in lecithin-cholesterol acyltransferase activity and cholesterol efflux capacity. Here we provide a current update of the pathophysiological consequences of MPO-induced changes in the structure and function of HDL and discuss possible therapeutic implications and options. Preclinical studies with a fully functional apoA-I variant with pronounced resistance to oxidative inactivation by MPO-generated oxidants are currently ongoing. Understanding the relationships between pathophysiological processes that affect the molecular composition and function of HDL and associated diseases is central to the future use of HDL in diagnostics, therapy, and ultimately disease management.

7 citations

Journal ArticleDOI
TL;DR: The functions of individual protein components of HDL, rendering them either anti-inflammatory or pro-inflammatory are described in detail and Alterations of HDL proteome in patients with chronic inflammatory diseases and their impact on cardiovascular health are discussed.
Abstract: Chronic inflammatory diseases, such as rheumatoid arthritis, steatohepatitis, periodontitis, chronic kidney disease, and others are associated with an increased risk of atherosclerotic cardiovascular disease, which persists even after accounting for traditional cardiac risk factors. The common factor linking these diseases to accelerated atherosclerosis is chronic systemic low-grade inflammation triggering changes in lipoprotein structure and metabolism. HDL, an independent marker of cardiovascular risk, is a lipoprotein particle with numerous important anti-atherogenic properties. Besides the essential role in reverse cholesterol transport, HDL possesses antioxidative, anti-inflammatory, antiapoptotic, and antithrombotic properties. Inflammation and inflammation-associated pathologies can cause modifications in HDL’s proteome and lipidome, transforming HDL from atheroprotective into a pro-atherosclerotic lipoprotein. Therefore, a simple increase in HDL concentration in patients with inflammatory diseases has not led to the desired anti-atherogenic outcome. In this review, the functions of individual protein components of HDL, rendering them either anti-inflammatory or pro-inflammatory are described in detail. Alterations of HDL proteome (such as replacing atheroprotective proteins by pro-inflammatory proteins, or posttranslational modifications) in patients with chronic inflammatory diseases and their impact on cardiovascular health are discussed. Finally, molecular, and clinical aspects of HDL-targeted therapies, including those used in therapeutical practice, drugs in clinical trials, and experimental drugs are comprehensively summarised.

5 citations

Journal ArticleDOI
TL;DR: In this paper , the authors used Cox proportional regression analysis and a case-cohort design to test associations of HDL proteins with incident CVD (myocardial infarction, coronary artery bypass grafting, angioplasty, or death from coronary heart disease).

5 citations

References
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Journal ArticleDOI
TL;DR: The relatively low density of the lipoproteins was utilized by Lindgren, Elliott, and Gofman to separate them from the other serum proteins by ultracentrifugal flotation, and quantitation was subsequently performed by refractometric methods in the analytical ultracentRifuge.
Abstract: In the past few years several methods have been developed for the analysis of serum lipoproteins Lindgren, Elliott, and Gofman (1) have utilized the relatively low density of the lipoproteins to separate them from the other serum proteins by ultracentrifugal flotation Quantitation was subsequently performed by refractometric methods in the analytical ultracentrifuge Separations of lipoproteins have also been made by Cohn fractionation in cold ethanol, and the quantities of lipoprotein have been estimated from the lipid content of the fractions (2, 3) Widely used at the present time is the method of zone electrophoresis with quantitation either by staining (4) or by chemical analysis of eluates from the support

8,544 citations

Journal ArticleDOI
TL;DR: The observations suggest that HDL plays previously unsuspected roles in regulating the complement system and protecting tissue from proteolysis and that the protein cargo of HDL contributes to its antiinflammatory and antiatherogenic properties.
Abstract: HDL lowers the risk for atherosclerotic cardiovascular disease by promoting cholesterol efflux from macrophage foam cells. However, other antiatherosclerotic properties of HDL are poorly understood. To test the hypothesis that the lipoprotein carries proteins that might have novel cardioprotective activities, we used shotgun proteomics to investigate the composition of HDL isolated from healthy subjects and subjects with coronary artery disease (CAD). Unexpectedly, our analytical strategy identified multiple complement-regulatory proteins and a diverse array of distinct serpins with serine-type endopeptidase inhibitor activity. Many acute-phase response proteins were also detected, supporting the proposal that HDL is of central importance in inflammation. Mass spectrometry and biochemical analyses demonstrated that HDL3 from subjects with CAD was selectively enriched in apoE, raising the possibility that HDL carries a unique cargo of proteins in humans with clinically significant cardiovascular disease. Collectively, our observations suggest that HDL plays previously unsuspected roles in regulating the complement system and protecting tissue from proteolysis and that the protein cargo of HDL contributes to its antiinflammatory and antiatherogenic properties.

895 citations

Journal ArticleDOI
TL;DR: Physiological concentrations of HDLs inhibit tumor necrosis factor-alpha or interleukin-1 (IL-1) induction of these leukocyte adhesion molecules in a concentration-dependent manner and have no effect on TNF-alpha-induced expression of ICAM-1 by human foreskin fibroblasts, suggesting that the effect is cell-type restricted.
Abstract: While an elevated plasma concentration of HDLs is protective against the development of atherosclerosis and ensuing coronary heart disease (CHD), the mechanism of this protection is unknow...

754 citations

Journal ArticleDOI
TL;DR: Cell-surface HSPG play a critical role in remnant uptake, not only in the important initial sequestration or capture step in the space of Disse, but also as an essential or integral component of the H SPG-LRP pathway.

683 citations

Journal ArticleDOI
TL;DR: Direct assessment of lipoprotein particle numbers us now possible through nuclear magnetic resonance spectroscopic analysis.

646 citations