High-Density Lipoproteins

Abstract

Low plasma levels of high-density lipoprotein (HDL) cholesterol are associated with increased risks of coronary artery disease (CAD). HDL particles exert many effects in vitro and in vivo that may protect arteries from chemical or biological harm or facilitate repair of injuries. Nevertheless, HDL has not yet been successfully exploited for therapy. One potential reason for this shortfall is the structural and functional complexity of HDL particles, which carry more than 80 different proteins and more than 200 lipid species as well as several microRNAs and other potentially bioactive molecules. This physiological heterogeneity is further increased in several inflammatory conditions that increase cardiovascular risk, including CAD itself but also diabetes mellitus, chronic kidney disease, and rheumatic diseases. The quantitative and qualitative modifications of the proteome and lipidome, as well as the resulting loss of functions or gain of dysfunctions, are not recovered by the biomarker HDL-cholesterol. As yet the relative importance of the many physiological and pathological activities of normal and dysfunctional HDL, respectively, for the pathogenesis of atherosclerosis is unknown. The answer to this question, as well as detailed knowledge of structure-function-relationships of HDL-associated molecules, is a prerequisite to exploit HDL for the development of anti-atherogenic drugs as well as of diagnostic biomarkers for the identification, personalized treatment stratification, and monitoring of patients at increased cardiovascular risk. 2433Multifunctional but Vulnerable HDL munication of results. 15 As yet, clinical and epidemiological studies have come to discrepant and inconsistent conclusions on the prognostic performance of HDL subclasses differentiated by size. 14,20-24 Sometimes the associations of cardiovascular risk with the various HDL subclass concentrations were not stronger than with HDL-C, 20,21 and even if so, the associations with size were discrepant: significant associations with risk of cardiovascular events or stroke were found for small HDL in some studies, 22,23 but for medium-sized HDL 21,23 or large HDL 14,20,21,24 in others.Previous proteomic, lipidomic, and transcriptomic studies revealed a much greater structural complexity of HDLs: 80 different proteins, 25,26 more than 200 lipid species, 27,28 and several microRNAs 29,30 have been identified in HDL isolated from plasma by either ultracentrifugation, gel filtration, or immunoaffinity chromatography (Figure 1). Among the proteins, apoA-II is present in HDLs at the highest concentration after that of apoA-I and has been investigated for its cardiovascular risk association by several studies. In contrast to initial findings, large prospective studies did not find any significant differences in the risk association between apoA-II-containing and apoA-II-free HDL. [15][16][17] Despite their much lower concentrations relative to the 2 major proteins apoA-I and apoA-II and relative to the major lipids, many quantitatively minor componen...

Impact of Virgin Olive Oil and Phenol-Enriched Virgin Olive Oils on the HDL Proteome in Hypercholesterolemic Subjects: A Double Blind, Randomized, Controlled, Cross-Over Clinical Trial (VOHF Study)

“…Both proteins participate in reverse cholesterol transport and present anti-inflammatory and antioxidant properties [24,25]. The increase in Apo A-I concurred with the results observed by Solà et al [26] in high CVD risk subjects after following a Mediterranean diet rich in VOO.…”

HIV infection induces structural and functional changes in high density lipoproteins

“…HDL has been established as a major anti-atherogenic lipoprotein, both because of its role in reverse cholesterol transport and its anti-inflammatory properties 18 . Low HDL levels are associated with a high risk of atherosclerosis in animal models and in humans 19 .…”

A fast semi-quantitative LC–MS method for measurement of intact apolipoprotein A-I reveals novel proteoforms in serum

“…In combination with the genetic isoforms and truncations, the different posttranslational ApoA-I proteoforms give rise to a significant set of modified ApoA-I molecules each one of which may unevenly contribute to HDL particle formation, HDL metabolism and RCT functionality [1]. Proteoforms of ApoA-I has earlier been measured with rather tedious and less reproducible and standardized methods such as 2-D electrophoresis combined with mass spectrometry in a bottom-up fashion and to quantitate glycated ApoA-I, boronate affinity chromatography combined with conventional immunochemistry has been employed [13][14][15].…”

“…Several posttranslational modifications of the ApoA-I protein relating to ongoing pathobiologically relevant metabolic changes have been reported such as glycation, oxidation and truncation some of which may affect the anti-inflammatory actions locally in the plaque as well as the efficiency of HDL to function in the RCT pathway [1]. Earlier studies have implicated glycation as well as oxidation of ApoA-I as associated with atherosclerotic disease or as diagnostic markers [2,3].…”

“…Earlier studies have implicated glycation as well as oxidation of ApoA-I as associated with atherosclerotic disease or as diagnostic markers [2,3]. Among the complex HDL-proteome consisting of more than 80 different proteins or peptides, ApoA-I, a protein of 243 amino acids (MW = 28 kDa), is a crucial contributor to RCT acting as a means of shuttling excess cholesterol from atherogenic foam cells to the exterior via hepatic biliary secretion [1]. As the prime protein constituent of the HDL-proteome, circulating ApoA-I is believed to contribute to the early nascence of the HDL particle via its interaction with ATP-binding cassette protein A1, ATP-binding cassette sub-family G member 1 and scavenger receptor class B member 1 enhancing cholesterol efflux to nascent as well as more mature HDL particles.…”