Abstract 260: Knockout of Apolipoprotein A-II Has Dramatic Effects on High-Density Lipoprotein Subspecies Distribution

High density lipoproteins (HDL) are a highly heterogeneous population of particles composed of various lipids and proteins. They have been demonstrated to possess a diverse variety of functional properties which are thought to contribute to protection against cardiovascular disease (CVD). Proteomics studies have identified up to 75 different proteins which can associate with HDL. The basis for the compositional diversity of HDL is not known but a better understanding will yield important information about its broad functional diversity. To investigate the impact of common HDL apolipoproteins on the distribution of other apolipoproteins, we have begun to systematically fractionate plasma from various HDL apolipoprotein KO mice. Plasma from apoA-I, apoA-IV and apoA-II global KO mice was applied to gel filtration chromatography to distinguish HDL size populations. HDL particles sequestered by a phospholipid binding resin were proteomically analyzed by electrospray ionization mass spectrometry. By comparing elution volume shifts (i.e. particle size variations) for each HDL protein between WT controls and the KO models, we assessed the impact of the deleted protein on HDL size distributions. Ablation of apoA-I, while decreasing total HDL phospholipid by 70%, had a surprisingly small impact on the distribution of the majority of other HDL associated proteins - affecting only 9 of them. Genetic apoA-IV ablation had a similar modest effect shifting a distinct subset of 9 proteins. However, loss of apoA-II, in addition to causing a similar 70% reduction in overall HDL phospholipids, affected the size distribution of some 45 HDL proteins (including several complement proteins and paraoxonase-1). These data suggest that apoA-I, while associated with the majority of HDL phospholipid, may actually interact with relatively few of the lower abundance proteins known to be associated with HDL. ApoA-II on the other hand, may interact with many of these, perhaps acting as a docking site or adaptor molecule.

Download Full-text

High-Density Lipoproteins and the Kidney

Cells ◽

10.3390/cells10040764 ◽

2021 ◽

Vol 10 (4) ◽

pp. 764

Author(s):

Arianna Strazzella ◽

Alice Ossoli ◽

Laura Calabresi

Keyword(s):

Kidney Disease ◽

Renal Disease ◽

Cholesterol Acyltransferase ◽

Density Lipoprotein ◽

Hdl Cholesterol ◽

High Density ◽

High Density Lipoproteins ◽

Lcat Deficiency ◽

Progression Of Renal Disease ◽

The Impact

Dyslipidemia is a typical trait of patients with chronic kidney disease (CKD) and it is typically characterized by reduced high-density lipoprotein (HDL)-cholesterol(c) levels. The low HDL-c concentration is the only lipid alteration associated with the progression of renal disease in mild-to-moderate CKD patients. Plasma HDL levels are not only reduced but also characterized by alterations in composition and structure, which are responsible for the loss of atheroprotective functions, like the ability to promote cholesterol efflux from peripheral cells and antioxidant and anti-inflammatory proprieties. The interconnection between HDL and renal function is confirmed by the fact that genetic HDL defects can lead to kidney disease; in fact, mutations in apoA-I, apoE, apoL, and lecithin–cholesterol acyltransferase (LCAT) are associated with the development of renal damage. Genetic LCAT deficiency is the most emblematic case and represents a unique tool to evaluate the impact of alterations in the HDL system on the progression of renal disease. Lipid abnormalities detected in LCAT-deficient carriers mirror the ones observed in CKD patients, which indeed present an acquired LCAT deficiency. In this context, circulating LCAT levels predict CKD progression in individuals at early stages of renal dysfunction and in the general population. This review summarizes the main alterations of HDL in CKD, focusing on the latest update of acquired and genetic LCAT defects associated with the progression of renal disease.

Download Full-text

Dysfunctional high-density lipoprotein: the role of myeloperoxidase and paraoxonase-1

Current Medicinal Chemistry ◽

10.2174/0929867327999200716112353 ◽

2020 ◽

Vol 27 ◽

Cited By ~ 1

Author(s):

Tiziana Bacchetti ◽

Gianna Ferretti ◽

Federico Carbone ◽

Stefano Ministrini ◽

Fabrizio Montecucco ◽

...

Keyword(s):

Metabolic Syndrome ◽

Protective Factor ◽

Density Lipoprotein ◽

High Density ◽

Paraoxonase 1 ◽

High Density Lipoproteins ◽

Atherosclerotic Cardiovascular Disease ◽

Potential Marker ◽

And Function

: Low circulating high-density lipoproteins (HDL) are not only a defining criteria for metabolic syndrome, but are more generally associated with atherosclerotic cardiovascular disease (ASCVD) and other chronic diseases. Oxidative stress, a hallmark of cardio-metabolic disease, further influences HDL activity by suppressing their function. Especially the leukocyte-derived enzyme myeloperoxidase (MPO) has recently attracted great interest as it catalyzes the formation of oxidizing reactive species that modify the structure and function of HDL, ultimately increasing cardiovascular risk. Contrariwise, paraoxonase-1 (PON1) is an HDL-associated enzyme that protects HDL from lipid oxidation, and then acts as a protective factor against ASCVD. Noteworthy, recent studies have demonstrated how MPO, PON1 and HDL form a functional complex in which PON1 partially inhibits the MPO activity, while MPO in turn partially inactivates PON1.In line with that, high MPO/PON1 ratio characterizes patients with ASCVD and metabolic syndrome and has been suggested as a potential marker of dysfunctional HDL as well as a predictor of ASCVD. In this review, we summarize the evidence on the interactions between MPO and PON1 with regard to their structure, function and interaction with HDL activity. We also provide an overview on in vitro and experimental animal models, finally focusing on clinical evidence from cohort of patients with ASCVD and metabolic syndrome.

Download Full-text

Changes in High-Density Lipoproteins Related to Outcomes in Patients with Acute Stroke

Journal of Clinical Medicine ◽

10.3390/jcm9072269 ◽

2020 ◽

Vol 9 (7) ◽

pp. 2269

Author(s):

Lourdes M. Varela ◽

Elena Meseguer ◽

Bertrand Lapergue ◽

David Couret ◽

Pierre Amarenco ◽

...

Keyword(s):

Endothelial Cells ◽

Density Lipoprotein ◽

Intravenous Thrombolysis ◽

High Density ◽

Paraoxonase 1 ◽

Intercellular Adhesion Molecule ◽

High Density Lipoproteins ◽

Stroke Patients ◽

Lipoprotein Subfractions ◽

Anti Inflammatory

Modifications in high-density lipoprotein (HDL) particle sizes and HDL-binding proteins have been reported in stroke patients. We evaluated whether the lipoprotein profile, HDL composition and functionality were altered in stroke patients according to their clinical outcome using the modified Rankin Score at 3 months. Plasma samples were obtained from stroke patients treated with intravenous thrombolysis. Levels of cardiovascular and inflammatory markers in plasma were measured using the Human CVD Panel 1 (Milliplex® MAP). Lipoprotein subfractions from plasma were quantified by non-denaturing acrylamide gel electrophoresis, using the Lipoprint®-System (Quantimetrix®), and HDLs were isolated by ultracentrifugation. Relative amounts of paraoxonase-1 (PON1) and alpha-1 anti-trypsin (AAT) in the isolated HDLs were determined by Western blot. HDL anti-inflammatory function was evaluated in human blood–brain barrier endothelial cells stimulated with 100 ng/mL TNFα, and HDL antioxidant function was evaluated via their capacity to limit copper-induced low-density lipoprotein oxidation. Stroke patients with unfavorable outcomes had a lower proportion of small-sized HDLs and increased plasma levels of E-selectin (SELE) and the intercellular adhesion molecule 1 (ICAM1). HDLs from patients with unfavorable outcomes had lower levels of PON1 and displayed a blunted capacity to reduce the expression of SELE, interleukin 8 (IL8) and the monocyte chemoattractant protein-1 (MCP1) mRNA induced by TNFα in endothelial cells. These HDLs also had a reduced antioxidant capacity relative to HDLs from healthy donors. In conclusion, an increased ratio of large/small HDLs with impaired anti-inflammatory and antioxidant capacities was associated with unfavorable outcomes in stroke patients. Alteration of HDL functionality was mainly associated with a low amount of PON1 and high amount of AAT.

Download Full-text

An obesity model and corona multiomics analysis reveal high-density lipoprotein effects on lipid nanoparticle function

10.21203/rs.3.rs-827883/v1 ◽

2021 ◽

Author(s):

Kai Liu ◽

Ralf Nilsson ◽

Elisa Lázaro-Ibáñez ◽

Tasso Miliotis ◽

Michael Lerche ◽

...

Keyword(s):

Density Lipoprotein ◽

Lipid Nanoparticles ◽

High Density ◽

High Density Lipoproteins ◽

Nucleic Acid Delivery ◽

Cargo Delivery ◽

Corona Formation ◽

Obese Rats ◽

The Impact ◽

The Relationship

Abstract Lipid nanoparticles (LNPs) are currently of great interest for therapeutic nucleic acid delivery. Lipid-based nanoparticles are, however, difficult to study analytically and so our understanding of the interaction between LNPs and biological systems remains obscure, particularly in terms of biomolecular corona formation and the impact this has on therapeutic efficacy and targeting. Ideally, we would like to engineer particles to acquire corona components that facilitate targeting, cargo delivery and improved safety. This requires studying the relationship between LNPs, biofluids and the resulting coronas. The particle-corona complexes are, however, fragile and biofluids also contain particles (such as lipoproteins) with sizes and biochemical characteristics similar to lipid nanoparticles, so contamination with biological components is a challenge. Here we describe a rapid, automated, and unbiased isolation method for LNP biomolecular coronas, coupled with proteomic and lipidomic analysis. Using these analytical methods, we systematically studied, in lean and obese rats, the variation in LNP-mediated mRNA delivery caused by individual physiology. A comprehensive multivariate model links LNP corona content to efficacy, identifying and validating high-density lipoproteins as a previously unidentified factor affecting particle efficacy.

Download Full-text

Current Therapies Focused on High-Density Lipoproteins Associated with Cardiovascular Disease

Molecules ◽

10.3390/molecules23112730 ◽

2018 ◽

Vol 23 (11) ◽

pp. 2730 ◽

Cited By ~ 9

Author(s):

Diego Estrada-Luna ◽

María Ortiz-Rodriguez ◽

Lizett Medina-Briseño ◽

Elizabeth Carreón-Torres ◽

Jeannett Izquierdo-Vega ◽

...

Keyword(s):

Cardiovascular Diseases ◽

Molecular Mechanisms ◽

Density Lipoprotein ◽

Protein Composition ◽

Inverse Correlation ◽

Epidemiological Studies ◽

High Density ◽

High Density Lipoproteins ◽

Current Therapies ◽

The Impact

High-density lipoproteins (HDL) comprise a heterogeneous family of lipoprotein particles divided into subclasses that are determined by density, size and surface charge as well as protein composition. Epidemiological studies have suggested an inverse correlation between High-density lipoprotein-cholesterol (HDL-C) levels and the risk of cardiovascular diseases and atherosclerosis. HDLs promote reverse cholesterol transport (RCT) and have several atheroprotective functions such as anti-inflammation, anti-thrombosis, and anti-oxidation. HDLs are considered to be atheroprotective because they are associated in serum with paraoxonases (PONs) which protect HDL from oxidation. Polyphenol consumption reduces the risk of chronic diseases in humans. Polyphenols increase the binding of HDL to PON1, increasing the catalytic activity of PON1. This review summarizes the evidence currently available regarding pharmacological and alternative treatments aimed at improving the functionality of HDL-C. Information on the effectiveness of the treatments has contributed to the understanding of the molecular mechanisms that regulate plasma levels of HDL-C, thereby promoting the development of more effective treatment of cardiovascular diseases. For that purpose, Scopus and Medline databases were searched to identify the publications investigating the impact of current therapies focused on high-density lipoproteins.

Download Full-text

Protection against Glucolipotoxicity by High Density Lipoprotein in Human PANC-1 Hybrid 1.1B4 Pancreatic Beta Cells: The Role of microRNA

Biology ◽

10.3390/biology10030218 ◽

2021 ◽

Vol 10 (3) ◽

pp. 218

Author(s):

Jamie M.R. Tarlton ◽

Richard J. Lightbody ◽

Steven Patterson ◽

Annette Graham

Keyword(s):

High Density Lipoprotein ◽

Beta Cells ◽

Pancreatic Beta Cells ◽

Cell Model ◽

Density Lipoprotein ◽

High Density ◽

High Density Lipoproteins ◽

Microrna Profile ◽

Altered Gene ◽

The Impact

High-density lipoproteins provide protection against the damaging effects of glucolipotoxicity in beta cells, a factor which sustains insulin secretion and staves off onset of type 2 diabetes mellitus. This study examines epigenetic changes in small non-coding microRNA sequences induced by high density lipoproteins in a human hybrid beta cell model, and tests the impact of delivery of a single sequence in protecting against glucolipotoxicity. Human PANC-1.1B4 cells were used to establish Bmax and Kd for [3H]cholesterol efflux to high density lipoprotein, and minimum concentrations required to protect cell viability and reduce apoptosis to 30mM glucose and 0.25 mM palmitic acid. Microchip array identified the microRNA signature associated with high density lipoprotein treatment, and one sequence, hsa-miR-21-5p, modulated via delivery of a mimic and inhibitor. The results confirm that low concentrations of high-density lipoprotein can protect against glucolipotoxicity, and report the global microRNA profile associated with this lipoprotein; delivery of miR-21-5p mimic altered gene targets, similar to high density lipoprotein, but could not provide sufficient protection against glucolipotoxicity. We conclude that the complex profile of microRNA changes due to HDL treatment may be difficult to replicate using a single microRNA, findings which may inform current drug strategies focused on this approach.

Download Full-text

Fetal High-Density Lipoproteins: Current Knowledge on Particle Metabolism, Composition and Function in Health and Disease

Biomedicines ◽

10.3390/biomedicines9040349 ◽

2021 ◽

Vol 9 (4) ◽

pp. 349

Author(s):

Julia T. Stadler ◽

Christian Wadsack ◽

Gunther Marsche

Keyword(s):

Fetal Development ◽

Current Knowledge ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

High Density ◽

Paraoxonase 1 ◽

High Density Lipoproteins ◽

Low Density ◽

Protein Activity ◽

And Function

Cholesterol and other lipids carried by lipoproteins play an indispensable role in fetal development. Recent evidence suggests that maternally derived high-density lipoprotein (HDL) differs from fetal HDL with respect to its proteome, size, and function. Compared to the HDL of adults, fetal HDL is the major carrier of cholesterol and has a unique composition that implies other physiological functions. Fetal HDL is enriched in apolipoprotein E, which binds with high affinity to the low-density lipoprotein receptor. Thus, it appears that a primary function of fetal HDL is the transport of cholesterol to tissues as is accomplished by low-density lipoproteins in adults. The fetal HDL-associated bioactive sphingolipid sphingosine-1-phosphate shows strong vasoprotective effects at the fetoplacental vasculature. Moreover, lipoprotein-associated phospholipase A2 carried by fetal-HDL exerts anti-oxidative and athero-protective functions on the fetoplacental endothelium. Notably, the mass and activity of HDL-associated paraoxonase 1 are about 5-fold lower in the fetus, accompanied by an attenuation of anti-oxidative activity of fetal HDL. Cholesteryl ester transfer protein activity is reduced in fetal circulation despite similar amounts of the enzyme in maternal and fetal serum. This review summarizes the current knowledge on fetal HDL as a potential vasoprotective lipoprotein during fetal development. We also provide an overview of whether and how the protective functionalities of HDL are impaired in pregnancy-related syndromes such as pre-eclampsia or gestational diabetes mellitus.

Download Full-text

High-Density Lipoproteins and Cardiovascular Disease: The Good, the Bad and the Future

Biomedicines ◽

10.3390/biomedicines9080857 ◽

2021 ◽

Vol 9 (8) ◽

pp. 857

Author(s):

Josep Julve ◽

Joan Carles Escolà-Gil

Keyword(s):

Cardiovascular Disease ◽

High Density Lipoprotein ◽

High Density Lipoprotein Cholesterol ◽

Density Lipoprotein ◽

Epidemiological Studies ◽

High Density ◽

High Density Lipoproteins ◽

Atherosclerotic Cardiovascular Disease ◽

Plasma High Density ◽

Low Levels

Epidemiological studies have shown that low levels of plasma high-density lipoprotein cholesterol (HDL-C) are associated with increased atherosclerotic cardiovascular disease (CVD) [...]

Download Full-text