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

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 October 2020).

Special Issue Editors

Dr. Joan Carles Escolà-Gil
Website
Guest Editor
Institut d’Investigacions Biomèdiques (IIB) Sant Pau, CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain
Interests: atherosclerosis; cholesterol; genetically-modified mice; HDL; lipoproteins
Special Issues and Collections in MDPI journals
Dr. Josep Julve
Website
Guest Editor
Institut d’Investigacions Biomèdiques (IIB) Sant Pau, CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain
Interests: obesity; diabetes; lipoprotein metabolism; metabolic syndrome; therapeutics
Special Issues and Collections in MDPI journals

Special Issue Information

Dear colleagues,

Epidemiological, clinical, and experimental studies have shown that low levels of plasma high-density lipoprotein (HDL) cholesterol are associated with increased atherosclerotic cardiovascular disease. Nevertheless, HDL-targeted drugs, such as cholesteryl ester transfer protein inhibitors, fibrates, and niacin, have failed to reduce cardiovascular events in clinical trials, thereby casting doubt on the beneficial effects of raising HDL levels.

Experimental studies have identified several HDL cardioprotective functions, including the enhancement of macrophage reverse cholesterol transport and endothelial function, as well as its antioxidant, anti-inflammatory, and anti-thrombotic properties. HDL is highly heterogeneous and carries a large variety of lipids, proteins, and microRNAs. The different composition of HDL subpopulations is directly related to their cardioprotective functions, but the assignment of specific molecules to HDL functions is not completely understood.

Compelling available data strongly indicate that increased HDL cholesterol levels do not always correlate with enhanced beneficial HDL properties, thus questioning their potential as a biomarker of HDL functionality. In addition, the association between low HDL cholesterol and cardiovascular disease can be further confounded by several factors, including insulin resistance, inflammation, and/or metabolic derangements leading to altered plasma lipids, thereby indicating that low HDL levels could simply be a marker of an underlying pathology. Current research is moving towards both the development of robust HDL function tests and the identification of specific HDL molecules (many of them bioactive) within HDL that can be widely applied in translational and pre-clinical studies. The application of novel HDL-based approaches for therapeutic purposes requires the development of validated and reproducible measures of these key atheroprotective HDL functions.

This Special Issue is jointly organized between IJMS and Biomedicines journals. According to the Aims and Scope of these journals, articles showing basic studies in biochemistry, molecular biology, and molecular medicine can be submitted to IJMS, while articles presenting more clinical content can be submitted to Biomedicines.

Dr. Joan Carles Escolà-Gil
Dr. Josep Julve
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • atherosclerosis
  • cardiovascular
  • diabetes
  • cholesterol
  • HDL
  • inflammation
  • mice
  • oxidation
  • therapy

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Published Papers (19 papers)

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Research

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Open AccessArticle
Endothelial Lipase Modulates Paraoxonase 1 Content and Arylesterase Activity of HDL
Int. J. Mol. Sci. 2021, 22(2), 719; https://doi.org/10.3390/ijms22020719 - 13 Jan 2021
Abstract
Endothelial lipase (EL) is a strong modulator of the high-density lipoprotein (HDL) structure, composition, and function. Here, we examined the impact of EL on HDL paraoxonase 1 (PON1) content and arylesterase (AE) activity in vitro and in vivo. The incubation of HDL with [...] Read more.
Endothelial lipase (EL) is a strong modulator of the high-density lipoprotein (HDL) structure, composition, and function. Here, we examined the impact of EL on HDL paraoxonase 1 (PON1) content and arylesterase (AE) activity in vitro and in vivo. The incubation of HDL with EL-overexpressing HepG2 cells decreased HDL size, PON1 content, and AE activity. The EL modification of HDL did not diminish the capacity of HDL to associate with PON1 when EL-modified HDL was incubated with PON1-overexpressing cells. The overexpression of EL in mice significantly decreased HDL serum levels but unexpectedly increased HDL PON1 content and HDL AE activity. Enzymatically inactive EL had no effect on the PON1 content of HDL in mice. In healthy subjects, EL serum levels were not significantly correlated with HDL levels. However, HDL PON1 content was positively associated with EL serum levels. The EL-induced changes in the HDL-lipid composition were not linked to the HDL PON1 content. We conclude that primarily, the interaction of enzymatically active EL with HDL, rather than EL-induced alterations in HDL size and composition, causes PON1 displacement from HDL in vitro. In vivo, the EL-mediated reduction of HDL serum levels and the consequently increased PON1-to-HDL ratio in serum increase HDL PON1 content and AE activity in mice. In humans, additional mechanisms appear to underlie the association of EL serum levels and HDL PON1 content. Full article
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Open AccessArticle
Early Signs of Atherogenic Features in the HDL Lipidomes of Normolipidemic Patients Newly Diagnosed with Type 2 Diabetes
Int. J. Mol. Sci. 2020, 21(22), 8835; https://doi.org/10.3390/ijms21228835 - 22 Nov 2020
Abstract
Cardiovascular disease (CVD) is the major cause of death in patients with type-2 diabetes mellitus (T2DM), although the factors that accelerate atherosclerosis in these patients are poorly understood. The identification of the altered quantity and quality of lipoproteins, closely related to atherogenesis, is [...] Read more.
Cardiovascular disease (CVD) is the major cause of death in patients with type-2 diabetes mellitus (T2DM), although the factors that accelerate atherosclerosis in these patients are poorly understood. The identification of the altered quantity and quality of lipoproteins, closely related to atherogenesis, is limited in routine to a pattern of high triglycerides and low HDL-cholesterol (HDL-C) and in research as dysfunctional HDLs. We used the emerging NMR-based lipidomic technology to investigate compositional features of the HDLs of healthy individuals with normal coronary arteries, drug-naïve; recently diagnosed T2DM patients with normal coronary arteries; and patients with recent acute coronary syndrome. Patients with T2DM and normal serum lipid profiles even at diagnosis presented significant lipid alterations in HDL, characterized by higher triglycerides, lysophosphatidylcholine and saturated fatty acids; and lower cholesterol, phosphatidylcholine, phosphatidylethanolamine, sphingomyelin, plasmalogens and polyunsaturated fatty acids, an atherogenic pattern that may be involved in the pathogenesis of atherosclerosis. These changes are qualitatively similar to those found, more profoundly, in normolipidemic patients with established Coronary Heart Disease (CHD). We also conclude that NMR-based lipidomics offer a novel holistic exploratory approach for identifying and quantifying lipid species in biological matrixes in physiological processes and disease states or in disease biomarker discovery. Full article
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Open AccessArticle
High-Density Lipoprotein (HDL) Inhibits Serum Amyloid A (SAA)-Induced Vascular and Renal Dysfunctions in Apolipoprotein E-Deficient Mice
Int. J. Mol. Sci. 2020, 21(4), 1316; https://doi.org/10.3390/ijms21041316 - 15 Feb 2020
Cited by 3
Abstract
Serum amyloid A (SAA) promotes endothelial inflammation and dysfunction that is associated with cardiovascular disease and renal pathologies. SAA is an apoprotein for high-density lipoprotein (HDL) and its sequestration to HDL diminishes SAA bioactivity. Herein we investigated the effect of co-supplementing HDL on [...] Read more.
Serum amyloid A (SAA) promotes endothelial inflammation and dysfunction that is associated with cardiovascular disease and renal pathologies. SAA is an apoprotein for high-density lipoprotein (HDL) and its sequestration to HDL diminishes SAA bioactivity. Herein we investigated the effect of co-supplementing HDL on SAA-mediated changes to vascular and renal function in apolipoprotein E-deficient (ApoE/) mice in the absence of a high-fat diet. Male ApoE−/− mice received recombinant human SAA or vehicle (control) by intraperitoneal (i.p.) injection every three days for two weeks with or without freshly isolated human HDL supplemented by intravenous (i.v.) injection in the two weeks preceding SAA stimulation. Aorta and kidney were harvested 4 or 18 weeks after commencement of treatment. At 4 weeks after commencement of treatment, SAA increased aortic vascular cell adhesion molecule (VCAM)-1 expression and F2-isoprostane level and decreased cyclic guanosine monophosphate (cGMP), consistent with SAA stimulating endothelial dysfunction and promoting atherosclerosis. SAA also stimulated renal injury and inflammation that manifested as increased urinary protein, kidney injury molecule (KIM)-1, and renal tissue cytokine/chemokine levels as well as increased protein tyrosine chlorination and P38 MAPkinase activation and decreased in Bowman’s space, confirming that SAA elicited a pro-inflammatory phenotype in the kidney. At 18 weeks, vascular lesions increased significantly in the cohort of ApoE−/− mice treated with SAA alone. By contrast, pretreatment of mice with HDL decreased SAA pro-inflammatory activity, inhibited SAA enhancement of aortic lesion size and renal function, and prevented changes to glomerular Bowman’s space. Taken together, these data indicate that supplemented HDL reduces SAA-mediated endothelial and renal dysfunction in an atherosclerosis-prone mouse model. Full article
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Open AccessArticle
The Mechanism of Bisphenol A Atherogenicity Involves Apolipoprotein A-I Downregulation through NF-κB Activation
Int. J. Mol. Sci. 2019, 20(24), 6281; https://doi.org/10.3390/ijms20246281 - 12 Dec 2019
Cited by 2
Abstract
Apolipoprotein A-I (apoA-I) is the major protein component of high-density lipoproteins (HDL), mediating many of its atheroprotective properties. Increasing data reveal the pro-atherogenic effects of bisphenol A (BPA), one of the most prevalent environmental chemicals. In this study, we investigated the mechanisms by [...] Read more.
Apolipoprotein A-I (apoA-I) is the major protein component of high-density lipoproteins (HDL), mediating many of its atheroprotective properties. Increasing data reveal the pro-atherogenic effects of bisphenol A (BPA), one of the most prevalent environmental chemicals. In this study, we investigated the mechanisms by which BPA exerts pro-atherogenic effects. For this, LDLR−/− mice were fed with a high-fat diet and treated with 50 µg BPA/kg body weight by gavage. After two months of treatment, the area of atherosclerotic lesions in the aorta, triglycerides and total cholesterol levels were significantly increased, while HDL-cholesterol was decreased in BPA-treated LDLR−/− mice as compared to control mice. Real-Time PCR data showed that BPA treatment decreased hepatic apoA-I expression. BPA downregulated the activity of the apoA-I promoter in a dose-dependent manner. This inhibitory effect was mediated by MEKK1/NF-κB signaling pathways. Transfection experiments using apoA-I promoter deletion mutants, chromatin immunoprecipitation, and protein-DNA interaction assays demonstrated that treatment of hepatocytes with BPA induced NF-κB signaling and thus the recruitment of p65/50 proteins to the multiple NF-κB binding sites located in the apoA-I promoter. In conclusion, BPA exerts pro-atherogenic effects downregulating apoA-I by MEKK1 signaling and NF-κB activation in hepatocytes. Full article
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Open AccessArticle
Cholesterol Acceptors Regulate the Lipidome of Macrophage Foam Cells
Int. J. Mol. Sci. 2019, 20(15), 3784; https://doi.org/10.3390/ijms20153784 - 02 Aug 2019
Cited by 4
Abstract
Arterial foam cells are central players of atherogenesis. Cholesterol acceptors, apolipoprotein A-I (apoA-I) and high-density lipoprotein (HDL), take up cholesterol and phospholipids effluxed from foam cells into the circulation. Due to the high abundance of cholesterol in foam cells, most previous studies focused [...] Read more.
Arterial foam cells are central players of atherogenesis. Cholesterol acceptors, apolipoprotein A-I (apoA-I) and high-density lipoprotein (HDL), take up cholesterol and phospholipids effluxed from foam cells into the circulation. Due to the high abundance of cholesterol in foam cells, most previous studies focused on apoA-I/HDL-mediated free cholesterol (FC) transport. However, recent lipidomics of human atherosclerotic plaques also identified that oxidized sterols (oxysterols) and non-sterol lipid species accumulate as atherogenesis progresses. While it is known that these lipids regulate expression of pro-inflammatory genes linked to plaque instability, how cholesterol acceptors impact the foam cell lipidome, particularly oxysterols and non-sterol lipids, remains unexplored. Using lipidomics analyses, we found cholesterol acceptors remodel foam cell lipidomes. Lipid subclass analyses revealed various oxysterols, sphingomyelins, and ceramides, species uniquely enriched in human plaques were significantly reduced by cholesterol acceptors, especially by apoA-I. These results indicate that the function of lipid-poor apoA-I is not limited to the efflux of cholesterol and phospholipids but suggest that apoA-I serves as a major regulator of the foam cell lipidome and might play an important role in reducing multiple lipid species involved in the pathogenesis of atherosclerosis. Full article
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Open AccessArticle
HDL Triglycerides: A New Marker of Metabolic and Cardiovascular Risk
Int. J. Mol. Sci. 2019, 20(13), 3151; https://doi.org/10.3390/ijms20133151 - 27 Jun 2019
Cited by 9
Abstract
While cholesterol content in high-density lipoproteins (HDLs) is a well-established inverse marker of cardiovascular risk, the importance of HDL–triglyceride (HDL-TG) concentration is not well known. We aim to examine plasma HDL-TG concentrations, assessed by 1H-NMR, in patients with metabolic diseases and their [...] Read more.
While cholesterol content in high-density lipoproteins (HDLs) is a well-established inverse marker of cardiovascular risk, the importance of HDL–triglyceride (HDL-TG) concentration is not well known. We aim to examine plasma HDL-TG concentrations, assessed by 1H-NMR, in patients with metabolic diseases and their association with classical biomarkers. In this cross-sectional study, we included 502 patients with type 2 diabetes or metabolic syndrome attending the lipid unit of our University Hospital. The presence of arteriosclerotic plaques was assessed by ultrasonography. A complete lipoprotein profile was performed by 1H-NMR (Liposcale test). HDL-TG was strongly positively correlated with total triglycerides, glycerol, and fatty liver index, while a strong negative correlation was observed with HDL-cholesterol (HDL-C) and HDL-particle number (HDL-P). HDL-TG was associated with all triglyceride-rich lipoprotein parameters and had an opposite association with HDL-C and HDL-P. It was also significantly correlated with circulating cholesterol ester transfer protein (CETP). HDL-TG concentrations were higher as metabolic syndrome components increased. HDL-TG was also higher with worsening glucose metabolism. Patients with carotid plaques also showed higher HDL-TG. In contrast to HDL-C, HDL-TG is directly associated with metabolism and arteriosclerotic vascular alterations. HDL-TG should be considered a biomarker of metabolic and cardiovascular risk and could be a marker of HDL dysfunction. Full article
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Open AccessArticle
Lipoprotein Lipase Inhibitor, Nordihydroguaiaretic Acid, Aggravates Metabolic Phenotypes and Alters HDL Particle Size in the Western Diet-Fed db/db Mice
Int. J. Mol. Sci. 2019, 20(12), 3057; https://doi.org/10.3390/ijms20123057 - 22 Jun 2019
Cited by 3
Abstract
Lipoprotein lipase (LPL) hydrolyzes triglycerides in lipoprotein to supply fatty acids, and its deficiency leads to hypertriglyceridemia, thereby inducing metabolic syndrome (MetSyn). Nordihydroguaiaretic acid (NDGA) has been recently reported to inhibit LPL secretion by endoplasmic reticulum (ER)-Golgi redistribution. However, the role of NDGA [...] Read more.
Lipoprotein lipase (LPL) hydrolyzes triglycerides in lipoprotein to supply fatty acids, and its deficiency leads to hypertriglyceridemia, thereby inducing metabolic syndrome (MetSyn). Nordihydroguaiaretic acid (NDGA) has been recently reported to inhibit LPL secretion by endoplasmic reticulum (ER)-Golgi redistribution. However, the role of NDGA on dyslipidemia and MetSyn remains unclear. To address this question, leptin receptor knock out (KO)-db/db mice were randomly assigned to three different groups: A normal AIN76-A diet (CON), a Western diet (WD) and a Western diet with 0.1% NDGA and an LPL inhibitor, (WD+NDGA). All mice were fed for 12 weeks. The LPL inhibition by NDGA was confirmed by measuring the systemic LPL mass and adipose LPL gene expression. We investigated whether the LPL inhibition by NDGA alters the metabolic phenotypes. NDGA led to hyperglycemia, hypertriglyceridemia, and hypercholesterolemia. More strikingly, the supplementation of NDGA increased the percentage of high density lipoprotein (HDL)small (HDL3a+3b+3c) and decreased the percentage of HDLlarge (HDL2a+2b) compared to the WD group, which indicates that LPL inhibition modulates HDL subclasses. was NDGA increased adipose inflammation but had no impact on hepatic stress signals. Taken together, these findings demonstrated that LPL inhibition by NDGA aggravates metabolic parameters and alters HDL particle size. Full article
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Open AccessArticle
Effective Treatment of Diabetic Cardiomyopathy and Heart Failure with Reconstituted HDL (Milano) in Mice
Int. J. Mol. Sci. 2019, 20(6), 1273; https://doi.org/10.3390/ijms20061273 - 13 Mar 2019
Cited by 11
Abstract
The risk of heart failure (HF) is prominently increased in patients with type 2 diabetes mellitus. The objectives of this study were to establish a murine model of diabetic cardiomyopathy induced by feeding a high-sugar/high-fat (HSHF) diet and to evaluate the effect of [...] Read more.
The risk of heart failure (HF) is prominently increased in patients with type 2 diabetes mellitus. The objectives of this study were to establish a murine model of diabetic cardiomyopathy induced by feeding a high-sugar/high-fat (HSHF) diet and to evaluate the effect of reconstituted HDLMilano administration on established HF in this model. The HSHF diet was initiated at the age of 12 weeks and continued for 16 weeks. To investigate the effect of reconstituted HDLMilano on HF, eight intraperitoneal administrations of MDCO-216 (100 mg/kg protein concentration) or of an identical volume of control buffer were executed with a 48-h interval starting at the age of 28 weeks. The HSHF diet-induced obesity, hyperinsulinemia, and type 2 diabetes mellitus. Diabetic cardiomyopathy was present in HSHF diet mice as evidenced by cardiac hypertrophy, increased interstitial and perivascular fibrosis, and decreased myocardial capillary density. Pressure-volume loop analysis indicated the presence of both systolic and diastolic dysfunction and of decreased cardiac output in HSHF diet mice. Treatment with MDCO-216 reversed pathological remodelling and cardiac dysfunction and normalized wet lung weight, indicating effective treatment of HF. No effect of control buffer injection was observed. In conclusion, reconstituted HDLMilano reverses HF in type 2 diabetic mice. Full article
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Open AccessArticle
Plasma Levels of Preβ1-HDL Are Significantly Elevated in Non-Dialyzed Patients with Advanced Stages of Chronic Kidney Disease
Int. J. Mol. Sci. 2019, 20(5), 1202; https://doi.org/10.3390/ijms20051202 - 09 Mar 2019
Cited by 4
Abstract
In chronic kidney disease (CKD), the level of high-density lipoprotein (HDL) decreases markedly, but there is no strong inverse relationship between HDL-cholesterol (HDL-C) and cardiovascular diseases. This indicates that not only the HDL-C level, but also the other quantitative changes in the HDL [...] Read more.
In chronic kidney disease (CKD), the level of high-density lipoprotein (HDL) decreases markedly, but there is no strong inverse relationship between HDL-cholesterol (HDL-C) and cardiovascular diseases. This indicates that not only the HDL-C level, but also the other quantitative changes in the HDL particles can influence the protective functionality of these particles, and can play a key role in the increase of cardiovascular risk in CKD patients. The aim of the present study was the evaluation of the parameters that may give additional information about the HDL particles in the course of progressing CKD. For this purpose, we analyzed the concentrations of HDL containing apolipoprotein A-I without apolipoprotein A-II (LpA-I), preβ1-HDL, and myeloperoxidase (MPO), and the activity of paraoxonase-1 (PON-1) in 68 patients at various stages of CKD. The concentration of HDL cholesterol, MPO, PON-1, and lecithin-cholesterol acyltransferase (LCAT) activity were similar in all of the analyzed stages of CKD. We did not notice significant changes in the LpA-I concentrations in the following stages of CKD (3a CKD stage: 57 ± 19; 3b CKD stage: 54 ± 15; 4 CKD stage: 52 ± 14; p = 0.49). We found, however, that the preβ1-HDL concentration and preβ1-HDL/LpA-I ratio increased along with the progress of CKD, and were inversely correlated with the estimated glomerular filtration rate (eGFR), even after adjusting for age, gender, triacylglycerols (TAG), HDL cholesterol, and statin therapy (β = −0.41, p < 0.001; β = −0.33, p = 0.001, respectively). Our results support the earlier hypothesis that kidney disease leads to the modification of HDL particles, and show that the preβ1-HDL concentration is significantly elevated in non-dialyzed patients with advanced stages of CKD. Full article
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Open AccessArticle
Compositional Features of HDL Particles Interact with Albuminuria to Modulate Cardiovascular Disease Risk
Int. J. Mol. Sci. 2019, 20(4), 977; https://doi.org/10.3390/ijms20040977 - 23 Feb 2019
Abstract
Lipoproteins containing apolipoprotein B modify associations of elevated urinary albumin excretion (UAE) with cardiovascular disease (CVD). Additionally, it is known that elevated UAE alters high-density lipoprotein functionality. Accordingly, we examined whether HDL features might also modify UAE-associated CVD. Multivariable Cox proportional-hazards modeling was [...] Read more.
Lipoproteins containing apolipoprotein B modify associations of elevated urinary albumin excretion (UAE) with cardiovascular disease (CVD). Additionally, it is known that elevated UAE alters high-density lipoprotein functionality. Accordingly, we examined whether HDL features might also modify UAE-associated CVD. Multivariable Cox proportional-hazards modeling was performed on participants of the PREVEND (Prevention of Renal and Vascular Endstage Disease) study at the baseline screening with standard lipid/lipoprotein analyses and, three-to-four years later (second screen), with nuclear magnetic resonance lipoprotein analyses focusing on HDL parameters including HDL particle (HDL-P) and apolipoprotein A-I concentrations. These were used with UAE and derived measures of HDL apoA-I content (apoA-I/HDL-C and apoA-I/HDL-P) in risk models adjusted for gender, age, apoB, diabetes, past CVD history, CRP and GFR. Interaction analysis was also performed. Baseline screening revealed significant associations inverse for HDL-C and apoA-I and direct for apoA-I/HDL-C. The second screening demonstrated associations inverse for HDL-P, large HDL-P, medium HDL-P, HDL size, and apoA-I/HDL-P. Significant interactions with UAE included apoA-I/HDL-C at the baseline screening, and apoA-I/HDL-P and medium HDL-P but not apoA-I/HDL-C at the second screening. We conclude that features of HDL particles including apoA-I/HDL-P, indicative of HDL apoA-I content, and medium HDL-P modify associations of elevated UAE with CVD risk. Full article
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Open AccessArticle
Human ApoA-I Overexpression Enhances Macrophage-Specific Reverse Cholesterol Transport but Fails to Prevent Inherited Diabesity in Mice
Int. J. Mol. Sci. 2019, 20(3), 655; https://doi.org/10.3390/ijms20030655 - 02 Feb 2019
Cited by 1
Abstract
Human apolipoprotein A-I (hApoA-I) overexpression improves high-density lipoprotein (HDL) function and the metabolic complications of obesity. We used a mouse model of diabesity, the db/db mouse, to examine the effects of hApoA-I on the two main functional properties of HDL, i.e., macrophage-specific reverse [...] Read more.
Human apolipoprotein A-I (hApoA-I) overexpression improves high-density lipoprotein (HDL) function and the metabolic complications of obesity. We used a mouse model of diabesity, the db/db mouse, to examine the effects of hApoA-I on the two main functional properties of HDL, i.e., macrophage-specific reverse cholesterol transport (m-RCT) in vivo and the antioxidant potential, as well as the phenotypic features of obesity. HApoA-I transgenic (hA-I) mice were bred with nonobese control (db/+) mice to generate hApoA-I-overexpressing db/+ offspring, which were subsequently bred to obtain hA-I-db/db mice. Overexpression of hApoA-I significantly increased weight gain and the incidence of fatty liver in db/db mice. Weight gain was mainly explained by the increased caloric intake of hA-I-db/db mice (>1.2-fold). Overexpression of hApoA-I also produced a mixed type of dyslipidemia in db/db mice. Despite these deleterious effects, the overexpression of hApoA-I partially restored m-RCT in db/db mice to levels similar to nonobese control mice. Moreover, HDL from hA-I-db/db mice also enhanced the protection against low-density lipoprotein (LDL) oxidation compared with HDL from db/db mice. In conclusion, overexpression of hApoA-I in db/db mice enhanced two main anti-atherogenic HDL properties while exacerbating weight gain and the fatty liver phenotype. These adverse metabolic side-effects were also observed in obese mice subjected to long-term HDL-based therapies in independent studies and might raise concerns regarding the use of hApoA-I-mediated therapy in obese humans. Full article
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Open AccessArticle
Vasoprotective Functions of High-Density Lipoproteins Relevant to Alzheimer’s Disease Are Partially Conserved in Apolipoprotein B-Depleted Plasma
Int. J. Mol. Sci. 2019, 20(3), 462; https://doi.org/10.3390/ijms20030462 - 22 Jan 2019
Cited by 4
Abstract
High-density lipoproteins (HDL) are known to have vasoprotective functions in peripheral arteries and many of these functions extend to brain-derived endothelial cells. Importantly, several novel brain-relevant HDL functions have been discovered using brain endothelial cells and in 3D bioengineered human arteries. The cerebrovascular [...] Read more.
High-density lipoproteins (HDL) are known to have vasoprotective functions in peripheral arteries and many of these functions extend to brain-derived endothelial cells. Importantly, several novel brain-relevant HDL functions have been discovered using brain endothelial cells and in 3D bioengineered human arteries. The cerebrovascular benefits of HDL in healthy humans may partly explain epidemiological evidence suggesting a protective association of circulating HDL levels against Alzheimer’s Disease (AD) risk. As several methods exist to prepare HDL from plasma, here we compared cerebrovascular functions relevant to AD using HDL isolated by density gradient ultracentrifugation relative to apoB-depleted plasma prepared by polyethylene-glycol precipitation, a common high-throughput method to evaluate HDL cholesterol efflux capacity in clinical biospecimens. We found that apoB-depleted plasma was functionally equivalent to HDL isolated by ultracentrifugation in terms of its ability to reduce vascular Aβ accumulation, suppress TNFα-induced vascular inflammation and delay Aβ fibrillization. However, only HDL isolated by ultracentrifugation was able to suppress Aβ-induced vascular inflammation, improve Aβ clearance, and induce endothelial nitric oxide production. Full article
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Review

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Open AccessReview
Obesity-Related Changes in High-Density Lipoprotein Metabolism and Function
Int. J. Mol. Sci. 2020, 21(23), 8985; https://doi.org/10.3390/ijms21238985 - 26 Nov 2020
Abstract
In obese individuals, atherogenic dyslipidemia is a very common and important factor in the increased risk of cardiovascular disease. Adiposity-associated dyslipidemia is characterized by low high-density lipoprotein cholesterol (HDL-C) levels and an increase in triglyceride-rich lipoproteins. Several factors and mechanisms are involved in [...] Read more.
In obese individuals, atherogenic dyslipidemia is a very common and important factor in the increased risk of cardiovascular disease. Adiposity-associated dyslipidemia is characterized by low high-density lipoprotein cholesterol (HDL-C) levels and an increase in triglyceride-rich lipoproteins. Several factors and mechanisms are involved in lowering HDL-C levels in the obese state and HDL quantity and quality is closely related to adiponectin levels and the bioactive lipid sphingosine-1-phosphate. Recent studies have shown that obesity profoundly alters HDL metabolism, resulting in altered HDL subclass distribution, composition, and function. Importantly, weight loss through gastric bypass surgery and Mediterranean diet, especially when enriched with virgin olive oil, is associated with increased HDL-C levels and significantly improved metrics of HDL function. A thorough understanding of the underlying mechanisms is crucial for a better understanding of the impact of obesity on lipoprotein metabolism and for the development of appropriate therapeutic approaches. The objective of this review article was to summarize the newly identified changes in the metabolism, composition, and function of HDL in obesity and to discuss possible pathophysiological consequences. Full article
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Open AccessReview
High-Density Lipoproteins as Homeostatic Nanoparticles of Blood Plasma
Int. J. Mol. Sci. 2020, 21(22), 8737; https://doi.org/10.3390/ijms21228737 - 19 Nov 2020
Abstract
It is well known that blood lipoproteins (LPs) are multimolecular complexes of lipids and proteins that play a crucial role in lipid transport. High-density lipoproteins (HDL) are a class of blood plasma LPs that mediate reverse cholesterol transport (RCT)—cholesterol transport from the peripheral [...] Read more.
It is well known that blood lipoproteins (LPs) are multimolecular complexes of lipids and proteins that play a crucial role in lipid transport. High-density lipoproteins (HDL) are a class of blood plasma LPs that mediate reverse cholesterol transport (RCT)—cholesterol transport from the peripheral tissues to the liver. Due to this ability to promote cholesterol uptake from cell membranes, HDL possess antiatherogenic properties. This function was first observed at the end of the 1970s to the beginning of the 1980s, resulting in high interest in this class of LPs. It was shown that HDL are the prevalent class of LPs in several types of living organisms (from fishes to monkeys) with high resistance to atherosclerosis and cardiovascular disorders. Lately, understanding of the mechanisms of the antiatherogenic properties of HDL has significantly expanded. Besides the contribution to RCT, HDL have been shown to modulate inflammatory processes, blood clotting, and vasomotor responses. These particles also possess antioxidant properties and contribute to immune reactions and intercellular signaling. Herein, we review data on the structure and mechanisms of the pleiotropic biological functions of HDL from the point of view of their evolutionary role and complex dynamic nature. Full article
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Open AccessReview
ApoE Lipidation as a Therapeutic Target in Alzheimer’s Disease
Int. J. Mol. Sci. 2020, 21(17), 6336; https://doi.org/10.3390/ijms21176336 - 01 Sep 2020
Cited by 1
Abstract
Apolipoprotein E (APOE) is the major cholesterol carrier in the brain, affecting various normal cellular processes including neuronal growth, repair and remodeling of membranes, synaptogenesis, clearance and degradation of amyloid β (Aβ) and neuroinflammation. In humans, the APOE gene has three [...] Read more.
Apolipoprotein E (APOE) is the major cholesterol carrier in the brain, affecting various normal cellular processes including neuronal growth, repair and remodeling of membranes, synaptogenesis, clearance and degradation of amyloid β (Aβ) and neuroinflammation. In humans, the APOE gene has three common allelic variants, termed E2, E3, and E4. APOE4 is considered the strongest genetic risk factor for Alzheimer’s disease (AD), whereas APOE2 is neuroprotective. To perform its normal functions, apoE must be secreted and properly lipidated, a process influenced by the structural differences associated with apoE isoforms. Here we highlight the importance of lipidated apoE as well as the APOE-lipidation targeted therapeutic approaches that have the potential to correct or prevent neurodegeneration. Many of these approaches have been validated using diverse cellular and animal models. Overall, there is great potential to improve the lipidated state of apoE with the goal of ameliorating APOE-associated central nervous system impairments. Full article
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Open AccessReview
Advances in HDL: Much More than Lipid Transporters
Int. J. Mol. Sci. 2020, 21(3), 732; https://doi.org/10.3390/ijms21030732 - 22 Jan 2020
Cited by 4
Abstract
High Density Lipoprotein (HDL) particles, beyond serving as lipid transporters and playing a key role in reverse cholesterol transport, carry a highly variable number of proteins, micro-RNAs, vitamins, and hormones, which endow them with the ability to mediate a plethora of cellular and [...] Read more.
High Density Lipoprotein (HDL) particles, beyond serving as lipid transporters and playing a key role in reverse cholesterol transport, carry a highly variable number of proteins, micro-RNAs, vitamins, and hormones, which endow them with the ability to mediate a plethora of cellular and molecular mechanisms that promote cardiovascular health. It is becoming increasingly evident, however, that the presence of cardiovascular risk factors and co-morbidities alters HDLs cargo and protective functions. This concept has led to the notion that metrics other than HDL-cholesterol levels, such as HDL functionality and composition, may better capture HDL cardiovascular protection. On the other hand, the potential of HDL as natural delivery carriers has also fostered the design of engineered HDL-mimetics aiming to improve HDL efficacy or as drug-delivery agents with therapeutic potential. In this paper, we first provide an overview of the molecules known to be transported by HDL particles and mainly discuss their functions in the cardiovascular system. Second, we describe the impact of cardiovascular risk factors and co-morbidities on HDL remodeling. Finally, we review the currently developed HDL-based approaches. Full article
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Open AccessReview
The Role and Function of HDL in Patients with Chronic Kidney Disease and the Risk of Cardiovascular Disease
Int. J. Mol. Sci. 2020, 21(2), 601; https://doi.org/10.3390/ijms21020601 - 17 Jan 2020
Cited by 7
Abstract
Chronic kidney disease (CKD) is a worldwide health problem with steadily increasing occurrence. Significantly elevated cardiovascular morbidity and mortality have been observed in CKD. Cardiovascular diseases are the most important and frequent cause of death of CKD patients globally. The presence of CKD [...] Read more.
Chronic kidney disease (CKD) is a worldwide health problem with steadily increasing occurrence. Significantly elevated cardiovascular morbidity and mortality have been observed in CKD. Cardiovascular diseases are the most important and frequent cause of death of CKD patients globally. The presence of CKD is related to disturbances in lipoprotein metabolism whose consequences are dyslipidemia and the accumulation of atherogenic particles. CKD not only fuels the reduction of high-density lipoprotein (HDL) cholesterol concentration, but also it modifies the composition of this lipoprotein. The key role of HDL is the participation in reverse cholesterol transport from peripheral tissues to the liver. Moreover, HDL prevents the oxidation of low-density lipoprotein (LDL) cholesterol by reactive oxygen species (ROS) and protects against the adverse effects of oxidized LDL (ox-LDL) on the endothelium. Numerous studies have demonstrated the ability of HDL to promote the production of nitric oxide (NO) by endothelial cells (ECs) and to exert antiapoptotic and anti-inflammatory effects. Increasing evidence suggests that in patients with chronic inflammatory disorders, HDLs may lose important antiatherosclerotic properties and become dysfunctional. So far, no therapeutic strategy to raise HDL, or alter the ratio of HDL subfractions, has been successful in slowing the progression of CKD or reducing cardiovascular disease in patients either with or without CKD. Full article
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Open AccessReview
Novel Insights into the Role of HDL-Associated Sphingosine-1-Phosphate in Cardiometabolic Diseases
Int. J. Mol. Sci. 2019, 20(24), 6273; https://doi.org/10.3390/ijms20246273 - 12 Dec 2019
Cited by 3
Abstract
Sphingolipids are key signaling molecules involved in the regulation of cell physiology. These species are found in tissues and in circulation. Although they only constitute a small fraction in lipid composition of circulating lipoproteins, their concentration in plasma and distribution among plasma lipoproteins [...] Read more.
Sphingolipids are key signaling molecules involved in the regulation of cell physiology. These species are found in tissues and in circulation. Although they only constitute a small fraction in lipid composition of circulating lipoproteins, their concentration in plasma and distribution among plasma lipoproteins appears distorted under adverse cardiometabolic conditions such as diabetes mellitus. Sphingosine-1-phosphate (S1P), one of their main representatives, is involved in regulating cardiomyocyte homeostasis in different models of experimental cardiomyopathy. Cardiomyopathy is a common complication of diabetes mellitus and represents a main risk factor for heart failure. Notably, plasma concentration of S1P, particularly high-density lipoprotein (HDL)-bound S1P, may be decreased in patients with diabetes mellitus, and hence, inversely related to cardiac alterations. Despite this, little attention has been given to the circulating levels of either total S1P or HDL-bound S1P as potential biomarkers of diabetic cardiomyopathy. Thus, this review will focus on the potential role of HDL-bound S1P as a circulating biomarker in the diagnosis of main cardiometabolic complications frequently associated with systemic metabolic syndromes with impaired insulin signaling. Given the bioactive nature of these molecules, we also evaluated its potential of HDL-bound S1P-raising strategies for the treatment of cardiometabolic disease. Full article
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Open AccessReview
HDL Cholesterol as a Marker of Disease Severity and Prognosis in Patients with Pulmonary Arterial Hypertension
Int. J. Mol. Sci. 2019, 20(14), 3514; https://doi.org/10.3390/ijms20143514 - 18 Jul 2019
Cited by 8
Abstract
The impact of high-density lipoprotein (HDL) cholesterol on the development of atherosclerosis and diseases of systemic circulation has been well documented both in experimental and registry studies. Recent discoveries in pulmonary arterial hypertension (PAH) revealed a significant impact of HDL on pulmonary artery [...] Read more.
The impact of high-density lipoprotein (HDL) cholesterol on the development of atherosclerosis and diseases of systemic circulation has been well documented both in experimental and registry studies. Recent discoveries in pulmonary arterial hypertension (PAH) revealed a significant impact of HDL on pulmonary artery vasoreactivity and patients’ prognosis. The vasoprotective activity of HDL primarily involves vascular endothelium that also plays a central role in pulmonary arterial hypertension (PAH) pathobiology. However, the exact mechanism in which this lipoprotein fraction exerts its effect in pulmonary circulation is still under investigation. This paper reviews potential vasoprotective mechanisms of HDL in pulmonary circulation and presents current clinical reports on the role of HDL in PAH patients. Full article
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