Publications by authors named "Anatol Kontush"

105 Publications

Endothelial Lipase Modulates Paraoxonase 1 Content and Arylesterase Activity of HDL.

Int J Mol Sci 2021 Jan 13;22(2). Epub 2021 Jan 13.

Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Molecular Biology and Biochemistry, Medical University of Graz, Neue Stiftingtalstraße 6/6, 8010 Graz, Austria.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms22020719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828365PMC
January 2021

Comparative analysis of the variability of carotid intima-media thickness in primary prevention populations of Moscow and Paris.

Am J Cardiovasc Dis 2020 15;10(4):463-472. Epub 2020 Oct 15.

Research Institute of Human Morphology 3 Tsyurupa Street, Moscow 117418, Russia.

It is well-known that the distribution of traditional cardiovascular risk factors (CVRFs) of atherosclerosis, including hypertension, dyslipidemia, smoking, obesity, and diabetes is considerably variable between different countries, however, with some important geographical trends. Thus, CVRFs contribute differently to atherosclerosis development in different countries. Common carotid artery intima-media thickness (CCA IMT) is a validated biomarker of subclinical atherosclerosis that is used in clinical and epidemiological studies to evaluate the impact of CVRFs on atherosclerosis development. This comparative cohort study included a random sample of 1200 participants (n = 600 men and n = 600 women) from Moscow, Russia and Paris, France, aged between 55 and 79 years, and free of clinical symptoms of atherosclerosis. The study was conducted to determine the interpopulation variability of CCA IMT. CCA IMT was measured by ultrasonic scanning at the high-resolution regimen. Statistical analysis was performed using Stata 9.1. For comparison of mean values of continuous variables, Mann-Whitney U-test was used; Chi-square, Pearson's test was used for comparison of categorical variables. To determine to what extent presented differences can be explained by differences in traditional CVRFs, the regression model was applied. Path analysis (plug Passport Litigation Decision Analysis & Optimization Module, Datacert, USA) was used to assess the impact of traditional CVRFs on the CCA IMT in both Moscow and Paris study populations. There was a significant difference in the distribution of most of the traditional CVRFs between the study populations, including blood pressure, lipid profile, statin treatment, hormone replacement therapy in women, and CVD history. The remarkably high level of difference in the mean values of the CCA IMT was found between Moscow and Paris study populations. In women of both Moscow and Paris study populations, the mean value of CCA IMT was 0.78 and 0.63, respectively. In men of both Moscow and Paris study populations, the mean CCA IMT value was 0.84 and 0.67, respectively. In the Moscow study population, the effects (direct and indirect) of traditional CVRs can explain 42% of the CCA IMT variance in women and 30% - in men. In the Paris study population, direct and indirect effects of traditional CVRFs can explain 27% of the CCA IMT variance in men and 14% - in women. The Paris study population significantly differed from the Moscow study population in the distribution and impact of traditional CVRFs. Traditional CVRFs can explain only a small proportion of the interpopulation differences in CCA IMT suggesting the presence of other factors, such as longitude, which can possibly influence these differences. Therefore, this study provided an additional piece of evidence towards the existence of a geographic gradient of carotid IMT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7675151PMC
October 2020

Rationale and design of the expanded combination of evolocumab plus empagliflozin in diabetes: EXCEED-BHS3 trial.

Ther Adv Chronic Dis 2020 28;11:2040622320959248. Epub 2020 Sep 28.

Brazilian Heart Study Group, Cardiology Division, State University of Campinas, Rua Tessália Vieira de Camargo, 126., Cidade Universitária Zeferino Vaz, Campinas, São Paulo, 13084-971, Brazil.

Background: Patients with type 2 diabetes mellitus (T2DM) remain at increased cardiovascular residual risk and endothelial dysfunction, even after optimizing metabolic control and treatment by sodium-glucose-2 transporter inhibitors (SGLT2-is). The present study was based on the hypothesis that proprotein convertase subtilisin/kexin 9 inhibitor (PCSK9i) therapy may mitigate endothelial dysfunction in T2DM patients who are on regular treatment by SGLT2-i.

Methods: The EXCEED-BHS3 is a prospective, single-center, investigator-blinded, open-label, randomized clinical trial. Participants ( = 110) will be randomized (1:1) to either empagliflozin 25 mg/day alone or empagliflozin 25 mg/day plus evolocumab 140 mg every 2 weeks in addition to optimal medical care. The primary endpoint was defined as the change in the 1-min flow-mediated dilation (FMD) after 16 weeks of treatment. The secondary endpoint is the FMD change after ischemia/reperfusion injury protocol (reserve FMD) after 16 weeks of treatment. Exploratory outcomes comprise the change in FMD and reserve FMD after 8 weeks of treatment and the change after 16 weeks of treatment in the following parameters: plasma levels of nitric oxide, vascular cell adhesion molecule-1 and isoprostane, high-density lipoprotein (HDL) and low-density lipoprotein subfractions profile, HDL function, blood pressure, body mass index, waist circumference and adipokines.

Conclusion: This will be the first study to evaluate the add-on effect of PCSK9i on endothelial function of T2DM patients under regular use of empagliflozin.

Trial Registration: ClinicalTrials.gov identifier: NCT03932721.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/2040622320959248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7534094PMC
September 2020

Increased ABCA1 (ATP-Binding Cassette Transporter A1)-Specific Cholesterol Efflux Capacity in Schizophrenia.

Arterioscler Thromb Vasc Biol 2020 11 10;40(11):2728-2737. Epub 2020 Sep 10.

ANZAC Research institute, Concord Repatriation General Hospital and University of Sydney, Australia (M.K., M.A., V.C., W.J., L.K.).

Objective: Patients with schizophrenia have increased long-term mortality attributable to cardiovascular disease and commonly demonstrate features of mixed dyslipidemia with low HDL-C (high-density lipoprotein cholesterol). The removal of cholesterol from cells by HDL via specific ATP-binding cholesterol transporters is a major functional property of HDL, and its measurement as cholesterol efflux capacity (CEC) can predict cardiovascular risk. Whether HDL function is impaired in patients with schizophrenia is unknown. Approach and Results: We measured basal and ABCA1 (ATP-binding cassette transporter A1)- and ABCG1 (ATP-binding cassette transporter G1)-dependent CEC, comparing patients with schizophrenia with age- and sex-matched healthy controls, and related our findings to nuclear magnetic resonance analysis of lipoprotein subclasses. Total plasma cholesterol and LDL-C (low-density lipoprotein cholesterol) were comparable between healthy controls (n=51) and patients (n=120), but patients with schizophrenia had increased total plasma triglyceride, low HDL-C and apo (apolipoprotein) A-I concentrations. Nuclear magnetic resonance analysis indicated a marked (15-fold) increase in large triglyceride-rich lipoprotein particle concentration, increased small dense LDL particles, and fewer large HDL particles. Despite lower HDL-C concentration, basal CEC was 13.7±1.6% higher, ABCA1-specific efflux was 35.9±1.6% higher, and ABCG1 efflux not different, in patients versus controls. In patients with schizophrenia, ABCA1-specific efflux correlated with the abundance of small 7.8 nm HDL particles but not with serum plasminogen or triglyceride levels.

Conclusions: Patients with schizophrenia have increased concentrations of atherogenic apoB-containing lipoproteins, decreased concentrations of large HDL particles, but enhanced ABCA1-mediated CEC. In this population, preventative strategies should focus on reducing atherogenic lipoproteins rather than increasing CEC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/ATVBAHA.120.314847DOI Listing
November 2020

HDL and Reverse Remnant-Cholesterol Transport (RRT): Relevance to Cardiovascular Disease.

Authors:
Anatol Kontush

Trends Mol Med 2020 12 26;26(12):1086-1100. Epub 2020 Aug 26.

National Institute for Health and Medical Research (INSERM), Research Unit 1166, Faculty of Medicine Pitié-Salpêtrière, Sorbonne University, Paris, France. Electronic address:

Cardiovascular diseases predominantly result from atherosclerosis, a natural biological phenomenon reflecting food intake and energy production in humans. Lipolysis of plasma triglyceride-rich lipoproteins (TGRLs) by lipoprotein lipase (LPL) is an essential element of energy production that delivers free fatty acids to peripheral cells. High-density lipoprotein (HDL) plays a key role in this process by acquiring surface lipids, including free cholesterol, that are released upon TGRL lipolysis. According to the reverse remnant-cholesterol transport (RRT) hypothesis, such removal of cholesterol from remnant lipoproteins followed by transport to the liver and excretion into the bile represents a major biological function of HDL that is essential for energy production, and which can reduce cholesterol influx into the arterial wall by accelerating the removal of atherogenic TGRL remnants from the circulation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.molmed.2020.07.005DOI Listing
December 2020

Free cholesterol transfer to high-density lipoprotein (HDL) upon triglyceride lipolysis underlies the U-shape relationship between HDL-cholesterol and cardiovascular disease.

Eur J Prev Cardiol 2020 Oct 15;27(15):1606-1616. Epub 2019 Dec 15.

National Institute for Health and Medical Research (INSERM) UMR_S 1166, Faculty of Medicine Pitié-Salpétrière, Paris, France.

Background: Low concentrations of high-density lipoprotein cholesterol (HDL-C) represent a well-established cardiovascular risk factor. Paradoxically, extremely high HDL-C levels are equally associated with elevated cardiovascular risk, resulting in the U-shape relationship of HDL-C with cardiovascular disease. Mechanisms underlying this association are presently unknown. We hypothesised that the capacity of high-density lipoprotein (HDL) to acquire free cholesterol upon triglyceride-rich lipoprotein (TGRL) lipolysis by lipoprotein lipase underlies the non-linear relationship between HDL-C and cardiovascular risk.

Methods: To assess our hypothesis, we developed a novel assay to evaluate the capacity of HDL to acquire free cholesterol (as fluorescent TopFluor® cholesterol) from TGRL upon in vitro lipolysis by lipoprotein lipase.

Results: When the assay was applied to several populations markedly differing in plasma HDL-C levels, transfer of free cholesterol was significantly decreased in low HDL-C patients with acute myocardial infarction (-45%) and type 2 diabetes (-25%), and in subjects with extremely high HDL-C of >2.59 mmol/L (>100 mg/dL) (-20%) versus healthy normolipidaemic controls. When these data were combined and plotted against HDL-C concentrations, an inverse U-shape relationship was observed. Consistent with these findings, animal studies revealed that the capacity of HDL to acquire cholesterol upon lipolysis was reduced in low HDL-C apolipoprotein A-I knock-out mice and was negatively correlated with aortic accumulation of [H]-cholesterol after oral gavage, attesting this functional characteristic as a negative metric of postprandial atherosclerosis.

Conclusions: Free cholesterol transfer to HDL upon TGRL lipolysis may underlie the U-shape relationship between HDL-C and cardiovascular disease, linking HDL-C to triglyceride metabolism and atherosclerosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/2047487319894114DOI Listing
October 2020

Antiatherogenic properties of high-density lipoproteins from arterial plasma are attenuated as compared to their counterparts of venous origin.

Nutr Metab Cardiovasc Dis 2020 01 3;30(1):33-39. Epub 2019 Aug 3.

National Institute for Health and Medical Research (INSERM), UMR ICAN 1166, Sorbonne University Paris 6, Pitié-Salpêtrière - Charles Foix Hospital, AP-HP, Paris, France; Department of Endocrinology and Metabolism, Pitié-Salpêtrière - Charles Foix Hospital, AP-HP, Paris, France. Electronic address:

Background And Aims: High-density lipoprotein (HDL) particles play atheroprotective roles by their ability to efflux cholesterol from foam cells and to protect low-density lipoproteins (LDLs) from oxidative damage in the arterial intima. We hypothesized that antioxidative properties of HDLs can be attenuated in the oxygen-rich prooxidative arterial environment, contributing to the development of atherosclerosis. To evaluate this hypothesis, we compared antioxidative activity of HDLs from arterial and venous plasmas.

Methods And Results: Arterial and venous blood samples were simultaneously obtained from 16 patients (age 68 ± 10 years; 75% males) presenting with ischemic or valvular heart disease. Major HDL subfractions and total HDLs were isolated by density gradient ultracentrifugation and their chemical composition and the capacity to protect LDLs from in vitro oxidation were evaluated. HDL-cholesterol, triglycerides and apolipoprotein (apo) B-100 levels were slightly but significantly reduced by -4 to -8% (p < 0.01) in the arterial vs. venous samples. Total mass of HDL subpopulations was similar and HDL subpopulations did not reveal marked compositional differences between the arterial and venous circulation. Potent antioxidative activity of the small, dense HDL3c subpopulation was significantly reduced in the particles of arterial origin vs. their counterparts from venous plasma (increase of +21% in the propagation rate of LDL oxidation, p < 0.05). Interestingly, antioxidative properties of venous HDLs were enhanced in statin-treated patients relative to untreated subjects.

Conclusion: Antioxidative properties of small, dense HDLs from arterial plasma are attenuated as compared to the particles of venous origin, consistent with the development of atherosclerosis in the arterial wall.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.numecd.2019.07.022DOI Listing
January 2020

Elevated serum ceramides are linked with obesity-associated gut dysbiosis and impaired glucose metabolism.

Metabolomics 2019 10 11;15(11):140. Epub 2019 Oct 11.

Sorbonne Université, INSERM, Nutrition and Obesities; Systemic Approaches Research Unit (NutriOmics), Paris, France.

Introduction: Low gut microbiome richness is associated with dyslipidemia and insulin resistance, and ceramides and other sphingolipids are implicated in the development of diabetes.

Objectives: Determine whether circulating sphingolipids, particularly ceramides, are associated with alterations in the gut microbiome among obese patients with increased diabetes risk.

Methods: This was a cross-sectional and longitudinal retrospective analysis of a dietary/weight loss intervention. Fasted serum was collected from 49 participants (41 women) and analyzed by HPLC-MS/MS to quantify 45 sphingolipids. Shotgun metagenomic sequencing of stool was performed to profile the gut microbiome.

Results: Confirming the link to deteriorated glucose homeostasis, serum ceramides were positively correlated with fasting glucose, but inversely correlated with fasting and OGTT-derived measures of insulin sensitivity and β-cell function. Significant associations with gut dysbiosis were demonstrated, with SM and ceramides being inversely correlated with gene richness. Ceramides with fatty acid chain lengths of 20-24 carbons were the most associated with low richness. Diet-induced weight loss, which improved gene richness, decreased most sphingolipids. Thirty-one MGS, mostly corresponding to unidentified bacteria species, were inversely correlated with ceramides, including a number of Bifidobacterium and Methanobrevibacter smithii. Higher ceramide levels were also associated with increased metagenomic modules for lipopolysaccharide synthesis and flagellan synthesis, two pathogen-associated molecular patterns, and decreased enrichment of genes involved in methanogenesis and bile acid metabolism.

Conclusion: This study identifies an association between gut microbiota richness, ceramides, and diabetes risk in overweight/obese humans, and suggests that the gut microbiota may contribute to dysregulation of lipid metabolism in metabolic disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11306-019-1596-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7165363PMC
October 2019

Alterations of HDL particle phospholipid composition and role of inflammation in rheumatoid arthritis.

J Physiol Biochem 2019 Nov 7;75(4):453-462. Epub 2019 Aug 7.

Unité de Nutrition Humaine (UNH), INRA/Université Clermont Auvergne, 63009, Clermont-Ferrand, France.

The increased cardiovascular risk in RA (rheumatoid arthritis) cannot be explained by common quantitative circulating lipid parameters. The objective of the study was to characterize the modifications in HDL phosphosphingolipidome in patients with RA to identify qualitative modifications which could better predict the risk for CVD. Nineteen patients with RA were compared to control subjects paired for age, sex, BMI, and criteria of metabolic syndrome. The characterization of total HDL phosphosphingolipidome was performed by LC-MS/MS. RA was associated with an increased HDL content of lysophosphatidylcholine and a decreased content of PC (phosphatidylcholine), respectively, positively and negatively associated with cardiovascular risk. A discriminant molecular signature composed of 18 lipids was obtained in the HDL from RA patients. The detailed analysis of phospholipid species showed that molecules carrying omega-3 FA (fatty acids), notably docosahexaenoic acid (C22:6 n-3), were depleted in HDL isolated from RA patients. By contrast, two PE (phosphatidylethanolamine) species carrying arachidonic acid (C20:4 n-6) were increased in HDL from RA patients. Furthermore, disease activity and severity indexes were associated with altered HDL content of 4 PE and 2 PC species. In conclusion, the composition of HDL phosphosphingolipidome is altered during RA. Identification of a lipidomic signature could therefore represent a promising biomarker for CVD risk. Although a causal link remains to be demonstrated, pharmacological and nutritional interventions targeting the normalization of the FA composition of altered phospholipids could help to fight against RA-related inflammation and CVD risk.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s13105-019-00694-4DOI Listing
November 2019

Reciprocal Multifaceted Interaction Between HDL (High-Density Lipoprotein) and Myocardial Infarction.

Arterioscler Thromb Vasc Biol 2019 08 13;39(8):1550-1564. Epub 2019 Jun 13.

Lipoprotein Metabolism Section, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (L.S., A.T.R.).

Despite decades of therapeutic advances, myocardial infarction remains a leading cause of death worldwide. Recent studies have identified HDLs (high-density lipoproteins) as a potential candidate for mitigating coronary ischemia/reperfusion injury via a broad spectrum of signaling pathways. HDL ligands, such as S1P (sphingosine-1-phosphate), Apo (apolipoprotein) A-I, clusterin, and miRNA, may influence the opening of the mitochondrial channel, insulin sensitivity, and production of vascular autacoids, such as NO, prostacyclin, and endothelin-1. In parallel, antioxidant activity and sequestration of oxidized molecules provided by HDL can attenuate the oxidative stress that triggers ischemia/reperfusion. Nevertheless, during myocardial infarction, oxidation and the capture of oxidized and proinflammatory molecules generate large phenotypic and functional changes in HDL, potentially limiting its beneficial properties. In this review, new findings from cellular and animal models, as well as from clinical studies, will be discussed to describe the cardioprotective benefits of HDL on myocardial infarction. Furthermore, mechanisms by which HDL modulates cardiac function and potential strategies to mitigate postmyocardial infarction risk damage by HDL will be detailed throughout the review.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/ATVBAHA.119.312880DOI Listing
August 2019

Distinct phospholipid and sphingolipid species are linked to altered HDL function in apolipoprotein A-I deficiency.

J Clin Lipidol 2019 May - Jun;13(3):468-480.e8. Epub 2019 Feb 25.

UMR-ICAN 1166, National Institute for Health and Medical Research (INSERM), Sorbonne University, Paris, France. Electronic address:

Background: Familial apolipoprotein A-I (apoA-I) deficiency (FAID) involving low levels of both apoA-I and high-density lipoprotein (HDL) cholesterol is associated with accelerated atherosclerosis.

Objective: The objective of this study was to define distinctive patterns in the lipidome of HDL subpopulations in FAID in relationship to antiatherogenic activities.

Methods: Five HDL subfractions were isolated by ultracentrifugation from plasma of FAID Caucasian patients (n = 5) and age-matched healthy normolipidemic Caucasian controls (n = 8), and the HDL lipidome (160 molecular species of 9 classes of phospholipids and sphingolipids) was quantitatively evaluated.

Results: Increased concentrations of numerous molecular species of lysophosphatidylcholine (up to 12-fold), ceramides (up to 3-fold), phosphatidylserine (up to 34-fold), phosphatidic acid (up to 71-fold), and phosphatidylglycerol (up to 20-fold) were detected throughout all five HDL subpopulations as compared with their counterparts from controls, whereas concentrations of phosphatidylethanolamine species were decreased (up to 5-fold). Moderately to highly abundant, within their lipid class, species of phosphatidylcholine, sphingomyelin, phosphatidylinositol, phosphatidylethanolamine, phosphatidylserine, and ceramide featuring multiple unsaturations were primarily affected by apoA-I deficiency; their HDL content, particularly that of phosphatidylcholine (34:2), was strongly correlated with HDL function, impaired in FAID. Metabolic pathway analysis revealed that sphingolipid, glycerophospholipid, and linoleic acid metabolism was significantly affected by FAID.

Conclusion: These data reveal that altered content of specific phospholipid and sphingolipid species is linked to deficient antiatherogenic properties of HDL in FAID.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jacl.2019.02.004DOI Listing
May 2020

HDL-Targeted Therapies During Myocardial Infarction.

Cardiovasc Drugs Ther 2019 06;33(3):371-381

National Heart, Lung and Blood Institute, National Institutes of Health, 10 Center Dr. Building 10 8N222, Bethesda, MD, USA.

It is now apparent that a variety of deleterious mechanisms intrinsic to myocardial infarction (MI) exists and underlies its high residual lethality. Indeed, despite effective coronary patency therapies, ischemia and reperfusion (I/R) injury accounts for about 50% of the infarcted mass. In this context, recent studies in animal models have demonstrated that coronary reperfusion with high-density lipoproteins (HDL) may reduce MI size in up to 30%. A spectrum of mechanisms mediated by either HDL-related apolipoproteins or phospholipids attenuates myocardial cell death. Hence, promising therapeutic approaches such as infusion of reconstituted HDL particles, new HDL by genomic therapy, or the infusion of apoA-I mimetic peptides have been sought as a way of ensuring protection against I/R injury. In this review, we will explore the limitations and potential therapeutic effects of HDL therapies during the acute phase of MI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10557-019-06865-1DOI Listing
June 2019

Glycosylation of human plasma lipoproteins reveals a high level of diversity, which directly impacts their functional properties.

Biochim Biophys Acta Mol Cell Biol Lipids 2019 05 12;1864(5):643-653. Epub 2019 Jan 12.

Genos Glycoscience Research Laboratory, Borongajska cesta 83H, HR-10 000 Zagreb, Croatia.

Aims: Human plasma lipoproteins are known to contain various glycan structures whose composition and functional importance are starting to be recognized. We assessed N-glycosylation of human plasma HDL and LDL and the role of their glycomes in cellular cholesterol metabolism.

Methods: N-glycomic profiles of native and neuraminidase-treated HDL and LDL were obtained using HILIC-UHPLC-FLD. Relative abundance of the individual chromatographic peaks was quantitatively expressed as a percentage of total integrated area and N-glycan structures present in each peak were elucidated by MALDI-TOF MS. The capacity of HDL to mediate cellular efflux of cholesterol and the capacity of LDL to induce cellular accumulation of cholesteryl esters were evaluated in THP-1 cells.

Results: HILIC-UHPLC-FLD analysis of HDL and LDL N-glycans released by PNGase F resulted in 22 and 18 distinct chromatographic peaks, respectively. The majority of N-glycans present in HDL (~70%) and LDL (~60%) were sialylated with one or two sialic acid residues. The most abundant N-glycan structure in both HDL and LDL was a complex type biantennary N-glycan with one sialic acid (A2G2S1). Relative abundances of several N-glycan structures were dramatically altered by the neuraminidase treatment, which selectively removed sialic acid residues. Native HDL displayed significantly greater efficacy in removing cellular cholesterol from THP-1 cells as compared to desialylated HDL (p < 0.05). Cellular accumulation of cholesteryl esters in THP-1 cells was significantly higher after incubations with desialylated LDL particles as compared to native LDL (p < 0.05).

Conclusions: N-glycome of human plasma lipoproteins reveals a high level of diversity, which directly impacts functional properties of the lipoproteins.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbalip.2019.01.005DOI Listing
May 2019

Phosphatidylglycerols are induced by gut dysbiosis and inflammation, and favorably modulate adipose tissue remodeling in obesity.

FASEB J 2019 04 4;33(4):4741-4754. Epub 2019 Jan 4.

Nutriomics Team, INSERM, Unité 1166-Sorbonne Université, Paris, France.

Lipidomic techniques can improve our understanding of complex lipid interactions that regulate metabolic diseases. Here, a serum phospholipidomics analysis identified associations between phosphatidylglycerols (PGs) and gut microbiota dysbiosis. Compared with the other phospholipids, serum PGs were the most elevated in patients with low microbiota gene richness, which were normalized after a dietary intervention that restored gut microbial diversity. Serum PG levels were positively correlated with metagenomic functional capacities for bacterial LPS synthesis and host markers of low-grade inflammation; transcriptome databases identified PG synthase, the first committed enzyme in PG synthesis, as a potential mediator. Experiments in mice and cultured human-derived macrophages demonstrated that LPS induces PG release. Acute PG treatment in mice altered adipose tissue gene expression toward remodeling and inhibited ex vivo lipolysis in adipose tissue, suggesting that PGs favor lipid storage. Indeed, several PG species were associated with the severity of obesity in mice and humans. Finally, despite enrichment in PGs in bacterial membranes, experiments employing gnotobiotic mice colonized with recombinant PG overproducing Lactococcus lactis showed limited direct contribution of microbial PGs to the host. In summary, PGs are inflammation-responsive lipids indirectly regulated by the gut microbiota via endotoxins and regulate adipose tissue homeostasis in obesity.-Kayser, B. D., Lhomme, M., Prifti, E., Da Cunha, C., Marquet, F., Chain, F., Naas, I., Pelloux, V., Dao, M.-C., Kontush, A., Rizkalla, S. W., Aron-Wisnewsky, J., Bermúdez-Humarán, L. G., Oakley, F., Langella, P., Clément, K., Dugail, I. Phosphatidylglycerols are induced by gut dysbiosis and inflammation, and favorably modulate adipose tissue remodeling in obesity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1096/fj.201801897RDOI Listing
April 2019

Cholesterol efflux capacity of large, small and total HDL particles is unaltered by atorvastatin in patients with type 2 diabetes.

Atherosclerosis 2018 10 24;277:72-79. Epub 2018 Aug 24.

Unidad de Investigación de Enfermedades Metabólicas, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Avenue Vasco de Quiroga 15, Tlalpán, CP 14080, Mexico City, Mexico; Departamento de Endocrinología y Metabolismo, Instituto Nacional de Ciencias Médicas y Nutrición Salvador, Avenue Vasco de Quiroga 15, Tlalpán, CP 14080, Mexico City, Mexico; Tecnológico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Calle del puente 222, Ejidos de Huipulco, Tlalpán, 14380, Mexico City, Mexico. Electronic address:

Background And Aims: Research on the biologic activities of HDL, such as cholesterol efflux capacity and HDL composition, has allowed the understanding of the effect of interventions directed to improve cardiovascular risk. Previously, statin therapy has shown conflicting results about its effects on cholesterol efflux capacity of HDL; the underlying mechanisms are unclear but studies with positive effects are associated with an increase of HDL-cholesterol levels. We investigated if 10 weeks of atorvastatin therapy changes HDL efflux capacity and the chemical composition of its subpopulations.

Methods: In a before-after design basis, HDL-cholesterol levels, chemical composition and cholesterol efflux capacity from HDL subpopulations isolated by isophynic ultracentrifugation were assessed in plasma samples from 60 patients with type 2 diabetes mellito (T2DM) at baseline and after 10 weeks of treatment with 20 mg atorvastatin. Cholesterol efflux was measured from human THP-1 cells using large, light HDL2b and small, dense 3c subpopulations as well as total HDL as acceptors. Changes of cholesterol efflux and chemical composition of HDL after treatment were analyzed. Correlations among variables potentially involved in cholesterol efflux were evaluated.

Results: A significant decrease of 4% in HDL-cholesterol levels was observed from 47 (42-54) to 45 (39-56) mg/dL, p = 0.02. Cholesterol efflux from total-HDL and HDL2b and 3c subfractions was maintained unchanged after treatment. The total mass of HDL remained unaffected, except for the HDL3a subpopulation accounted for by a significant increase in total protein content. No significant correlations for variables previously known to be associated with cholesterol efflux were found in our study.

Conclusions: Short therapy of 10 weeks with 20 mg of atorvastatin does not modify the cholesterol efflux capacity neither the total mass of HDL2b, HDL3c and total HDL. The discrepancy with previous reports may be due to the selective effects among different classes of statins or differences in the approaches to measure cellular cholesterol efflux.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.atherosclerosis.2018.08.027DOI Listing
October 2018

HDL activates expression of genes stimulating cholesterol efflux in human monocyte-derived macrophages.

Exp Mol Pathol 2018 10 16;105(2):202-207. Epub 2018 Aug 16.

The George Washington University School of Medicine and Health Sciences, Washington, DC, USA. Electronic address:

High density lipoproteins (HDL) are key components of reverse cholesterol transport pathway. HDL removes excessive cholesterol from peripheral cells, including macrophages, providing protection from cholesterol accumulation and conversion into foam cells, which is a key event in pathogenesis of atherosclerosis. The mechanism of cellular cholesterol efflux stimulation by HDL involves interaction with the ABCA1 lipid transporter and ensuing transfer of cholesterol to HDL particles. In this study, we looked for additional proteins contributing to HDL-dependent cholesterol efflux. Using RNAseq, we analyzed mRNAs induced by HDL in human monocyte-derived macrophages and identified three genes, fatty acid desaturase 1 (FADS1), insulin induced gene 1 (INSIG1), and the low-density lipoprotein receptor (LDLR), expression of which was significantly upregulated by HDL. We individually knocked down these genes in THP-1 cells using gene silencing by siRNA, and measured cellular cholesterol efflux to HDL. Knock down of FADS1 did not significantly change cholesterol efflux (p = 0.70), but knockdown of INSIG1 and LDLR resulted in highly significant reduction of the efflux to HDL (67% and 75% of control, respectively, p < 0.001). Importantly, the suppression of cholesterol efflux was independent of known effects of these genes on cellular cholesterol content, as cells were loaded with cholesterol using acetylated LDL. These results indicate that HDL particles stimulate expression of genes that enhance cellular cholesterol transfer to HDL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.yexmp.2018.08.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6247801PMC
October 2018

Impact of Lipoproteins on Atherobiology: Emerging Insights.

Cardiol Clin 2018 May;36(2):193-201

National Institute for Health and Medical Research (INSERM) and University of Pierre and Marie Curie - Paris 6, Pitié-Salpêtrière University Hospital, 91 Boulevard de l'Hôpital, Paris 75013, France. Electronic address:

Apolipoprotein B-containing lipoproteins and low-density lipoprotein play a key role in atherosclerotic vascular disease. Modified forms of low-density lipoprotein drive inflammation, an integral aspect of plaque progression. High-density lipoprotein particles are equipped to protect low-density lipoprotein from enzymatic and nonenzymatic modification. Under normal conditions, high-density lipoproteins facilitate cholesterol efflux from tissues, preventing its accumulation with deleterious consequences. However, the high-density lipoprotein particles characteristic of dyslipidemic states associated with premature atherosclerosis are typically dysfunctional as a result of alteration in their metabolism and consequently their structure and composition. Such an effect indirectly enhances low-density lipoprotein atherogenicity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ccl.2017.10.001DOI Listing
May 2018

Identifying mitotane-induced mitochondria-associated membranes dysfunctions: metabolomic and lipidomic approaches.

Oncotarget 2017 Dec 4;8(66):109924-109940. Epub 2017 Jul 4.

INSERM UMR-S 1185, Le Kremlin-Bicêtre, France.

Mitotane (o,p'DDD), the most effective drug in adrenocortical carcinoma, concentrates into the mitochondria and impacts mitochondrial functions. To address the molecular mechanisms of mitotane action and to identify its potential target, metabolomic and lipidomic approaches as well as imaging analyses were employed in human adrenocortical H295R cells allowing identification of Mitochondria-Associated Membranes dysfunction as a critical impact of mitotane. Study of intracellular energetic metabolites by NMR spectroscopy showed that mitotane significantly decreased aspartate while concomitantly increased glutamate content in a time- and concentration-dependent manner. Such alterations were very likely linked to the previously described, mitotane-induced respiratory chain defect. Lipidomic studies of intracellular and intramitochondrial phospholipids revealed that mitotane exposure markedly reduced the phosphatidylserine/phosphatidylethanolamine ratio, indicative of a dysfunction of phosphatidylserine decarboxylase located in Mitochondria-Associated Membranes. Expression levels of Mitochondria-Associated Membranes proteins phosphatidylserine decarboxylase, DRP1, ATAD3A or TSPO were greatly reduced by mitotane as assessed by western blot analyses. Mitotane exposure markedly altered endogenous Mitochondria-Associated Membranes integrity and reduced the magnitude of mitochondria and the endoplasmic reticulum interactions as demonstrated by high resolution deconvolution microscopy and quantification. Finally, we showed that PK11195, a pharmacological inhibitor of the cholesterol translocator TSPO, embedded in Mitochondria-Associated Membranes, exerts a synergetic effect with mitotane in inducing Mitochondria-Associated Membranes disruption, apoptosis and in inhibiting steroid secretion. Altogether, our results demonstrate Mitochondria-Associated Membranes dysfunction in H295R cells treated with mitotane and that TSPO inhibition significantly potentiates mitotane antitumoral and antisecretory actions . This constitutes a potential and promising pharmacological strategy for patients with adrenocortical carcinoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.18968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5746354PMC
December 2017

Intestinal lymphatic HDL miR-223 and ApoA-I are reduced during insulin resistance and restored with niacin.

FASEB J 2018 03 3;32(3):1602-1612. Epub 2018 Jan 3.

Metabolic and Cardiovascular Diseases Laboratory, Group on the Molecular Cell Biology of Lipids.

The intestine is involved in whole-body lipid and cholesterol homeostasis and secretes lipoproteins containing apolipoprotein (Apo)B48 and discrete ApoA-I into the mesenteric lymph. The lymphatic system has been proposed to have a significant role in the reverse cholesterol transport pathway associated with HDL-ApoA-I. In conditions of insulin resistance (IR), there is intestinal overproduction of chylomicrons containing ApoB48; however, there is limited data on the intestinal synthesis and secretion of HDL-ApoA-I. microRNA (miR)-223 has been shown to regulate peripheral HDL metabolism and may impact intestinal-derived HDL. Niacin (nicotinic acid; vitamin B3) is known to regulate lipid metabolism, but the role of niacin in modulating intestinal lipid and lipoprotein (ApoB48 and ApoA-I) metabolism is unknown. The aim of this study was to determine the secretion of intestinal lymphatic HDL-ApoA-I and the effect of dietary intervention with niacin on these pathways in a rodent model of IR. HDL was isolated from intestinal mesenteric lymph by density ultracentrifugation, and subsequent HDL miR analysis was developed in collaboration with Exiqon Services. Insulin-resistant rodents were fed chow or chow with niacin (1% w/w) for 6 wk. Intestinal lymph HDL-ApoA-I and miR-223 expression were lower by at least 45 and 60%, respectively, and lymph HDL was associated with 85% higher triglyceride (TG) content in IR compared to non-IR control group. Niacin was found to increase secretion of lymph HDL and miR-223 by at least 50-60% and to deplete the TGs associated with HDL compared with the nontreated IR group. Niacin significantly increased peroxisome proliferator-activating nuclear receptor α and carnitine palmitoyltransferase I α mRNA and annulled Tnf-α mRNA expression in intestinal (jejunal) explants. Altered intestinal lymphatic HDL-ApoA-I and miR-223 metabolism in IR and modulation by niacin may provide insight into the intestinal-mediated regulation of the reverse cholesterol transport pathway.-Mangat, R., Borthwick, F., Haase, T., Jacome, M., Nelson, R., Kontush, A., Vine, D. F., Proctor, S. D. Intestinal lymphatic HDL miR-223 and ApoA-I are reduced during insulin resistance and restored with niacin.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1096/fj.201600298RRDOI Listing
March 2018

Small dense HDLs display potent vasorelaxing activity, reflecting their elevated content of sphingosine-1-phosphate.

J Lipid Res 2018 01 17;59(1):25-34. Epub 2017 Nov 17.

National Institute for Health and Medical Research (INSERM), UMR-S 1166 ICAN, University of Pierre and Marie Curie-Paris 6, and AP-HP, Groupe Hospitalier Pitié-Salpétrière, Paris, France

The functional heterogeneity of HDL is attributed to its diverse bioactive components. We evaluated whether the vasodilatory effects of HDL differed across HDL subpopulations, reflecting their distinct molecular composition. The capacity of five major HDL subfractions to counteract the inhibitory effects of oxidized LDL on acetylcholine-induced vasodilation was tested in a rabbit aortic rings model. NO production, an essential pathway in endothelium-dependent vasorelaxation, was studied in simian vacuolating virus 40-transformed murine endothelial cells (SVECs). Small dense HDL3 subfractions displayed potent vasorelaxing activity (up to +31% vs. baseline, < 0.05); in contrast, large light HDL2 did not induce aortic-ring relaxation when compared on a total protein basis. HDL3 particles were enriched with sphingosine-1-phosphate (S1P) (up to 3-fold vs. HDL2), with the highest content in HDL3b and -3c that concomitantly revealed the strongest vasorelaxing properties. NO generation was enhanced by HDL3c in SVECs (1.5-fold, < 0.01), a phenomenon that was blocked by the S1P receptor antagonist, VPC 23019. S1P-enriched reconstituted HDL (rHDL) was a 1.8-fold ( < 0.01) more potent vasorelaxant than control rHDL in aortic rings. Small dense HDL3 particles displayed potent protective effects against oxidative stress-associated endothelium dysfunction, potentially reflecting their elevated content of S1P that might facilitate interaction with S1P receptors and ensuing NO generation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1194/jlr.M076927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5748494PMC
January 2018

Antioxidative activity of high-density lipoprotein (HDL): Mechanistic insights into potential clinical benefit.

BBA Clin 2017 Dec 19;8:66-77. Epub 2017 Aug 19.

National Institute for Health and Medical Research (INSERM), UMR ICAN 1166, University of Pierre and Marie Curie-Paris 6, AP-HP, Groupe hospitalier Pitié-Salpétrière, Paris F-75013, France.

Uptake of low-density lipoprotein (LDL) particles by macrophages represents a key step in the development of atherosclerotic plaques, leading to the foam cell formation. Chemical modification of LDL is however necessary to induce this process. Proatherogenic LDL modifications include aggregation, enzymatic digestion and oxidation. LDL oxidation by one-electron (free radicals) and two-electron oxidants dramatically increases LDL affinity to macrophage scavenger receptors, leading to rapid LDL uptake and fatty streak formation. Circulating high-density lipoprotein (HDL) particles, primarily small, dense, protein-rich HDL3, provide potent protection of LDL from oxidative damage by free radicals, resulting in the inhibition of the generation of pro-inflammatory oxidized lipids. HDL-mediated inactivation of lipid hydroperoxides involves their initial transfer from LDL to HDL and subsequent reduction to inactive hydroxides by redox-active Met residues of apolipoprotein A-I. Several HDL-associated enzymes are present at elevated concentrations in HDL3 relative to large, light HDL2 and can be involved in the inactivation of short-chain oxidized phospholipids. Therefore, HDL represents a multimolecular complex capable of acquiring and inactivating proatherogenic lipids. Antioxidative function of HDL can be impaired in several metabolic and inflammatory diseases. Structural and compositional anomalies in the HDL proteome and lipidome underlie such functional deficiency. Concomitant normalization of the metabolism, circulating levels, composition and biological activities of HDL particles, primarily those of small, dense HDL3, can constitute future therapeutic target.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbacli.2017.07.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5597817PMC
December 2017

Paradoxical coronary artery disease in humans with hyperalphalipoproteinemia is associated with distinct differences in the high-density lipoprotein phosphosphingolipidome.

J Clin Lipidol 2017 Sep - Oct;11(5):1192-1200.e3. Epub 2017 Jul 8.

Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Electronic address:

Background: Plasma high-density lipoprotein cholesterol (HDL-C) levels are inversely associated with risk of coronary artery disease (CAD) in epidemiologic studies. Despite this, the directionality of this relationship and the underlying biology behind it remain to be firmly established, especially at the extremes of HDL-C levels.

Objective: We investigated differences in the HDL phosphosphingolipidome in a rare population of subjects with premature CAD despite high HDL-C levels to gain insight into the association between the HDL lipidome and CAD disease status in this unusual phenotype. We sought to assess differences in HDL composition that are associated with CAD in subjects with HDL-C >90th percentile. We predicted that quantitative lipidomic analysis of HDL particles would reveal novel differences between CAD patients and healthy subjects with matched HDL-C levels.

Methods: We collected plasma samples from 25 subjects with HDL-C >90th percentile and clinically manifest CAD and healthy controls with HDL-C >90th percentile and without self-reported CAD. More than 140 individual HDL phospholipid and sphingolipid species were analyzed by LC/MS/MS.

Results: Significant reductions in HDL phosphatidylcholine (-2.41%, Q value = 0.025) and phosphatidylinositol (-10.7%, Q value = 0.047) content, as well as elevated sphingomyelin (+10.0%, Q value = 0.025) content, and sphingomyelin/phosphatidylcholine ratio (+12.8%, P value = .005) were associated with CAD status in subjects with high HDL-C.

Conclusions: These differences may lay the groundwork for further analysis of the relationship between the HDL lipidome and disease states, as well as for the development of biomarkers of CAD status and HDL function.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jacl.2017.06.018DOI Listing
May 2018

Pleiotropic effects of apolipoprotein C3 on HDL functionality and adipose tissue metabolic activity.

J Lipid Res 2017 09 12;58(9):1869-1883. Epub 2017 Jul 12.

Pharmacology Department, University of Patras Medical School, Rio Achaias TK 26500, Greece

APOC3 is produced mainly by the liver and intestine and approximately half of plasma APOC3 associates with HDL. Though it was believed that APOC3 associates with HDL by simple binding to preexisting particles, recent data support that biogenesis of APOC3-containing HDL (APOC3-HDL) requires Abca1. Moreover, APOC3-HDL contributes to plasma triglyceride homeostasis by preventing APOC3 association with triglyceride-rich lipoproteins. Interestingly, APOC3-HDL also shows positive correlation with the morbidly obese phenotype. However, the roles of APOC3 in HDL functionality and adipose tissue metabolic activity remain unknown. Therefore, here we investigated the direct effects of APOC3 expression on HDL structure and function, as well as white adipose tissue (WAT) and brown adipose tissue (BAT) metabolic activity. C57BL/6 mice were infected with an adenovirus expressing human APOC3 or a recombinant attenuated control adenovirus expressing green fluorescent protein and blood and tissue samples were collected at 5 days postinfection. HDL was then analyzed for its apolipoprotein and lipid composition and particle functionality. Additionally, purified mitochondria from BAT and WAT were analyzed for uncoupling protein 1, cytochrome c (Cytc), and Cytc oxidase subunit 4 protein levels as an indirect measure of their metabolic activity. Serum metabolomic analysis was performed by NMR. Combined, our data show that APOC3 modulates HDL structure and function, while it selectively promotes BAT metabolic activation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1194/jlr.M077925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5580900PMC
September 2017

Structure-function relationships in reconstituted HDL: Focus on antioxidative activity and cholesterol efflux capacity.

Biochim Biophys Acta Mol Cell Biol Lipids 2017 Sep 18;1862(9):890-900. Epub 2017 May 18.

National Institute for Health and Medical Research (INSERM), INSERM UMR 1166 ICAN, Paris, France; University of Pierre and Marie Curie-Paris 6, Paris, France; AP-HP, Groupe Hospitalier Pitié Salpétrière, Paris, France. Electronic address:

Aims: High-density lipoprotein (HDL) contains multiple components that endow it with biological activities. Apolipoprotein A-I (apoA-I) and surface phospholipids contribute to these activities; however, structure-function relationships in HDL particles remain incompletely characterised.

Methods: Reconstituted HDLs (rHDLs) were prepared from apoA-I and soy phosphatidylcholine (PC) at molar ratios of 1:50, 1:100 and 1:150. Oxidative status of apoA-I was varied using controlled oxidation of Met112 residue. HDL-mediated inactivation of PC hydroperoxides (PCOOH) derived from mildly pre-oxidized low-density lipoprotein (LDL) was evaluated by HPLC with chemiluminescent detection in HDL+LDL mixtures and re-isolated LDL. Cellular cholesterol efflux was characterised in RAW264.7 macrophages.

Results: rHDL inactivated LDL-derived PCOOH in a dose- and time-dependent manner. The capacity of rHDL to both inactivate PCOOH and efflux cholesterol via ATP-binding cassette transporter A1 (ABCA1) increased with increasing apoA-I/PC ratio proportionally to the apoA-I content in rHDL. Controlled oxidation of apoA-I Met112 gradually decreased PCOOH-inactivating capacity of rHDL but increased ABCA1-mediated cellular cholesterol efflux.

Conclusions: Increasing apoA-I content in rHDL enhanced its antioxidative activity towards oxidized LDL and cholesterol efflux capacity via ABCA1, whereas oxidation of apoA-I Met112 decreased the antioxidative activity but increased the cholesterol efflux. These findings provide important considerations in the design of future HDL therapeutics. Non-standard abbreviations and acronyms: AAPH, 2,2'-azobis(-amidinopropane) dihydrochloride; ABCA1, ATP-binding cassette transporter A1; apoA-I, apolipoprotein A-I; BHT, butylated hydroxytoluene; CV, cardiovascular; EDTA, ethylenediaminetetraacetic acid; HDL-C, high-density lipoprotein cholesterol; LOOH, lipid hydroperoxides; Met(O), methionine sulfoxide; Met112, methionine 112 residue; Met86, methionine 86 residue; oxLDL, oxidized low-density lipoprotein; PBS, phosphate-buffered saline; PC, phosphatidylcholine; PL, phospholipid; PCOOH, phosphatidylcholine hydroperoxide; PLOOH, phospholipid hydroperoxide.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbalip.2017.05.010DOI Listing
September 2017

Poor glycemic control in type 2 diabetes enhances functional and compositional alterations of small, dense HDL3c.

Biochim Biophys Acta Mol Cell Biol Lipids 2017 Feb 2;1862(2):188-195. Epub 2016 Nov 2.

INSERM UMR_S 1166, Faculte de Medecine Pitie-Salpetriere, 91 Bld de l'Hopital, 75013 Paris, France; University of Pierre and Marie Curie - Paris 6, Paris, France. Electronic address:

High-density lipoprotein (HDL) possesses multiple biological activities; small, dense HDL3c particles displaying distinct lipidomic composition exert potent antiatherogenic activities which can be compromised in dyslipidemic, hyperglycemic insulin-resistant states. However, it remains indeterminate (i) whether such functional HDL deficiency is related to altered HDL composition, and (ii) whether it originates from atherogenic dyslipidemia, dysglycemia, or both. In the present work we analyzed compositional characteristics of HDL subpopulations and functional activity of small, dense HDL3c particles in treatment-naïve patients with well-controlled (n=10) and poorly-controlled (n=8) type 2 diabetes (T2D) and in normolipidemic age- and sex-matched controls (n=11). Our data reveal that patients with both well- and poorly-controlled T2D displayed dyslipidemia and low-grade inflammation associated with altered HDL composition. Such compositional alterations in small, dense HDL subfractions were specifically correlated with plasma HbA1c levels. Further analysis using a lipidomic approach revealed that small, dense HDL3c particles from T2D patients with poor glycemic control displayed additional modifications of their chemical composition. In parallel, antioxidative activity of HDL3c towards oxidation of low-density lipoprotein was diminished. These findings indicate that defective functionality of small, dense HDL particles in patients with T2D is not only affected by the presence of atherogenic dyslipidemia, but also by the level of glycemic control, reflecting compositional alterations of HDL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbalip.2016.10.014DOI Listing
February 2017

Statin action enriches HDL3 in polyunsaturated phospholipids and plasmalogens and reduces LDL-derived phospholipid hydroperoxides in atherogenic mixed dyslipidemia.

J Lipid Res 2016 11 31;57(11):2073-2087. Epub 2016 Aug 31.

Clinical Biochemistry Service, APHP, HUPS, Bicêtre University Hospital, Le Kremlin Bicêtre, France

Atherogenic mixed dyslipidemia associates with oxidative stress and defective HDL antioxidative function in metabolic syndrome (MetS). The impact of statin treatment on the capacity of HDL to inactivate LDL-derived, redox-active phospholipid hydroperoxides (PCOOHs) in MetS is indeterminate. Insulin-resistant, hypertriglyceridemic, hypertensive, obese males were treated with pitavastatin (4 mg/day) for 180 days, resulting in marked reduction in plasma TGs (-41%) and LDL-cholesterol (-38%), with minor effects on HDL-cholesterol and apoAI. Native plasma LDL (baseline vs. 180 days) was oxidized by aqueous free radicals under mild conditions in vitro either alone or in the presence of the corresponding pre- or poststatin HDL2 or HDL3 at authentic plasma mass ratios. Lipidomic analyses revealed that statin treatment i) reduced the content of oxidizable polyunsaturated phosphatidylcholine (PUPC) species containing DHA and linoleic acid in LDL; ii) preferentially increased the content of PUPC species containing arachidonic acid (AA) in small, dense HDL3; iii) induced significant elevation in the content of phosphatidylcholine and phosphatidylethanolamine (PE) plasmalogens containing AA and DHA in HDL3; and iv) induced formation of HDL3 particles with increased capacity to inactivate PCOOH with formation of redox-inactive phospholipid hydroxide. Statin action attenuated LDL oxidability Concomitantly, the capacity of HDL3 to inactivate redox-active PCOOH was enhanced relative to HDL2, consistent with preferential enrichment of PE plasmalogens and PUPC in HDL3.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1194/jlr.P068585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5087874PMC
November 2016

HDL-Targeting Therapeutics: Past, Present and Future.

Curr Pharm Des 2017 ;23(8):1207-1215

INSERM UMR_S 1166, Faculte de Medecine Pitie-Salpetriere, Bld de L'Hopital 91, 75013 Paris. France.

Large-scale epidemiological studies firmly established the association between low plasma levels of high-density lipoprotein-cholesterol (HDL-C) and elevated risk of cardiovascular disease. This relationship is thought to reflect the key biological function of HDL, which involves reverse cholesterol transport from the arterial wall to the liver for further excretion from the body. Other aspects of the cardioprotective HDL functionality include antioxidative, anti-inflammatory, anti-apoptotic, anti-thrombotic, vasodilatory, anti-infectious and antidiabetic activities. Over the last decades, wide interest in HDL as an athero- and cardioprotective particle has resulted in the development of HDL-C raising as a therapeutic approach to reduce cardiovascular risk. Several strategies to increase circulating HDL-C concentrations were developed that primarily included use of niacin and fibrates as potent HDL-C raising agents. In the statin era, inhibition of cholesteryl ester transfer protein, infusion of artificially reconstituted HDL and administration of apolipoprotein A-I mimetics were established as novel approaches to raise HDL-C. More recently, other strategies targeting HDL metabolism, such as upregulation of apolipoprotein A-I production by the liver, were added to the list of HDL therapeutics. This review summarises current knowledge of novel HDL-targeting therapies and discusses perspectives of their use.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/1381612822666161027153140DOI Listing
April 2018

Lifestyle intervention enhances high-density lipoprotein function among patients with metabolic syndrome only at normal low-density lipoprotein cholesterol plasma levels.

J Clin Lipidol 2016 Sep-Oct;10(5):1172-81. Epub 2016 May 14.

INSERM UMRS 1166 ICAN, Université Pierre et Marie Curie Paris 6, Hôpital de la Pitie, Paris, France.

Background: Metabolic syndrome (MetS) is associated with altered lipoprotein metabolism and impairment in the functionality of small, dense high-density lipoprotein (HDL) particles secondary to compositional alterations.

Objective: The objective of this study was to investigate the capacity of a lifestyle program to improve the composition and antioxidative function (AOX) of small dense HDL3c in MetS.

Methods: Patients with MetS (n = 33) not taking lipid-lowering drugs were recruited to follow a 12-week educational program to reduce caloric intake and to increase physical activity. HDL subfractions were preparatively isolated by isopycnic density-gradient ultracentrifugation. AOX of HDL3c was assessed as its capacity to inhibit low-density lipoprotein oxidation induced by an azoinitiator.

Results: AOX of HDL3c was significantly improved (mean reduction in the propagation rate of low-density lipoprotein oxidation by HDL3c, -6.8%, P = .03) and systemic oxidative stress, assessed as plasma levels of 8-isoprostanes, tended to decrease in normocholesterolemic MetS patients (low-density lipoprotein cholesterol [LDL-C] < 130 mg/dL) but not in patients with elevated LDL-C levels and in the whole study population. In both the whole study population and the normocholesterolemic subgroup, lifestyle intervention resulted in a significant degree of normalization of HDL3c composition, (enrichment in apolipoprotein A-I and cholesteryl esters, depletion in triglycerides), which was more pronounced at LDL-C < 130 mg/dL.

Conclusion: In patients with MetS, a lifestyle program improves AOX of small, dense HDL in subjects with normal LDL-C levels. Correction of HDL composition, involving partial normalization of apoA-I content and core lipid composition, 2 central features of the lipid hydroperoxide-inactivating capacity of HDL, may account for this effect.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jacl.2016.05.008DOI Listing
October 2017

Enhanced HDL Functionality in Small HDL Species Produced Upon Remodeling of HDL by Reconstituted HDL, CSL112: Effects on Cholesterol Efflux, Anti-Inflammatory and Antioxidative Activity.

Circ Res 2016 Sep 19;119(6):751-63. Epub 2016 Jul 19.

From the CSL Behring AG, Berne, Switzerland (S.A.D., A.V.N., P.S., M.O.S.); National Institute for Health and Medical Research (INSERM), UMR-ICAN 1166, Paris, France (A.M.O.C., M.J.C., A.K.); University of Pierre and Marie Curie - Paris 6, France (A.M.O.C., M.J.C., A.K.); Pitié - Salpétrière University Hospital; ICAN, Paris, France (A.M.O.C., M.J.C., A.K.); CSL Limited, Parkville, VIC, Australia (A.G.); AP-HP, HUPS Hôpital de Bicêtre, Le Kremlin-Bicêtre, France (P.T.); and CSL Behring, King of Prussia, PA (S.D.W.).

Rationale: CSL112, human apolipoprotein A-I (apoA-I) reconstituted with phosphatidylcholine, is known to cause a dramatic rise in small high-density lipoprotein (HDL).

Objective: To explore the mechanisms by which the formation of small HDL particles is induced by CSL112.

Methods And Results: Infusion of CSL112 into humans caused elevation of 2 small diameter HDL fractions and 1 large diameter fraction. Ex vivo studies showed that this remodeling does not depend on lipid transfer proteins or lipases. Rather, interaction of CSL112 with purified HDL spontaneously gave rise to 3 HDL species: a large, spherical species composed of apoA-I from native HDL and CSL112; a small, disc-shaped species composed of apoA-I from CSL112, but smaller because of the loss of phospholipids; and the smallest species, lipid-poor apoA-I composed of apoA-I from HDL and CSL112. Time-course studies suggest that remodeling occurs by an initial fusion of CSL112 with HDL and subsequent fission leading to the smaller forms. Functional studies showed that ATP-binding cassette transporter 1-dependent cholesterol efflux and anti-inflammatory effects in whole blood were carried by the 2 small species with little activity in the large species. In contrast, the ability to inactivate lipid hydroperoxides in oxidized low-density lipoprotein was carried predominantly by the 2 largest species and was low in lipid-poor apoA-I.

Conclusions: We have described a mechanism for the formation of small, highly functional HDL species involving spontaneous fusion of discoidal HDL with spherical HDL and subsequent fission. Similar remodeling is likely to occur during the life cycle of apoA-I in vivo.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCRESAHA.116.308685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5006797PMC
September 2016

Associations between disease activity, markers of HDL functionality and arterial stiffness in patients with rheumatoid arthritis.

Atherosclerosis 2016 08 11;251:438-444. Epub 2016 Jun 11.

Laboratory of Lipids and Lipoproteins, School of Pharmacy and Biochemistry, INFIBIOC, University of Buenos Aires, CONICET, Buenos Aires, Argentina.

Background And Aims: Rheumatoid arthritis (RA) is a chronic, inflammatory disease associated with increased risk of cardiovascular disease (CVD). Measures of HDL metabolism/function were shown to be altered in RA patients with high disease activity. We aimed at evaluating the effect of HDL characteristics on arterial stiffness in RA patients classified according to the inflammatory disease activity.

Methods: RA patients were classified according to disease activity (DAS-28) into active RA (n = 27; DAS-28 > 3.2) and inactive RA patients (n = 17; DAS-28 < 3.2). A control group of healthy individuals was also studied (n = 33). Clinical and biochemical characteristics, cholesteryl ester transfer protein (CETP) and paraoxonase 1 (phenylacetate and paraoxonase) activities and carotid-femoral pulse wave velocity (cf-PWV) were determined.

Results: Anthropometric characteristics were similar in all groups. In accordance with the inflammatory status, active RA patients presented elevated hsCRP levels (p < 0.001). There were no differences in the lipid profile between groups. Similarly, features of insulin resistance were absent in RA patients (p = non-significant). Active RA patients presented higher CETP activity than the other two groups (p = 0.026). Phenylacetate and paraoxonase activities were altered in active RA patients in comparison with the other groups (p = 0.034 and p = 0.041, respectively). Cf-PWV was significantly higher in active RA patients in comparison with controls, following adjustment by age (p = 0.030). Age (βst = 0.468, p = 0.013) and apo A-I levels (βst = -0.405, p = 0.029) were independent predictors of cf-PWV in a model including hsCRP, HOMA-IR, and phenylacetate activity (r(2) = 0.42).

Conclusions: High DAS-28 identifies patients with alterations in HDL characteristics. Plasma levels of apo A-I can be used as a marker of arterial stiffness in RA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.atherosclerosis.2016.06.009DOI Listing
August 2016