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1.
FASEB J ; 36(5): e22274, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35416331

RESUMO

Phosphatidylserine (PS) is a minor phospholipid constituent of high-density lipoprotein (HDL) that exhibits potent anti-inflammatory activity. It remains indeterminate whether PS incorporation can enhance anti-inflammatory effects of reconstituted HDL (rHDL). Human macrophages were treated with rHDL containing phosphatidylcholine alone (PC-rHDL) or PC and PS (PC/PS-rHDL). Interleukin (IL)-6 secretion and expression was more strongly inhibited by PC/PS-rHDL than PC-rHDL in both tumor necrosis factor (TNF)-α- and lipopolysaccharide (LPS)-stimulated macrophages. siRNA experiments revealed that the enhanced anti-inflammatory effects of PC/PS-rHDL required scavenger receptor class B type I (SR-BI). Furthermore, PC/PS-rHDL induced a greater increase in Akt1/2/3 phosphorylation than PC-rHDL. In addition, PC/PS but not PC-rHDL decreased the abundance of plasma membrane lipid rafts and p38 mitogen-activated protein kinase (p38 MAPK) phosphorylation. Finally, when these rHDL formulations were administered to dyslipidemic low-density lipoprotein (LDL)-receptor knockout mice fed a high-cholesterol diet, circulating IL-6 levels were significantly reduced only in PC/PS-rHDL-treated mice. In parallel, enhanced Akt1/2/3 phosphorylation by PC/PS-rHDL was observed in the mouse aortic tissue using immunohistochemistry. We concluded that the incorporation of PS into rHDLs enhanced their anti-inflammatory activity by modulating Akt1/2/3- and p38 MAPK-mediated signaling through SR-BI in stimulated macrophages. These data identify PS as a potent anti-inflammatory component capable of enhancing therapeutic potential of rHDL-based therapy.


Assuntos
Lipoproteínas HDL , Fosfatidilserinas , Animais , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacologia , Lipoproteínas HDL/metabolismo , Macrófagos/metabolismo , Camundongos , Fosfatidilserinas/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
2.
Artigo em Inglês | MEDLINE | ID: mdl-34624514

RESUMO

The failure of high-density lipoprotein (HDL)-raising agents to reduce cardiovascular disease (CVD) together with recent findings of increased cardiovascular mortality in subjects with extremely high HDL-cholesterol levels provide new opportunities to revisit our view of HDL. The concept of HDL function developed to explain these contradictory findings has recently been expanded by a role played by HDL in the lipolysis of triglyceride-rich lipoproteins (TGRLs) by lipoprotein lipase. According to the reverse remnant-cholesterol transport (RRT) hypothesis, HDL critically contributes to TGRL lipolysis via acquirement of surface lipids, including free cholesterol, released from TGRL. Ensuing cholesterol transport to the liver with excretion into the bile may reduce cholesterol influx in the arterial wall by accelerating removal from circulation of atherogenic, cholesterol-rich TGRL remnants. Such novel function of HDL opens wide therapeutic applications to reduce CVD in statin-treated patients, which primarily involve activation of cholesterol flux upon lipolysis.


Assuntos
Colesterol/sangue , Lipólise/genética , Lipase Lipoproteica/sangue , Lipoproteínas HDL/sangue , Colesterol/genética , Humanos , Lipídeos/sangue , Lipídeos/classificação , Lipase Lipoproteica/genética , Lipoproteínas/sangue , Lipoproteínas HDL/genética , Triglicerídeos/sangue
3.
Eur J Pharmacol ; 908: 174308, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34245747

RESUMO

Liposomes have been suggested as potential tools for cholesterol deposit mobilization from atherosclerotic lesions. Here, we explored the anti-atherosclerotic effects of phosphatidylserine (PS)-containing liposomes in vivo. High-fat diet-fed New Zealand white rabbits which were divided into groups receiving weekly intravenous injections of PS liposomes, atorvastatin-loaded PS (PSA) liposomes (100 µg phospholipid/kg), or control buffer for four weeks. The size and severity grade of atherosclerotic plaques as well as lipid profile were evaluated at the completion of study. In vitro, the expression and levels of anti/pro-inflammatory genes and proteins, respectively, and macrophage cholesterol efflux capacity (CEC) of nanoliposomes were evaluated. Both PS and PSA lowered serum LDL-C (P = 0.0034, P = 0.0041) and TC (P = 0.029, P = 0.0054) levels but did not alter TG and HDL-C levels. Plaque size and grade were reduced by PS (P = 0.0025, P = 0.0031) and PSA (P = 0.016, P = 0.027) versus control. Moreover, intima-media thickness was significantly reduced in the PS vs. control group (P = 0.01). In cultured cells, ICAM-1 expression in the PS (P = 0.022) and VCAM-1 expression in the PS and PSA groups (P = 0.037, P = 0.004) were suppressed while TGF-ß expression was induced by both PS and PSA (P = 0.048, P = 0.046). Moreover, CEC from macrophages to nanoliposomes was enhanced by PSA (P = 0.003). Administration of anionic PS-containing liposomes could improve lipid profile and promote plaque regression through mechanisms that may involve cholesterol efflux and modulation of adhesion molecules.


Assuntos
Hipercolesterolemia , Lipossomos , Animais , Espessura Intima-Media Carotídea , Placa Aterosclerótica , Coelhos
5.
Rheumatol Ther ; 8(2): 803-815, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33811316

RESUMO

BACKGROUND: In patients with rheumatoid arthritis (RA), qualitative alterations of low and high-density lipoproteins (LDL and HDL, respectively) might partially explain their increased cardiovascular risk. Tocilizumab has been associated with an increase in lipids, including triglyceride (TG) and cholesterol levels. The aim of this study is to evaluate the effect of tocilizumab on certain LDL and HDL characteristics (oxidized LDL levels, HDL-associated enzymes, chemical composition of both total HDL and HDL3c subpopulation, and their capacity to promote cellular cholesterol efflux) at baseline and 3 months after the start of treatment in patients with RA. METHODS: Twenty-eight RA patients (ACR/EULAR 2010 criteria) with indication of treatment with tocilizumab were included in the present study. Clinical assessment [Health assessment questionnaire (HAQ)], disease activity score 28 (DAS28), high-sensitivity C reactive protein (hsCRP) concentration, lipid profile, and lipoprotein (a) [Lp(a)] levels were evaluated in all patients at baseline and after 3 months of treatment with tocilizumab. Lipoprotein characteristics were evaluated through the levels of oxidized LDL (OxLDL), the activity of paraoxonase (PON) 1, the composition of total HDL and small, dense HDL3c subpopulation, and their ability to promote cellular cholesterol efflux. RESULTS: After 3 months of treatment with tocilizumab, HAQ (- 23%, p < 0.05), DAS28 (- 49%, p < 0.001), and hsCRP (- 94%, p < 0.01) levels decreased significantly. Total cholesterol (TC), LDL-C, non-HDL-C, and apo B levels showed a significant increase after treatment (TC: + 7.0%, p < 0.01; LDL-C: + 10%, p < 0.01; non-HDL-C: + 9.9%, p < 0.01; and apo B: + 9.6%, p < 0.05). Decreases in Lp(a) and OxLDL levels were also observed after treatment [Lp(a): - 50%, p < 0.01; and oxLDL: - 5.4%, p < 0.05]. The latter was in accordance with the increment detected in PON activity. No changes were observed in HDL capacity to promote cholesterol efflux (p > 0.05) in the whole group. CONCLUSIONS: Treatment with tocilizumab reduced hsCRP levels and displayed positive effects on certain lipoprotein-related parameters, such as a potent decrease inLp(a) and a reduction in OxLDL levels. Moreover, HDL capacity to promote cellular cholesterol efflux was maintained after 3 months of treatment.

6.
Atherosclerosis ; 324: 1-8, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33798922

RESUMO

BACKGROUND AND AIMS: While low concentrations of high-density lipoprotein-cholesterol (HDL-C) represent a well-established cardiovascular risk factor, extremely high HDL-C is paradoxically associated with elevated cardiovascular risk, resulting in the U-shape relationship with cardiovascular disease. Free cholesterol transfer to HDL upon lipolysis of triglyceride-rich lipoproteins (TGRL) was recently reported to underlie this relationship, linking HDL-C to triglyceride metabolism and atherosclerosis. In addition to free cholesterol, other surface components of TGRL, primarily phospholipids, are transferred to HDL during lipolysis. It remains indeterminate as to whether such transfer is linked to HDL-C and cardiovascular disease. METHODS AND RESULTS: When TGRL was labelled with fluorescent phospholipid 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI), time- and dose-dependent transfer of DiI to HDL was observed upon incubations with lipoprotein lipase (LPL). The capacity of HDL to acquire DiI was decreased by -36% (p<0.001) in low HDL-C patients with acute myocardial infarction (n = 22) and by -95% (p<0.001) in low HDL-C subjects with Tangier disease (n = 7), unchanged in low HDL-C patients with Type 2 diabetes (n = 17) and in subjects with high HDL-C (n = 20), and elevated in subjects with extremely high HDL-C (+11%, p<0.05) relative to healthy normolipidemic controls. Across all the populations combined, HDL capacity to acquire DiI was directly correlated with HDL-C (r = 0.58, p<0.001). No relationship of HDL capacity to acquire DiI with both overall and cardiovascular mortality obtained from epidemiological studies for the mean HDL-C levels observed in the studied populations was obtained. CONCLUSIONS: These data indicate that the capacity of HDL to acquire phospholipid from TGRL upon LPL-mediated lipolysis is proportional to HDL-C and does not reflect cardiovascular risk in subjects widely differing in HDL-C levels.


Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Doenças Cardiovasculares/diagnóstico , Colesterol , Fatores de Risco de Doenças Cardíacas , Humanos , Lipólise , Lipase Lipoproteica/metabolismo , Lipoproteínas HDL/metabolismo , Fosfolipídeos , Fatores de Risco , Triglicerídeos
7.
Int J Mol Sci ; 22(2)2021 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-33450841

RESUMO

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.


Assuntos
Arildialquilfosfatase/metabolismo , Hidrolases de Éster Carboxílico/metabolismo , Endotélio/enzimologia , Lipase/metabolismo , Lipoproteínas HDL/metabolismo , Arildialquilfosfatase/química , Hidrolases de Éster Carboxílico/química , Linhagem Celular Tumoral , Ativação Enzimática , Humanos , Lipase/sangue , Lipase/química , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Ligação Proteica
8.
Am J Cardiovasc Dis ; 10(4): 463-472, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33224597

RESUMO

Background: 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. Material and methods: 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. Results: 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. Conclusion: 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.

9.
Ther Adv Chronic Dis ; 11: 2040622320959248, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33062236

RESUMO

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 (n = 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.

10.
Arterioscler Thromb Vasc Biol ; 40(11): 2728-2737, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32907370

RESUMO

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.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/metabolismo , Colesterol/sangue , Dislipidemias/sangue , Lipoproteínas/sangue , Esquizofrenia/sangue , Transportador 1 de Cassete de Ligação de ATP/genética , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Adulto , Animais , Antipsicóticos/uso terapêutico , Biomarcadores/sangue , Células CHO , Estudos de Casos e Controles , Cricetulus , Dislipidemias/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esquizofrenia/diagnóstico , Esquizofrenia/tratamento farmacológico , Triglicerídeos/sangue
11.
Trends Mol Med ; 26(12): 1086-1100, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32861590

RESUMO

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.


Assuntos
Doenças Cardiovasculares/metabolismo , Colesterol/metabolismo , Metabolismo dos Lipídeos , Lipoproteínas HDL/metabolismo , Transporte Biológico , Doenças Cardiovasculares/etiologia , Colesterol/sangue , Humanos , Lipólise , Lipoproteínas/metabolismo , Lipoproteínas HDL/sangue , Fígado/metabolismo , Triglicerídeos/metabolismo
12.
Eur J Prev Cardiol ; 27(15): 1606-1616, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-31840535

RESUMO

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 [3H]-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.


Assuntos
Aorta Torácica/metabolismo , Doenças Cardiovasculares/metabolismo , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , Lipólise/fisiologia , Lipoproteínas HDL/metabolismo , Triglicerídeos/metabolismo , Animais , Biomarcadores/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Lipase Lipoproteica/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Período Pós-Prandial
13.
Nutr Metab Cardiovasc Dis ; 30(1): 33-39, 2020 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-31753791

RESUMO

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.


Assuntos
Antioxidantes/análise , Artérias , Aterosclerose/sangue , Doenças das Valvas Cardíacas/sangue , Lipoproteínas HDL/sangue , Isquemia Miocárdica/sangue , Veias , Adulto , Idoso , Aterosclerose/diagnóstico , Aterosclerose/tratamento farmacológico , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Doenças das Valvas Cardíacas/diagnóstico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Masculino , Pessoa de Meia-Idade , Isquemia Miocárdica/diagnóstico , Oxirredução , Estresse Oxidativo
14.
Metabolomics ; 15(11): 140, 2019 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-31605240

RESUMO

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 ß-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.


Assuntos
Ceramidas/sangue , Disbiose/sangue , Glucose/metabolismo , Metabolômica , Obesidade/sangue , Adulto , Ceramidas/metabolismo , Cromatografia Líquida de Alta Pressão , Estudos Transversais , Disbiose/metabolismo , Feminino , Microbioma Gastrointestinal , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/metabolismo , Estudos Retrospectivos , Esfingolipídeos/sangue , Esfingolipídeos/metabolismo , Espectrometria de Massas em Tandem
15.
J Physiol Biochem ; 75(4): 453-462, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31392628

RESUMO

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.


Assuntos
Artrite Reumatoide/patologia , Doenças Cardiovasculares/diagnóstico , Ácidos Graxos Ômega-3/sangue , Fosfolipídeos/sangue , Doenças Cardiovasculares/patologia , Cromatografia Líquida/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Espectrometria de Massas em Tandem/métodos
16.
Arterioscler Thromb Vasc Biol ; 39(8): 1550-1564, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31189429

RESUMO

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.


Assuntos
Lipoproteínas HDL/fisiologia , Infarto do Miocárdio/prevenção & controle , Animais , Colesterol/metabolismo , Células Endoteliais/fisiologia , Glucose/metabolismo , Homeostase , Humanos , Lipoproteínas HDL/sangue , Lisofosfolipídeos/fisiologia , Estresse Oxidativo , Transdução de Sinais/fisiologia , Esfingosina/análogos & derivados , Esfingosina/fisiologia
17.
J Clin Lipidol ; 13(3): 468-480.e8, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31003938

RESUMO

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.


Assuntos
Apolipoproteína A-I/deficiência , Lipoproteínas HDL/sangue , Lipoproteínas HDL/química , Fosfolipídeos/química , Esfingolipídeos/química , Humanos
18.
Cardiovasc Drugs Ther ; 33(3): 371-381, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30778806

RESUMO

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.


Assuntos
Dislipidemias/terapia , Terapia Genética , Hipolipemiantes/uso terapêutico , Lipoproteínas HDL/uso terapêutico , Infarto do Miocárdio/prevenção & controle , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Peptídeos/uso terapêutico , Animais , Apolipoproteína A-I/sangue , Dislipidemias/sangue , Dislipidemias/genética , Terapia Genética/efeitos adversos , Humanos , Hipolipemiantes/efeitos adversos , Lipoproteínas HDL/efeitos adversos , Lipoproteínas HDL/genética , Mimetismo Molecular , Infarto do Miocárdio/sangue , Infarto do Miocárdio/genética , Traumatismo por Reperfusão Miocárdica/sangue , Traumatismo por Reperfusão Miocárdica/genética , Peptídeos/efeitos adversos , Resultado do Tratamento
19.
Biochim Biophys Acta Mol Cell Biol Lipids ; 1864(5): 643-653, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30641224

RESUMO

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.


Assuntos
Lipoproteínas HDL/metabolismo , Lipoproteínas LDL/metabolismo , Linhagem Celular , Colesterol/metabolismo , Ésteres do Colesterol/metabolismo , Glicosilação , Humanos , Lipoproteínas HDL/sangue , Lipoproteínas HDL/química , Lipoproteínas LDL/sangue , Lipoproteínas LDL/química , Ácido N-Acetilneuramínico/análise , Ácido N-Acetilneuramínico/metabolismo , Polissacarídeos/análise , Polissacarídeos/metabolismo
20.
FASEB J ; 33(4): 4741-4754, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30608881

RESUMO

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.


Assuntos
Tecido Adiposo/metabolismo , Disbiose/metabolismo , Inflamação/metabolismo , Obesidade/metabolismo , Fosfatidilgliceróis/metabolismo , Animais , Feminino , Humanos , Lipidômica/métodos , Lipólise/fisiologia , Masculino , Metagenômica/métodos , Camundongos
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