High-density Lipoprotein Phospholipids Research Articles

ABCA1 and apoA-I dependent 12-hydroxyeicosatetraenoic acid efflux regulates macrophage inflammatory signaling.

Aberrant high-density lipoprotein (HDL) function is implicated in inflammation-associated pathologies. While HDL ABCA1-mediated reverse cholesterol and phospholipid transport are well described, the movement of pro-/anti-inflammatory lipids has not been explored. HDL phospholipids are the largest reservoir of circulating arachidonic acid-derived oxylipins. Endotoxin-stimulation activates inflammatory cells leading to hydroxyeicosatetraenoic acid (HETE) production, oxylipins which are involved in inflammatory response coordination. Active signaling in the non-esterified (NE) pool is terminated by sequestration of HETEs as esterified (Es) forms and degradation. We speculate that an ABCA1-apoA-I-dependent efflux of HETEs from stimulated cells could regulate intracellular HETE availability. Here we test this hypothesis both in vitro and in vivo. In endotoxin-stimulated RAW-264.7 macrophages preloaded with d8-arachidonic acid we use compartmental tracer modeling to characterize the formation of HETEs, and their efflux into HDL. We found that in response to endotoxin: I) Cellular NE 12-HETE is positively associated with MCP-1 secretion (p<0.001); II) HETE transfer from NE to Es pools is ABCA1-depedent (p<0.001); III) Cellular Es HETEs are transported into media when both apoA-I and ABCA1 are present (p<0.001); IV) The stimulated efflux of HETEs >> arachidonate (p<0.001). Finally, in endotoxin challenged humans (n=17), we demonstrate that intravenous lipopolysaccharide (0.6 ng/kg body weight) resulted in accumulation of 12-HETE in HDL over a 168-hour follow-up. Therefore, HDL can suppress inflammatory responses in macrophages by regulating intracellular HETE content in an apoA-I/ABCA1 dependent manner. The described mechanism may apply to other oxylipins and explain anti-inflammatory properties of HDL. This newly defined HDL property opens new doors for the study of lipoprotein interactions in metabolic diseases.

Exploration of Metabolomic Markers Associated With Declining Kidney Function in People With Type 2 Diabetes Mellitus.

Metabolomics, the study of small molecules in biological systems, can provide valuable insights into kidney dysfunction in people with type 2 diabetes mellitus (T2DM), but prospective studies are scarce. We investigated the association between metabolites and kidney function decline in people with T2DM. The Edinburgh Type 2 Diabetes Study, a population-based cohort of 1066 men and women aged 60 to 75 years with T2DM. We measured 149 serum metabolites at baseline and investigated individual associations with baseline estimated glomerular filtration rate (eGFR), incident chronic kidney disease [CKD; eGFR <60 mL/min/(1.73 m)2], and decliner status (5% eGFR decline per year). At baseline, mean eGFR was 77.5 mL/min/(1.73 m)2 (n = 1058), and 216 individuals had evidence of CKD. Of those without CKD, 155 developed CKD over a median 7-year follow-up. Eighty-eight metabolites were significantly associated with baseline eGFR (β range -4.08 to 3.92; PFDR < 0.001). Very low density lipoproteins, triglycerides, amino acids (AAs), glycoprotein acetyls, and fatty acids showed inverse associations, while cholesterol and phospholipids in high-density lipoproteins exhibited positive associations. AA isoleucine, apolipoprotein A1, and total cholines were not only associated with baseline kidney measures (PFDR < 0.05) but also showed stable, nominally significant association with incident CKD and decline. Our study revealed widespread changes within the metabolomic profile of CKD, particularly in lipoproteins and their lipid compounds. We identified a smaller number of individual metabolites that are specifically associated with kidney function decline. Replication studies are needed to confirm the longitudinal findings and explore if metabolic signals at baseline can predict kidney decline.

Phospholipids impact the protective effects of HDL-mimetic nanodiscs against lipopolysaccharide-induced inflammation.

Aim: The impacts of synthetic high-density lipoprotein (sHDL) phospholipid components on anti-sepsis effects were investigated. Methods: sHDL composed with ApoA-I mimetic peptide (22A) and different phosphatidylcholines were prepared and characterized. Anti-inflammatory effects were investigated in vitro and in vivo on lipopolysaccharide (LPS)-induced inflammation models. Results: sHDLs composed with 1,2-dimyristoyl-sn-glycero-3-phosphocholine (22A-DMPC) most effectively neutralizes LPS, inhibits toll-like receptor 4 recruitment into lipid rafts, suppresses nuclear factor κB signaling and promotes activating transcription factor 3 activating. The lethal endotoxemia animal model showed the protective effects of 22A-DMPC. Conclusion: Phospholipid components affect the stability and fluidity of nanodiscs, impacting the anti-septic efficacy of sHDLs. 22A-DMPC presents the strongest LPS binding and anti-inflammatory effects in vitro and in vivo, suggesting a potential sepsis treatment.

Coupling capillary electrophoresis with mass spectrometry for the analysis of oxidized phospholipids in human high-density lipoproteins.

The oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (ox-PAPC) products in human high-density lipoproteins (HDLs) were investigated by low-flow capillary electrophoresis-mass spectrometry (low-flow CE-MS). To accelerate the optimization, native PAPC (n-PAPC) standard was first analyzed by a commercial CE instrument with a photodiode array detector. The optimal separation buffer contained 60% (v/v) acetonitrile, 40% (v/v) methanol, 20mM ammonium acetate, 0.5% (v/v) formic acid, and 0.1% (v/v) water. The selected separation voltage and capillary temperature were 20kV and 23°C. The optimal CE separation buffer was then used for the low-flow CE-MS analysis. The selected MS conditions contained heated capillary temperature (250°C), capillary voltage (10V), and injection time (1 s). No sheath gas was used for MS. The linear range for n-PAPC was 2.5-100.0µg/mL. The coefficient of determination (R2 ) was 0.9918. The concentration limit of detection was 1.52µg/mL, and the concentration limit of quantitation was 4.60µg/mL. The optimal low-flow CE-MS method showed good repeatability and sensitivity. The ox-PAPC products in human HDLs were determined based on the in vitro ox-PAPC products of n-PAPC standard. Twenty-one ox-PAPC products have been analyzed in human HDLs. Uremic patients showed significantly higher levels of 15 ox-PAPC products than healthy subjects.

HDL-Related Parameters and COVID-19 Mortality: The Importance of HDL Function.

COVID-19, caused by the SARS-CoV-2 coronavirus, emerged as a global pandemic in late 2019, resulting in significant global public health challenges. The emerging evidence suggests that diminished high-density lipoprotein (HDL) cholesterol levels are associated with the severity of COVID-19, beyond inflammation and oxidative stress. Here, we used nuclear magnetic resonance spectroscopy to compare the lipoprotein and metabolic profiles of COVID-19-infected patients with non-COVID-19 pneumonia. We compared the control group and the COVID-19 group using inflammatory markers to ensure that the differences in lipoprotein levels were due to COVID-19 infection. Our analyses revealed supramolecular phospholipid composite (SPC), phenylalanine, and HDL-related parameters as key discriminators between COVID-19-positive and non-COVID-19 pneumonia patients. More specifically, the levels of HDL parameters, including apolipoprotein A-I (ApoA-I), ApoA-II, HDL cholesterol, and HDL phospholipids, were significantly different. These findings underscore the potential impact of HDL-related factors in patients with COVID-19. Significantly, among the HDL-related metrics, the cholesterol efflux capacity (CEC) displayed the strongest negative association with COVID-19 mortality. CEC is a measure of how well HDL removes cholesterol from cells, which may affect the way SARS-CoV-2 enters cells. In summary, this study validates previously established markers of COVID-19 infection and further highlights the potential significance of HDL functionality in the context of COVID-19 mortality.

HDL cholesterol efflux capacity and phospholipid content are associated with the severity of acute ischemic stroke and predict its outcome

Background/AimsImpaired high-density lipoprotein (HDL) function and composition are more strongly related to cardiovascular morbidity than HDL concentration. However, it is unclear whether HDL function and composition predict ischemic stroke severity and outcome. We aimed to evaluate these associations. MethodsWe prospectively studied 199 consecutive patients who were admitted with acute ischemic stroke. The severity of stroke was evaluated at admission with the National Institutes of Health Stroke Scale (NIHSS). Severe stroke was defined as NIHSS ≥ 5. The outcome was assessed with dependency at discharge (modified Rankin scale 2–5) and in-hospital mortality. Cholesterol efflux capacity (CEC), phospholipid levels, lecithin:cholesterol acyl transferase (LCAT)-phospholipase activity, paraoxonase-1 (PON1)-arylesterase activity and serum amyloid A1 (SAA1) content of HDL were measured. ResultsCEC, phospholipid levels and LCAT-phospholipase activity of HDL were lower and SAA1 content of HDL was higher in patients with severe stroke. Patients who were dependent at discharge had lower CEC, PON1-arylesterase activity, phospholipid content and LCAT-phospholipase activity of HDL and higher HDL-SAA1 content. Independent predictors of dependency at discharge were the NIHSS at admission (RR 2.60, 95% CI 1.39–4.87), lipid-lowering treatment (RR 0.17, 95% CI 0.01–0.75), HDL-CEC (RR 0.21, 95% CI 0.05–0.87) and HDL-associated PON1-arylesterase activity (RR 0.95, 95% CI 0.91–0.99). In patients who died during hospitalization, phospholipids, LCAT-phospholipase and PON1-arylesterase activities of HDL were lower. ConclusionsChanges in CEC and composition of HDL appear to be associated with the severity and outcome of acute ischemic stroke and could represent biomarkers that may inform risk stratification and management strategies in these patients.

Normal HDL Cholesterol Efflux and Anti-Inflammatory Capacities in Type 2 Diabetes Despite Lipidomic Abnormalities.

ObjectiveTo assess whether, in type 2 diabetes (T2D) patients, lipidomic abnormalities in high-density lipoprotein (HDL) are associated with impaired cholesterol efflux capacity and anti-inflammatory effect, 2 pro-atherogenic abnormalities.Design and MethodsThis is a secondary analysis of the Lira-NAFLD study, including 20 T2D patients at T0 and 25 control subjects. Using liquid chromatography/tandem mass spectrometry, we quantified 110 species of the main HDL phospholipids and sphingolipids. Cholesterol efflux capacity was measured on THP-1 macrophages. The anti-inflammatory effect of HDL was measured as their ability to inhibit the tumor necrosis factor α (TNFα)-induced expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular cell adhesion molecule-1 (ICAM-1) on human vascular endothelial cells (HUVECs).ResultsThe cholesterol-to-triglyceride ratio was decreased in HDL from T2D patients compared with controls (-46%, P = 0.00008). As expressed relative to apolipoprotein AI, the amounts of phosphatidylcholines, sphingomyelins, and sphingosine-1-phosphate were similar in HDL from T2D patients and controls. Phosphatidylethanolamine-based plasmalogens and ceramides (Cer) were, respectively, 27% (P = 0.038) and 24% (P = 0.053) lower in HDL from T2D patients than in HDL from controls, whereas phosphatidylethanolamines were 41% higher (P = 0.026). Cholesterol efflux capacity of apoB-depleted plasma was similar in T2D patients and controls (36.2 ± 4.3 vs 35.5 ± 2.8%, P = 0.59). The ability of HDL to inhibit the TNFα-induced expression of both VCAM-1 and ICAM-1 at the surface of HUVECs was similar in T2D patients and controls (-70.6 ± 16.5 vs -63.5 ± 18.7%, P = 0.14; and -62.1 ± 13.2 vs -54.7 ± 17.7%, P = 0.16, respectively).ConclusionDespite lipidomic abnormalities, the cholesterol efflux and anti-inflammatory capacities of HDL are preserved in T2D patients.

Associations of Abdominal and Cardiovascular Adipose Tissue Depots With HDL Metrics in Midlife Women: the SWAN Study.

The menopause transition is accompanied by declines in the atheroprotective features of high-density lipoprotein (HDL), which are linked to deleterious cardiovascular (CV) outcomes. This work aimed to assess the relationship between abdominal and CV visceral adipose tissues (VAT) with future HDL metrics in midlife women, and the role of insulin resistance (IR) on these associations. Temporal associations compared abdominal and CV fat with later measures of HDL metrics. This community-based cohort comprised 299 women, baseline mean age 51.1 years (SD: 2.8 years), 67% White, 33% Black, from the Study of Women's Health Across the Nation (SWAN) HDL ancillary study. Exposures included volumes of abdominal VAT, epicardial AT (EAT), paracardial AT (PAT), or perivascular AT (PVAT). Main outcomes included HDL cholesterol efflux capacity (HDL-CEC); HDL phospholipids (HDL-PL), triglycerides (HDL-Tgs), and cholesterol (HDL-C); apolipoprotein A-I (ApoA-I), and HDL particles (HDL-P) and size. In multivariable models, higher abdominal VAT was associated with lower HDL-CEC, HDL-PL, HDL-C, and large HDL-P and smaller HDL size. Higher PAT was associated with lower HDL-PL, HDL-C, and large HDL-P and smaller HDL size. Higher EAT was associated with higher small HDL-P. Higher PVAT volume was associated with lower HDL-CEC. The Homeostatic Model Assessment of Insulin Resistance partially mediated the associations between abdominal AT depots with HDL-CEC, HDL-C, large HDL-P, and HDL size; between PVAT with HDL-CEC; and PAT with HDL-C, large HDL-P, and HDL size. In midlife women, higher VAT volumes predict HDL metrics 2 years later in life, possibly linking them to future CV disease. Managing IR may preclude the unfavorable effect of visceral fat on HDL metrics.

Towards early risk biomarkers: serum metabolic signature in childhood predicts cardio-metabolic risk in adulthood.

SummaryBackgroundCardiovascular diseases may originate in childhood. Biomarkers identifying individuals with increased risk for disease are needed to support early detection and to optimise prevention strategies.MethodsIn this prospective study, by applying a machine learning to high throughput NMR-based metabolomics data, we identified circulating childhood metabolic predictors of adult cardiovascular disease risk (MetS score) in a cohort of 396 females, followed from childhood (mean age 11·2 years) to early adulthood (mean age 18·1 years). The results obtained from the discovery cohort were validated in a large longitudinal birth cohort of females and males followed from puberty to adulthood (n = 2664) and in four cross-sectional data sets (n = 6341).FindingsThe identified childhood metabolic signature included three circulating biomarkers, glycoprotein acetyls (GlycA), large high-density lipoprotein phospholipids (L-HDL-PL), and the ratio of apolipoprotein B to apolipoprotein A-1 (ApoB/ApoA) that were associated with increased cardio-metabolic risk in early adulthood (AUC = 0·641‒0·802, all p<0·01). These associations were confirmed in all validation cohorts with similar effect estimates both in females (AUC = 0·667‒0·905, all p<0·01) and males (AUC = 0·734‒0·889, all p<0·01) as well as in elderly patients with and without type 2 diabetes (AUC = 0·517‒0·700, all p<0·01). We subsequently applied random intercept cross-lagged panel model analysis, which suggested bidirectional causal relationship between metabolic biomarkers and cardio-metabolic risk score from childhood to early adulthood.InterpretationThese results provide evidence for the utility of a circulating metabolomics panel to identify children and adolescents at risk for future cardiovascular disease, to whom preventive measures and follow-up could be indicated.

Associations of Endogenous Hormones With HDL Novel Metrics Across the Menopause Transition: The SWAN HDL Study.

Novel metrics of high-density lipoprotein (HDL) (subclasses, lipid content, and function) may improve characterization of the anti-atherogenic features of HDL. In midlife women, changes in these metrics vary by time relative to the final menstrual period (FMP), supporting a contribution of estradiol (E2) and follicle-stimulating hormone (FSH). We tested associations of endogenous E2 and FSH with novel HDL metrics and assessed whether these associations varied by time relative to FMP. This study was a longitudinal analysis from the Study of Women's Health Across the Nation (SWAN) HDL study, using a community-based cohort of 463 women, baseline mean age 50.2 (2.7) years. The main outcome measures were HDL cholesterol efflux capacity (HDL-CEC), HDL phospholipids (HDL-PL), HDL triglycerides (HDL-Tg), HDL particles (HDL-P), HDL size, and HDL cholesterol (HDL-C). In multivariable analyses, E2 was positively associated with HDL size, large HDL-P, HDL-CEC, and HDL-Tg, but negatively with medium HDL-P (P values < 0.05). The positive association between E2 and HDL-Tg was stronger 2 years post-FMP than before, (interaction P = 0.031). FSH was positively related to total and medium HDL-P, but negatively to HDL size, large HDL-P, and HDL-CEC per particle (P values < 0.05). Associations of higher FSH with greater total HDL-P and smaller HDL size were only evident at/after menopause (interaction P values < 0.05). Some of the associations linking E2 and FSH with novel HDL metrics were vulnerable to time relative to menopause onset. Whether a late initiation of hormone therapy relative to menopause could have a detrimental effect on lipid content of HDL particles should be tested in the future.

Plasma high density lipoproteins phospholipds as an indirect indicator of their cholesterol efflux capacity — new suspected atherosclerosis risk factor

High density lipoproteins (HDL) are a unique natural structure, protecting the body from the development of atherosclerotic vascular lesions and cardiovascular diseases due to this ability to remove cholesterol from cells. Plasma HDL level estimated by their cholesterol content, is a common lipid parameter, and its decrease is considered as an established atherosclerosis risk factor. However, a number of studies have shown the absence of positive clinical effects after drug-induced increase in HDL cholesterol. There is increasing evidence that not only HDL concentration, but also HDL properties, considered in this review are important. Many studies showed the decrease of HDL cholesterol efflux capacity in patients with coronary heart diseases and its association with disease severity. Some authors consider a decrease of this HDL capacity as a new additional risk factor of atherosclerosis. The review summarizes existing information on various protein and lipid components of HDL with a primary emphasis on the HDL. Special attention is paid to correlation between the HDL cholesterol efflux capacity and HDL phospholipids and the ratio "phospholipids/free cholesterol". The accumulated information indicates importance of evaluation in the HDL fraction not only in terms of their cholesterol, but also phospholipids. In addition to the traditionally used lipid criteria, this would provide more comprehensive information about the activity of the reverse cholesterol transport process in the body and could contribute to the targeted correction of the detected disorders.

Towards Early Risk Biomarkers: Serum Metabolic Signature in Childhood Predicts Cardio-Metabolic Risk in Adulthood

Background: Cardiovascular diseases may originate in childhood. Biomarkers identifying individuals with increased risk for disease are needed to support early detection and to optimise prevention strategies. Methods: By applying a machine learning approaches to high throughput NMR-based metabolomics data, we identified circulating childhood metabolic predictors of adult cardiovascular risk in a cohort of 396 females, followed from childhood (mean age 11·2 years) to early adulthood (mean age 18·1 years). The results obtained from the discovery cohort were validated in a large longitudinal birth cohort of females and males followed from puberty to adulthood (n = 2664) and in four cross-sectional data sets (n = 6341). Findings: The identified childhood metabolic signature included three circulating biomarkers, glycoprotein acetyls (GlycA), large high-density lipoprotein phospholipids (L-HDL-PL), and the ratio of apolipoprotein B to apolipoprotein A-1 (ApoB/ApoA) that robustly associated with increased cardiovascular risk in early adulthood (AUC = 0·641‒0·802, all p<0·01). These associations were confirmed in all validation cohorts with similar effect estimates both in females (AUC = 0·667‒0·905, all p<0·01) and males (AUC = 0·734‒0·889, all p<0·01) as well as in elderly patients with and without type 2 diabetes (AUC = 0·517‒0·700, all p<0·01). We subsequently applied random intercept cross-lagged panel model analysis, which suggested bidirectional causal relationship between metabolic biomarkers and cardio-metabolic risk score from childhood to early adulthood. Interpretation: These results provide evidence for the utility of a circulating metabolomics panel to identify children and adolescents at risk for future cardiovascular disease, to whom preventive measures and follow-up could be indicated. Funding: This study was financially supported by the Academy of Finland, Ministry of Education of Finland and University of Jyvaskyla, the National Nature Science Foundation of China (Grant 31571219), the 111 Project (B17029), the Shanghai Jiao Tong University Zhiyuan Foundation (Grant CP2014013), China Postdoc Scholarship Council (201806230001). Declaration of Interest: None to declare. Ethical Approval: Written informed consent was obtained from all participants and their parents. The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethic Committee of the Central Hospital of Central Finland and the Finnish National Agency of Medicines (memo 22/8/2008 and 5/2009).

Cholesterol Efflux Capacity and Cardiovascular Disease: The Ludwigshafen Risk and Cardiovascular Health (LURIC) Study.

(1) Background and Aims: Efforts to reduce coronary artery disease (CAD) by raising high-density lipoprotein (HDL) cholesterol (HDL-C) have not been uniformly successful. A more important factor than HDL-C may be cellular cholesterol efflux mediated by HDL, which has been shown to be associated with CAD. In this report, we analyzed the influence of cardiovascular biomarkers and risk factors on cholesterol efflux in a prospective observational study of patients referred to coronary angiography. (2) Methods: HDL-mediated efflux capacity was determined for 2468 participants of the Ludwigshafen Risk and Cardiovascular Health (LURIC) study who were referred to coronary angiography at baseline between 1997 and 2000. Median follow-up time was 9.9 years. Primary and secondary endpoints were cardiovascular and all-cause mortality, respectively. (3) Results: Cholesterol efflux strongly correlated with HDL-related markers including HDL cholesterol, HDL phospholipids, and apolipoproteins AI and AII, as well as HDL particle concentration, which was not seen for low density lipoprotein (LDL) markers including LDL cholesterol and apoB. Cholesterol efflux was associated negatively with C-reactive protein (CRP), fibrinogen, interleukin-6 (IL-6), and serum amyloid A. Cardiovascular mortality was higher in patients in the lowest cholesterol efflux quartile. This association was weakened, but not fully abolished, after adjustment for HDL cholesterol. (4) Conclusions: We demonstrate that cholesterol efflux was associated with HDL-composition as well as inflammatory burden in patients referred for coronary angiography, and that this inversely predicts cardiovascular mortality independently of HDL cholesterol.

Microencapsulated Pomegranate Modifies the Composition and Function of High-Density Lipoproteins (HDL) in New Zealand Rabbits.

Previous studies demonstrated that pomegranate, which is a source of several bioactive molecules, induces modifications of high-density lipoproteins (HDL) lipid composition and functionality. However, it remains unclear whether the beneficial effects of pomegranate are related to improvement in the lipid components of HDL. Therefore, in this placebo-controlled study, we characterized the size and lipid composition of HDL subclasses and assessed the functionality of these lipoproteins after 30 days of supplementation with a pomegranate microencapsulated (MiPo) in New Zealand white rabbits. We observed a significant decrease in plasma cholesterol, triglycerides, and non−HDL sphingomyelin, as well as increases in HDL cholesterol and HDL phospholipids after supplementation with MiPo. Concomitantly, the triglycerides of the five HDL subclasses isolated by electrophoresis significantly decreased, whereas phospholipids, cholesterol, and sphingomyelin of HDL subclasses, as well as the HDL size distribution remained unchanged. Of particular interest, the triglycerides content of HDL, estimated by the triglycerides-to-phospholipids ratio, decreased significantly after MiPo supplementation. The modification on the lipid content after the supplementation was associated with an increased resistance of HDL to oxidation as determined by the conjugated dienes formation catalyzed by Cu2+. Accordingly, paraoxonase-1 (PON1) activity determined with phenylacetate as substrate increased after MiPo. The effect of HDL on endothelial function was analyzed by the response to increasing doses of acetylcholine of aorta rings co-incubated with the lipoproteins in an isolated organ bath. The HDL from rabbits that received placebo partially inhibited the endothelium-dependent vasodilation. In contrast, the negative effect of HDL on endothelial function was reverted by MiPo supplementation. These results show that the beneficial effects of pomegranate are mediated at least in part by improving the functionality of HDL, probably via the reduction of the content of triglycerides in these lipoproteins.

Plasma Metabolomics Identifies Markers of Impaired Renal Function: A Meta-analysis of 3089 Persons with Type 2 Diabetes.

There is a need for novel biomarkers and better understanding of the pathophysiology of diabetic kidney disease. To investigate associations between plasma metabolites and kidney function in people with type 2 diabetes (T2D). 3089 samples from individuals with T2D, collected between 1999 and 2015, from 5 independent Dutch cohort studies were included. Up to 7 years follow-up was available in 1100 individuals from 2 of the cohorts. Plasma metabolites (n = 149) were measured by nuclear magnetic resonance spectroscopy. Associations between metabolites and estimated glomerular filtration rate (eGFR), urinary albumin-to-creatinine ratio (UACR), and eGFR slopes were investigated in each study followed by random effect meta-analysis. Adjustments included traditional cardiovascular risk factors and correction for multiple testing. In total, 125 metabolites were significantly associated (PFDR = 1.5×10-32 - 0.046; β = -11.98-2.17) with eGFR. Inverse associations with eGFR were demonstrated for branched-chain and aromatic amino acids (AAAs), glycoprotein acetyls, triglycerides (TGs), lipids in very low-density lipoproteins (VLDL) subclasses, and fatty acids (PFDR < 0.03). We observed positive associations with cholesterol and phospholipids in high-density lipoproteins (HDL) and apolipoprotein A1 (PFDR < 0.05). Albeit some metabolites were associated with UACR levels (P < 0.05), significance was lost after correction for multiple testing. Tyrosine and HDL-related metabolites were positively associated with eGFR slopes before adjustment for multiple testing (PTyr = 0.003; PHDLrelated < 0.05), but not after. This study identified metabolites associated with impaired kidney function in T2D, implying involvement of lipid and amino acid metabolism in the pathogenesis. Whether these processes precede or are consequences of renal impairment needs further investigation.

Postprandial remodeling of high-density lipoprotein following high saturated fat and high carbohydrate meals

Humans spend most of the time in the postprandial state, yet most knowledge about high-density lipoproteins (HDL) derives from the fasted state. HDL protein and lipid cargo mediate HDL's antiatherogenic effects, but whether these HDL constituents change in the postprandial state and are affected by dietary macronutrients remains unknown. This study aimed to assess changes in HDL protein and lipid composition after the consumption of a high-carbohydrate or high saturated fat (HSF) meal. We isolated HDL from plasma collected during a randomized, cross-over study of metabolically healthy subjects. Subjects consumed isocaloric meals consisting predominantly of either carbohydrate or fat. At baseline and at 3 and 6hours postprandial, we quantified HDL protein and lipid composition by liquid chromatography-mass spectrometry. A total of 15 subjects were included (60% female, aged 34±15years, body mass index: 24.1±2.7kg/m2). Consumption of the HSF meal led to HDL enrichment in total lipid (P=.006), triglyceride (P=.02), and phospholipid (P=.008) content and a corresponding depletion in protein content. After the HSF meal, 16 of the 25 measured phosphatidylcholine species significantly increased in abundance (P values range from .027 to <.001), along with several sphingolipids including ceramides (P<.004), lactosylceramide (P=.023), and sphingomyelin-14 (P=.013). Enrichment in apolipoprotein A-I (P=.001) was the only significant change in HDL protein composition after the HSF meal. The high-carbohydrate meal conferred only minimal changes in HDL composition. Meal macronutrient content acutely affects HDL composition in the postprandial state, with the HSF meal resulting in enrichment of HDL phospholipid content with possible consequences for HDL function.

Association between Small Dense Low-Density Lipoproteins and High-Density Phospolipid Content in Patients with Coronary Artery Disease with or without Diabetes.

To evaluate the phospholipid profile in total plasma, non-high-density lipoprotein (HDL), and HDL fractions. We tried to correlate the phospholipid profile to low-density lipoprotein (LDL) size, as reflected by cholesterol content in each LDL subclass. We measured small dense LDL-C levels after heparin-magnesium precipitation and measured high-density lipoprotein phospholipid (HDL-P) levels using a colorimetric enzymatic method. The correlation of the phospholipid profile to small dense LDL-C (sdLDL-C) in patients with coronary problems showed a negative association between small dense low-density lipoprotein (sdLDL) and HDL-P (r = -0.73; P = .02). Moreover, a strong positive correlation was detected between TG and the ratio HDL-P/HDL-C (r = 0.83; P <.001). HDL phospholipid has an antiatherogenic effect in coronary artery disease with or without diabetes. Further, large LDL modulation seems to be associated with diabetes rather than coronaropathy.

Development, synthesis, and 68Ga-Labeling of a Lipophilic complexing agent for atherosclerosis PET imaging

Cardiovascular disease is the leading cause of mortality and morbidity worldwide. Atherosclerosis accounts for 50% of deaths in western countries. This multifactorial pathology is characterized by the accumulation of lipids and inflammatory cells within the vascular wall, leading to plaque formation. We describe herein the synthesis of a PCTA-based 68Ga3+ chelator coupled to a phospholipid biovector 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), which is the main constituent of the phospholipid moiety of High-Density Lipoprotein (HDL) phospholipid moiety. The resulting 68Ga-PCTA-DSPE inserted into HDL particles was compared to 18F-FDG as a PET agent to visualize atherosclerotic plaques. Our agent markedly accumulated within mouse atheromatous aortas and more interestingly in human endarterectomy carotid samples. These results support the potential use of 68Ga-PCTA-DSPE-HDL for atherosclerosis PET imaging.

Recombinant LCAT (Lecithin:Cholesterol Acyltransferase) Rescues Defective HDL (High-Density Lipoprotein)-Mediated Endothelial Protection in Acute Coronary Syndrome.

Objective- Aim of this study was to evaluate changes in LCAT (lecithin:cholesterol acyltransferase) concentration and activity in patients with an acute coronary syndrome, to investigate if these changes are related to the compromised capacity of HDL (high-density lipoprotein) to promote endothelial nitric oxide (NO) production, and to assess if rhLCAT (recombinant human LCAT) can rescue the defective vasoprotective HDL function. Approach and Results- Thirty ST-segment-elevation myocardial infarction (STEMI) patients were enrolled, and plasma was collected at hospital admission, 48 and 72 hours thereafter, at hospital discharge, and at 30-day follow-up. Plasma LCAT concentration and activity were measured and related to the capacity of HDL to promote NO production in cultured endothelial cells. In vitro studies were performed in which STEMI patients' plasma was added with rhLCAT and HDL vasoprotective activity assessed by measuring NO production in endothelial cells. The plasma concentration of the LCAT enzyme significantly decreases during STEMI with a parallel significant reduction in LCAT activity. HDL isolated from STEMI patients progressively lose the capacity to promote NO production by endothelial cells, and the reduction is related to decreased LCAT concentration. In vitro incubation of STEMI patients' plasma with rhLCAT restores HDL ability to promote endothelial NO production, possibly related to significant modification in HDL phospholipid classes. Conclusions- Impairment of cholesterol esterification may be a major factor in the HDL dysfunction observed during acute coronary syndrome. rhLCAT is able to restore HDL-mediated NO production in vitro, suggesting LCAT as potential therapeutic target for restoring HDL functionality in acute coronary syndrome.

Дисфункциональные липопротеины высокой плотности: роль в атерогенезе и потенциальные мишени для фосфолипидной терапии

In recent years the number of articles on damages of high-density lipoproteins (HDL) properties in patients with atherosclerosis has sharply increased. First, it concerns their ability to accept cholesterol (CH) from macrophages - the basis of antiatherogenic action of HDL. This ability was assessed ex vivo - by activity of cell cholesterol (CH) efflux to HDL or into patient's serum. In many works inverse relationship was shown between CH acceptor capacity of HDL and severity of atherosclerotic disease or frequency of its exacerbations during long-term observation, independent from HDL CH concentration. This led to the emergence of the concept of importance of "not only HDL quantity but also of their quality", i. e. functionality. In this review we consider pathways of cellular CH efflux (mainly mediated by cell proteins), methods used for detection of dysfunctional HDL, and results of relevant studies in various categories of patients. These studies directed to identification of mechanisms of damages of HDL properties by means of analysis of their composition, used various approaches including those of proteomics and lipidomics. However, now there are no proven targets for correction of HDL dysfunctionality. The only factor, that is underlined by many authors, is the significance of HDL phospholipids, which level correlates with activity of cellular CH efflux. This allows to take a fresh look at previously used phospholipid therapy of atherosclerosis. Its mechanism is apparently not lowering of plasma CH, as was previously expected, but the improvement of HDL antiatherogenic properties. For its practical usage it is necessary to elaborate principally novel formulations with high bioavailability of phospholipids - for HDL enrichment by phospholipid and thereby normalization of their ability to remove CH from tissues.