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      HDL functions and their interaction in patients with ST elevation myocardial infarction: a case control study

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          Abstract

          Background

          Recent studies emphasize the importance of HDL function over HDL cholesterol measurement, as an important risk for cardiovascular diseases (CVD). We compared the HDL function of patients with acute coronary syndrome (ACS) and healthy controls.

          Methods

          We measured cholesterol efflux capacity of HDL using THP-1 macrophages labelled with fluorescently tagged (BODIPY) cholesterol. PON1 activities toward paraoxon and phenyl acetate were assessed by spectrophotometric methods.

          Results

          We recruited 150 ACS patients and 110 controls. The HDL function of all patients during acute phase and at six month follow-up was measured. The mean age of the patients and controls was 51.7 and 43.6 years respectively. The mean HDL cholesterol/apolipoprotein A-I levels (ratio) of patients during acute phase, follow-up and of controls were 40.2 mg/dl/ 112.5 mg/dl (ratio = 0.36), 38.3 mg/dl/ 127.2 mg/dl (ratio = 0.30) and 45.4 mg/dl/ 142.1 mg/dl (ratio = 0.32) respectively. The cholesterol efflux capacity (CEC) of HDL was positively correlated with apolipoprotein A-I levels during acute phase (r = 0.19, p = 0.019), follow-up (r = 0.26, p = 0.007) and of controls (r = 0.3, p = 0.0012) but not with HDL-C levels (acute phase: r = 0.07, p = 0.47; follow-up: r = 0.1, p = 0.2; control: r = 0.02, p = 0.82). Higher levels of cholesterol efflux capacity, PON1 activity and apolipoprotein A-I were associated with lower odds of development of ACS. We also observed that low CEC is associated with higher odds of having ACS if PON1 activity of HDL is also low and vice versa.

          Conclusion

          ACS is associated with reduced HDL functions which improves at follow-up. The predicted probability of ACS depends upon individual HDL functions and the interactions between them.

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          Most cited references20

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          The ability to promote efflux via ABCA1 determines the capacity of serum specimens with similar high-density lipoprotein cholesterol to remove cholesterol from macrophages.

          We measured efflux from macrophages to apolipoprotein B-depleted serum from 263 specimens and found instances in which serum having similar high-density lipoprotein cholesterol (HDL-C) differed in their efflux capacity. Thus, we wanted to elucidate why efflux capacity could be independent of total HDL-C or apolipoprotein A-I (apoA-I). To understand why sera with similar HDL-C or apoA-I could differ in total efflux capacity, we assessed their ability to promote efflux via the pathways expressed in cAMP-treated J774 macrophages. Briefly, macrophages were preincubated with probucol to block ABCA1, with BLT-1 to block SR-BI, and with both inhibitors to measure residual efflux. ABCG1 efflux was measured with transfected BHK-1 cells. We used apolipoprotein B-depleted serum from specimens with similar HDL-C values at the 25(th) and 75(th) percentiles. Specimens in each group were classified as having high or low efflux based on total efflux being above or below the group average. We found that independently of HDL-C, sera with higher efflux capacity had a significant increase in ABCA1-mediated efflux, which was significantly correlated to the concentration of pre beta-1 HDL. The same result was obtained when these sera were similarly analyzed based on similar apoA-I. Sera with similar HDL-C or apoA-I differ in their ability to promote macrophage efflux because of differences in the concentration of pre beta-1 HDL.
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            A sensitive assay for ABCA1-mediated cholesterol efflux using BODIPY-cholesterol.

            Studies have shown a negative association between cellular cholesterol efflux and coronary artery disease (CAD). Standard protocol for quantitating cholesterol efflux involves labeling cells with [(3)H]cholesterol and measuring release of the labeled sterol. Using [(3)H]cholesterol is not ideal for the development of a high-throughput assay to screen large numbers of serum as would be required in studying the link between efflux and CAD. We compared efflux using a fluorescent sterol (boron dipyrromethene difluoride linked to sterol carbon-24, BODIPY-cholesterol) with that of [(3)H]cholesterol in J774 macrophages. Fractional efflux of BODIPY-cholesterol was significantly higher than that of [(3)H]cholesterol when apo A-I, HDL(3), or 2% apoB-depleted human serum were used as acceptors. BODIPY-cholesterol efflux correlated significantly with [(3)H]cholesterol efflux (p < 0.0001) when apoB-depleted sera were used. The BODIPY-cholesterol efflux correlated significantly with preβ-1 (r(2) = 0.6) but not with total HDL-cholesterol. Reproducibility of the BODIPY-cholesterol efflux assay was excellent between weeks (r(2) = 0.98, inter-assay CV = 3.31%). These studies demonstrate that BODIPY-cholesterol provides an efficient measurement of efflux compared with [(3)H]cholesterol and is a sensitive probe for ABCA1-mediated efflux. The increased sensitivity of BODIPY-cholesterol assay coupled with the simplicity of measuring fluorescence results in a sensitive, high-throughput assay that can screen large numbers of sera, and thus establish the relationship between cholesterol efflux and atherosclerosis.
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              Antioxidative activity of high-density lipoprotein (HDL): Mechanistic insights into potential clinical benefit

              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.
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                Author and article information

                Contributors
                arch_singh@ymail.com
                Journal
                Lipids Health Dis
                Lipids Health Dis
                Lipids in Health and Disease
                BioMed Central (London )
                1476-511X
                15 April 2020
                15 April 2020
                2020
                : 19
                : 75
                Affiliations
                [1 ]GRID grid.413618.9, ISNI 0000 0004 1767 6103, Department of Biochemistry, , All India Institute of Medical Sciences, ; Room No. 3044, New Delhi, 110029 India
                [2 ]GRID grid.413618.9, ISNI 0000 0004 1767 6103, Department of Cardiology, , All India Institute of Medical Sciences, ; New Delhi, India
                [3 ]GRID grid.413618.9, ISNI 0000 0004 1767 6103, Department of Cardiac Biochemistry, , All India Institute of Medical Sciences, ; New Delhi, India
                [4 ]GRID grid.413618.9, ISNI 0000 0004 1767 6103, Department of Biostatistics, , All India Institute of Medical Sciences, ; New Delhi, India
                Author information
                https://orcid.org/0000-0002-2825-5190
                https://orcid.org/0000-0002-4268-0951
                https://orcid.org/0000-0001-6418-4388
                https://orcid.org/0000-0002-8582-3705
                https://orcid.org/0000-0001-6487-6632
                Article
                1260
                10.1186/s12944-020-01260-4
                7158160
                32293456
                bdabd9ff-e9a3-49c2-8706-32d8338e7e5f
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                : 10 January 2020
                : 8 April 2020
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100007338, All-India Institute of Medical Sciences;
                Award ID: IRG-321
                Award Recipient :
                Categories
                Research
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                © The Author(s) 2020

                Biochemistry
                cholesterol efflux capacity,paraoxonase-1,apolipoprotein a-i,high density lipoprotein,atherosclerosis

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