Publications by authors named "Alan T Remaley"

335 Publications

Serum levels of small HDL particles are negatively correlated with death or lung transplantation in an observational study of idiopathic pulmonary fibrosis.

Eur Respir J 2021 Jul 21. Epub 2021 Jul 21.

Laboratory of Asthma and Lung Inflammation, Pulmonary Branch, NHLBI, NIH, Bethesda, MD, USA.

Background: Serum lipoproteins, such as high density lipoproteins (HDL), may influence disease severity in idiopathic pulmonary fibrosis (IPF). Here, we investigated associations between serum lipids and lipoproteins and clinical endpoints in IPF.

Methods: Clinical data and serum lipids were analyzed from a discovery cohort (59 IPF subjects, 56 healthy volunteers) and validated using an independent, multicenter cohort (207 IPF subjects) from the Pulmonary Fibrosis Foundation registry. Associations between lipids and clinical endpoints (FVC, forced vital capacity; 6MWD, 6 min walk distance; GAP (Gender Age Physiology) index; death or lung transplantation) were examined using Pearson's correlation and multivariable analyses.

Results: Serum concentrations of small HDL particles (S-HDLP), measured by nuclear magnetic resonance (NMR) spectroscopy, correlated negatively with the GAP index in the discovery cohort of IPF subjects. The negative correlation of S-HDLP with GAP index was confirmed in the validation cohort of IPF subjects. Higher levels of S-HDLP were associated with lower odds of death or its competing outcome, lung transplantation (OR of 0.9 for each 1 μmol·L increase in S-HDLP, p<0.05), at 1, 2, and 3 years from study entry in a combined cohort of all IPF subjects.

Conclusions: Higher serum levels of S-HDLP are negatively correlated with the GAP index, as well as with lower observed mortality or lung transplantation in IPF subjects. These findings support the hypothesis that S-HDLP may modify mortality risk in patients with IPF.
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http://dx.doi.org/10.1183/13993003.04053-2020DOI Listing
July 2021

Effect of metformin on the high-density lipoprotein proteome in youth with type 1 diabetes.

Endocrinol Diabetes Metab 2021 Jul 9;4(3):e00261. Epub 2021 May 9.

Saha Cardiovascular Research Center University of Kentucky Lexington KY USA.

Background: Youth with type 1 diabetes (T1D) have normal or elevated High-Density Lipoprotein Cholesterol (HDL-C), however, the function of HDL, partly mediated by the HDL proteome, may be impaired. Metformin can be used as an adjunct therapy in youth with T1D, but its effects on the HDL proteome are unknown.

Objective: To determine the effect of metformin on the HDL proteome.

Subjects: Youth (12-20 years old) with T1D who had a BMI > 90th percentile, HbA1c > 8.0% and Tanner stage 5.

Methods: Double-blinded, placebo-controlled randomized sub-study. We examined the effects of metformin ( = 25) or placebo ( = 10) after 6 months on HDL proteome. Changes in HDL proteins were measured by data-independent acquisition (DIA) mass spectrometry and compared between treatment groups. As a secondary outcome, associations between proteins of interest and the most studied function of HDL, the cholesterol efflux capacity (CEC), was examined.

Results: The relative abundance of 84 HDL-associated proteins were measured. Two proteins were significantly affected by metformin treatment, peptidoglycan recognition protein 2 (PGRP2; +23.4%,  = .0058) and alpha-2-macroglobulin (A2MG; +29.8%,  = .049). Metformin did not significantly affect CEC. Changes in affected HDL proteins did not correlate with CEC.

Conclusions: Despite having little effect on HDL-C, metformin increased PGRP2 and A2MG protein on HDL in youth with T1D, but had no significant effect on CEC. Further studies are needed to understand the impact of PGRP2 and A2MG on other HDL functions.
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http://dx.doi.org/10.1002/edm2.261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279605PMC
July 2021

Validation by HPLC analyses of new equations for estimating cholesterol in plasma lipoprotein subfractions.

Biochim Biophys Acta Mol Cell Biol Lipids 2021 Sep 5;1866(9):158986. Epub 2021 Jun 5.

Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8519, Japan.

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http://dx.doi.org/10.1016/j.bbalip.2021.158986DOI Listing
September 2021

Phase 1 double-blind randomized safety trial of the Janus kinase inhibitor tofacitinib in systemic lupus erythematosus.

Nat Commun 2021 06 7;12(1):3391. Epub 2021 Jun 7.

Translational Immunology Section, NIAMS, NIH, Bethesda, MD, USA.

Increased risk of premature cardiovascular disease (CVD) is well recognized in systemic lupus erythematosus (SLE). Aberrant type I-Interferon (IFN)-neutrophil interactions contribute to this enhanced CVD risk. In lupus animal models, the Janus kinase (JAK) inhibitor tofacitinib improves clinical features, immune dysregulation and vascular dysfunction. We conducted a randomized, double-blind, placebo-controlled clinical trial of tofacitinib in SLE subjects (ClinicalTrials.gov NCT02535689). In this study, 30 subjects are randomized to tofacitinib (5 mg twice daily) or placebo in 2:1 block. The primary outcome of this study is safety and tolerability of tofacitinib. The secondary outcomes include clinical response and mechanistic studies. The tofacitinib is found to be safe in SLE meeting study's primary endpoint. We also show that tofacitinib improves cardiometabolic and immunologic parameters associated with the premature atherosclerosis in SLE. Tofacitinib improves high-density lipoprotein cholesterol levels (p = 0.0006, CI 95%: 4.12, 13.32) and particle number (p = 0.0008, CI 95%: 1.58, 5.33); lecithin: cholesterol acyltransferase concentration (p = 0.024, CI 95%: 1.1, -26.5), cholesterol efflux capacity (p = 0.08, CI 95%: -0.01, 0.24), improvements in arterial stiffness and endothelium-dependent vasorelaxation and decrease in type I IFN gene signature, low-density granulocytes and circulating NETs. Some of these improvements are more robust in subjects with STAT4 risk allele.
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http://dx.doi.org/10.1038/s41467-021-23361-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185103PMC
June 2021

Performance of novel low-density lipoprotein-cholesterol calculation methods in predicting clinical and subclinical atherosclerotic cardiovascular disease risk: The Multi-Ethnic Study of Atherosclerosis.

Atherosclerosis 2021 06 8;327:1-4. Epub 2021 May 8.

Department of Pathology and Laboratory Medicine, University of Minnesota, Twin Cities, USA. Electronic address:

Background And Aims: This study examined the performance of two novel low-density lipoprotein-cholesterol (LDL-C) calculations, LDL and LDL, on predicting atherosclerotic cardiovascular diseases (ASCVD) risk compared to traditional LDL according to the 2018 American Heart Association/American College of Cardiology (AHA/ACC) primary prevention guidelines.

Methods: A total of 6701 randomly recruited Multi-Ethnic Study of Atherosclerosis (MESA) participants free of ASCVD at baseline were followed for ASCVD during a median of 13.9 years and for subclinical ASCVD-coronary artery calcium (CAC) during a median of 12.5 years. Prevalence of borderline high triglyceride (≥1.7 mmol/L) was 15.2% and was at 13.5% for high triglyceride (≥2.3 mmol/L).

Results: Applying the criteria of LDL-C<1.8 mmol/L in 40-75 year olds without diabetes mellitus to be exempt from risk discussion, LDL and LDL classified less individuals in this category than LDL (p < 0.001), both had 20 individuals with ASCVD, versus 22 by LDL. Positive CAC in the discussion-exempt group were over 38% higher (p < 0.001) when classified by LDL than by LDL or LDL. Individuals with LDL-C≥4.9 mmol/L are recommended to high-intensity statin therapy by the AHA/ACC guidelines. The LDL≥4.9 mmol/L group had 20 ASCVD events, versus 21 in LDL and 22 in LDL group.

Conclusions: In a multi-ethnic USA population, LDL and LDL did not over- or under-estimate ASCVD risk compared to LDL in primary prevention according to AHA/ACC guidelines, while LDL under-estimated subclinical ASCVD risk in the low-risk population. These findings support the replacement of LDL by LDL or LDL for lipid screen in the general population.
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http://dx.doi.org/10.1016/j.atherosclerosis.2021.04.018DOI Listing
June 2021

A New Equation Based on the Standard Lipid Panel for Calculating Small Dense Low-Density Lipoprotein-Cholesterol and Its Use as a Risk-Enhancer Test.

Clin Chem 2021 Jul;67(7):987-997

Lipoprotein Metabolism Laboratory, Translational Vascular Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.

Background: Increased small dense low-density lipoprotein-cholesterol (sdLDL-C) is a risk factor for atherosclerotic cardiovascular disease (ASCVD) but typically requires advanced lipid testing. We describe two new equations, first one for calculating large buoyant LDL-C (lbLDL-C), based only upon results from the standard lipid panel, and the second one for sdLDL-C.

Methods: Equations for sdLDL-C and lbLDL-C were generated with least-squares regression analysis using the direct Denka sdLDL-C assay as reference (n = 20 171). sdLDL-C was assessed as a risk-enhancer test in the National Heart and Nutrition Examination Survey (NHANES), and for its association with ASCVD in the Multi-Ethnic Study of Atherosclerosis (MESA).

Results: The newly derived equations depend on two terms, namely LDL-C as determined by the Sampson equation, and an interaction term between LDL-C and the natural log of triglycerides (TG). The lbLDL-C equation (lbLDLC=1.43 × LDLC-0.14 ×(ln⁡(TG)× LDLC)- 8.99) was more accurate (R2 = 0.933, slope = 0.94) than the sdLDL-C equation (sdLDLC=LDLC- lbLDLC; R2 = 0.745, slope = 0.73). Using the 80th percentile (46 mg/dL) as a cut-point, sdLDL-C identified in NHANES additional high-risk patients not identified by other risk-enhancer tests based on TG, LDL-C, apolipoprotein B, and nonHDL-C. By univariate survival-curve analysis, estimated sdLDL-C was superior to other risk-enhancer tests in predicting ASCVD events in MESA. After multivariate adjustment for other known ASCVD risk factors, estimated sdLDL-C had the strongest association with ASCVD compared to other lipid parameters, including measured sdLDL-C.

Conclusions: Estimated sdLDL-C could potentially be calculated on all patients tested with a standard lipid panel to improve ASCVD risk stratification.
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http://dx.doi.org/10.1093/clinchem/hvab048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260186PMC
July 2021

Apolipoprotein Mimetic Peptides: Potential New Therapies for Cardiovascular Diseases.

Cells 2021 Mar 8;10(3). Epub 2021 Mar 8.

Lipoprotein Metabolism Laboratory, Translational Vascular Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.

Since the seminal breakthrough of treating diabetic patients with insulin in the 1920s, there has been great interest in developing other proteins and their peptide mimetics as therapies for a wide variety of other medical disorders. Currently, there are at least 60 different peptides that have been approved for human use and over 150 peptides that are in various stages of clinical development. Peptides mimetic of the major proteins on lipoproteins, namely apolipoproteins, have also been developed first as tools for understanding apolipoprotein structure and more recently as potential therapeutics. In this review, we discuss the biochemistry, peptide mimetics design and clinical trials for peptides based on apoA-I, apoE and apoC-II. We primarily focus on applications of peptide mimetics related to cardiovascular diseases. We conclude with a discussion on the limitations of peptides as therapeutic agents and the challenges that need to be overcome before apolipoprotein mimetic peptides can be developed into new drugs.
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http://dx.doi.org/10.3390/cells10030597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8000854PMC
March 2021

Virgin Olive Oil Phenolic Compounds Modulate the HDL Lipidome in Hypercholesterolaemic Subjects: A Lipidomic Analysis of the VOHF Study.

Mol Nutr Food Res 2021 05 18;65(9):e2001192. Epub 2021 Mar 18.

Facultat de Medicina i Ciències de la Salut, Departament de Medicina i Cirurgia, Universitat Rovira i Virgili, Grup Nutrició Funcional, Oxidació i Malalties Cardiovasculars (NFOC-Salut), Reus, 43201, Spain.

Scope: The lipidomic analysis of high-density lipoprotein (HDL) could be useful to identify new biomarkers of HDL function.

Methods And Results: A randomized, controlled, double-blind, crossover trial (33 hypercholesterolaemic subjects) is performed with a control virgin olive oil (VOO), VOO enriched with its own phenolic compounds (FVOO), or VOO enriched with additional phenolic compounds from thyme (FVOOT) for 3 weeks. HDL lipidomic analyses are performed using the Lipidyzer platform. VOO and FVOO intake increase monounsaturated-fatty acids (FAs) and decrease saturated and polyunsaturated FAs in triacylglyceride (TAG) species, among others species. In contrast, FVOOT intake does not induce these FAs changes. The decrease in TAG52:3(FA16:0) after VOO intake and the decrease in TAG52:5(FA18:2) after FVOO intake are inversely associated with changes in HDL resistance to oxidation. After FVOO intake, the decrease in TAG54:6(FA18:2) in HDL is inversely associated with changes in HDL cholesterol efflux capacity.

Conclusion: VOO and FVOO consumption has an impact on the HDL lipidome, in particular TAG species. Although TAGs are minor components of HDL mass, the observed changes in TAG modulated HDL functionality towards a cardioprotective mode. The assessment of the HDL lipidome is a valuable approach to identify and characterize new biomarkers of HDL function.
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http://dx.doi.org/10.1002/mnfr.202001192DOI Listing
May 2021

X-ray microtomosynthesis of unstained pathology tissue samples.

J Microsc 2021 Jul 18;283(1):9-20. Epub 2021 Feb 18.

National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland.

In pathology protocols, a tissue block, such as one containing a mouse brain or a biopsy sample from a patient, can produce several hundred thin sections. Substantial time may be required to analyse all sections. In cases of uncertainty regarding which sections to focus on, noninvasive scout imaging of intact blocks can help in guiding the pathology procedure. The scouting step is ideally done in a time window of minutes without special sample preparation that may interfere with the pathology procedures. The challenge is to obtain some visibility of unstained tissue structures at sub-10 µm resolution. We explored a novel x-ray tomosynthesis method as a way to maximise contrast-to-noise ratio, a determinant of tissue visibility. It provided a z-stack of thousands of images at 7.3 μm resolution (10% contrast, half-period of 68.5 line pairs/mm), in scans of 5-15 minutes. When compared with micro-CT scans, the straight-line tomosynthesis scan did not need to rotate the sample, which allowed flat samples, such as paraffin blocks, to be kept as close as possible to the x-ray source. Thus, given the same hardware, scan time and resolution, this mode maximised the photon flux density through the sample, which helped in maximising the contrast-to-noise ratio. The tradeoff of tomosynthesis is incomplete 3D information. The microtomosynthesis scanner has scanned 110 unstained human and animal tissue samples as part of their respective pathology protocols. In all cases, the z-stack of images showed tissue structures that guided sectioning or provided correlative structural information. We describe six examples that presented different levels of visibility of soft tissue structures. Additionally, in a set of coronary artery samples from an HIV patient donor, microtomosynthesis made a new discovery of isolated focal calcification in the internal elastic lamina of coronary wall, which was the onset of medial calcific sclerosis in the arteries.
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http://dx.doi.org/10.1111/jmi.13003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248055PMC
July 2021

Perioperative high density lipoproteins, oxidative stress, and kidney injury after cardiac surgery.

J Lipid Res 2021 Jan 14;62:100024. Epub 2021 Jan 14.

Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.

Oxidative stress promotes acute kidney injury (AKI). Higher HDL cholesterol concentrations are associated with less AKI. To test the hypothesis that HDL antioxidant activity is associated with AKI after cardiac surgery, we quantified HDL particle (HDL-P) size and number, paraoxonase-1 (PON-1) activity, and isofuran concentrations in 75 patients who developed AKI and 75 matched control patients. Higher preoperative HDL-P was associated with less AKI (OR: 0.80; 95% CI, 0.71-0.91; P = 0.001), higher PON-1 activity ( P < 0.001), and lower plasma concentrations of isofurans immediately after surgery (P = 0.02). Similarly, higher preoperative small HDL-P was associated with less AKI, higher PON-1 activity, and lower isofuran concentrations. Higher intraoperative particle losses were associated with less AKI (OR: 0.79; 95% CI 0.67-0.93; P = 0.005), and with decreased postoperative isofuran concentrations (P = 0.04) . Additionally, higher preoperative small HDL-P and increased intraoperative small particle loss were associated with improved long-term renal function (P = 0.003, 0.01, respectively). In conclusion, a higher preoperative concentration of HDL-P, particularly small particles, is associated with lower oxidative damage and less AKI. Perioperative changes in HDL-P concentrations are also associated with AKI. Small HDL-P may represent a novel modifiable risk factor for AKI.
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http://dx.doi.org/10.1016/j.jlr.2021.100024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905072PMC
January 2021

Apolipoprotein CIII and Angiopoietin-like Protein 8 are Elevated in Lipodystrophy and Decrease after Metreleptin.

J Endocr Soc 2021 Feb 4;5(2):bvaa191. Epub 2020 Dec 4.

National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.

Context: Lipodystrophy syndromes cause hypertriglyceridemia that improves with leptin treatment using metreleptin. Mechanisms causing hypertriglyceridemia and improvements after metreleptin are incompletely understood.

Objective: Determine relationship of circulating lipoprotein lipase (LPL) modulators with hypertriglyceridemia in healthy controls and in patients with lipodystrophy before and after metreleptin.

Methods: Cross-sectional comparison of patients with lipodystrophy (generalized lipodystrophy n = 3; partial lipodystrophy n = 11) vs age/sex-matched healthy controls (n = 28), and longitudinal analyses in patients before and after 2 weeks and 6 months of metreleptin. The study was carried out at the National Institutes of Health, Bethesda, Maryland. Outcomes were LPL stimulators apolipoprotein (apo) C-II and apoA-V and inhibitors apoC-III and angiopoietin-like proteins (ANGPTLs) 3, 4, and 8; ex vivo activation of LPL by plasma.

Results: Patients with lipodystrophy were hypertriglyceridemic and had higher levels of all LPL stimulators and inhibitors vs controls except for ANGPTL4, with >300-fold higher ANGPTL8, 4-fold higher apoC-III, 3.5-fold higher apoC-II, 1.9-fold higher apoA-V, 1.6-fold higher ANGPTL3 ( < .05 for all). At baseline, all LPL modulators except ANGPLT4 positively correlated with triglycerides. Metreleptin decreased apoC-II and apoC-III after 2 weeks and 6 months, and decreased ANGPTL8 after 6 months (P < 0.05 for all). Plasma from patients with lipodystrophy caused higher ex vivo LPL activation vs hypertriglyceridemic control plasma ( < .0001), which did not change after metreleptin.

Conclusion: Elevations in LPL inhibitors apoC-III and ANGPTL8 may contribute to hypertriglyceridemia in lipodystrophy, and may mediate reductions in circulating and hepatic triglycerides after metreleptin. These therefore are strong candidates for therapies to lower triglycerides in these patients.
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http://dx.doi.org/10.1210/jendso/bvaa191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787426PMC
February 2021

The extended lipid panel assay: a clinically-deployed high-throughput nuclear magnetic resonance method for the simultaneous measurement of lipids and Apolipoprotein B.

Lipids Health Dis 2020 Dec 1;19(1):247. Epub 2020 Dec 1.

Laboratory Corporation of America Holdings (LabCorp), Morrisville, NC, 27560, USA.

Background: Standard lipid panel assays employing chemical/enzymatic methods measure total cholesterol (TC), triglycerides (TG), and high-density lipoprotein cholesterol (HDL-C), from which are calculated estimates of low-density lipoprotein cholesterol (LDL-C). These lipid measures are used universally to guide management of atherosclerotic cardiovascular disease risk. Apolipoprotein B (apoB) is generally acknowledged to be superior to LDL-C for lipid-lowering therapeutic decision-making, but apoB immunoassays are performed relatively infrequently due to the added analytic cost. The aim of this study was to develop and validate the performance of a rapid, high-throughput, reagent-less assay producing an "Extended Lipid Panel" (ELP) that includes apoB, using the Vantera® nuclear magnetic resonance (NMR) analyzer platform already deployed clinically for lipoprotein particle and other testing.

Methods: Partial least squares regression models, using as input a defined region of proton NMR spectra of plasma or serum, were created to simultaneously quantify TC, TG, HDL-C, and apoB. Large training sets (n > ~ 1000) of patient sera analyzed independently for lipids and apoB by chemical methods were employed to ensure prediction models reflect the wide lipid compositional diversity of the population. The analytical performance of the NMR ELP assay was comprehensively evaluated.

Results: Excellent agreement was demonstrated between chemically-measured and ELP assay values of TC, TG, HDL-C and apoB with correlation coefficients ranging from 0.980 to 0.997. Within-run precision studies measured using low, medium, and high level serum pools gave coefficients of variation for the 4 analytes ranging from 1.0 to 3.8% for the low, 1.0 to 1.7% for the medium, and 0.9 to 1.3% for the high pools. Corresponding values for within-lab precision over 20 days were 1.4 to 3.6%, 1.2 to 2.3%, and 1.0 to 1.9%, respectively. Independent testing at three sites over 5 days produced highly consistent assay results. No major interference was observed from 38 endogenous or exogenous substances tested.

Conclusions: Extensive assay performance evaluations validate that the NMR ELP assay is efficient, robust, and substantially equivalent to standard chemistry assays for the clinical measurement of lipids and apoB. Routine reporting of apoB alongside standard lipid measures could facilitate more widespread utilization of apoB for clinical decision-making.
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http://dx.doi.org/10.1186/s12944-020-01424-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7709389PMC
December 2020

Association Among Noncalcified Coronary Burden, Fractional Flow Reserve, and Myocardial Injury in Psoriasis.

J Am Heart Assoc 2020 11 10;9(22):e017417. Epub 2020 Nov 10.

National Heart, Lung, and Blood Institute National Institutes of Health Bethesda MD.

Background Myocardial infarction and premature death have been observed in patients with psoriasis. Although inflammation-driven accelerated atherosclerosis has been proposed as a mechanism, the relationship between subclinical noncalcified coronary burden (NCB), functional coronary flow impairment, and myocardial injury is unclear. Methods and Results In an ongoing longitudinal cohort study, 202 consecutive patients with psoriasis (168 at 1 year) underwent coronary computed tomography angiography to identify coronary plaque, quantify NCB, and calculate coronary fractional flow reserve by computed tomography. Serum high-sensitivity troponin-T (hs-cTn-T) was measured using a fifth-generation assay. Overall, patients were middle-aged, predominantly male, and low cardiovascular risk. A higher than median NCB associated with a positive hs-cTn-T (fully adjusted model [odds ratio (OR), 1.72; 95% CI, 1.10-2.69, =0.018]) at baseline. Additionally, patients with a higher than median baseline NCB had higher odds of positive hs-cTn-T at 1 year in fully adjusted analyses (adjusted OR, 2.36; 95% CI, 1.47-3.79, <0.001). Higher NCB was associated with a higher frequency of fractional flow reserve by computed tomography ≤0.80 (36.11% versus 25.11%, Pearson χ=6.84, =0.009, unadjusted OR, 2.09; 95% CI, 1.36-3.22, <0.001) and higher frequency of a positive hs-cTn-T (54.36% versus 27.54%, Pearson χ=32.23, <0.001) in adjusted models (OR, 2.63; 95% CI, 1.56-4.42, <0.001). Conclusions NCB was associated with hs-cTn-T at baseline as well as at 1 year. Furthermore, patients with high NCB had higher prevalence of fractional flow reserve by computed tomography ≤0.80 and a >2- fold higher odds of positive hs-cTn-T. These findings underscore the importance of early vascular disease in driving myocardial injury, and support conduct of myocardial perfusion studies to better understand these findings.
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http://dx.doi.org/10.1161/JAHA.119.017417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763703PMC
November 2020

Oxidized Lipids and Lipoprotein Dysfunction in Psoriasis.

J Psoriasis Psoriatic Arthritis 2020 Oct 26;5(4):139-146. Epub 2020 Aug 26.

Section of Inflammation and Cardiometabolic Diseases, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.

Background: Psoriasis is a chronic immune-mediated inflammatory skin disease associated with increased development of metabolic abnormalities including obesity and dyslipidemia, as well as increased cardiovascular disease (CVD) risk. Shared pathophysiological mechanisms linking psoriasis to CVD include altered immune activation, elevated chronic systemic inflammation, and lipoprotein dysfunction characterized by oxidative damage to lipids and apolipoproteins.

Objective: This review aims to provide evidence-based proof for existing relationships between psoriatic inflammation, lipid oxidation, and increased CVD risk.

Methods: We included review articles and original research papers, published between 1980 and 2020, using the following key words: psoriasis, oxidized lipids, oxidation, dyslipidemia, and inflammation.

Results: Systemic inflammation underlying psoriasis leads to increased skin accumulation of pro-inflammatory oxidized lipids, derived from the omega-6 fatty acids, along with counteracting anti-inflammatory lipid mediators, products of the omega-3 polyunsaturated fatty acids. Imbalance in these metabolites culminates in impaired inflammation resolution and results in multisystemic biological alterations. Sustained systemic inflammation results in excessive lipid oxidation, generating proatherogenic oxidized low- and high-density lipoproteins. Together, these pathophysiological mechanisms contribute to increased CVD risk associated with psoriasis disease.

Conclusion: Available anti-inflammatory treatment showed promising clinical results in treating psoriasis, although further research is warranted on managing associated dyslipidemia and establishing novel cardiometabolic markers specific for both skin and vascular pathology.
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http://dx.doi.org/10.1177/2475530320950268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7646705PMC
October 2020

Targeting Lipid Rafts-A Potential Therapy for COVID-19.

Front Immunol 2020 29;11:574508. Epub 2020 Sep 29.

Department of Microbiology, Immunology and Tropical Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC, United States.

COVID-19 is a global pandemic currently in an acute phase of rapid expansion. While public health measures remain the most effective protection strategy at this stage, when the peak passes, it will leave in its wake important health problems. Historically, very few viruses have ever been eradicated. Instead, the virus may persist in communities causing recurrent local outbreaks of the acute infection as well as several chronic diseases that may arise from the presence of a "suppressed" virus or as a consequence of the initial exposure. An ideal solution would be an anti-viral medication that (i) targets multiple stages of the viral lifecycle, (ii) is insensitive to frequent changes of viral phenotype due to mutagenesis, (iii) has broad spectrum, (iv) is safe and (v) also targets co-morbidities of the infection. In this Perspective we discuss a therapeutic approach that owns these attributes, namely "lipid raft therapy." Lipid raft therapy is an approach aimed at reducing the abundance and structural modifications of host lipid rafts or at targeted delivery of therapeutics to the rafts. Lipid rafts are the sites of the initial binding, activation, internalization and cell-to-cell transmission of SARS-CoV-2. They also are key regulators of immune and inflammatory responses, dysregulation of which is characteristic to COVID-19 infection. Lipid raft therapy was successful in targeting many viral infections and inflammatory disorders, and can potentially be highly effective for treatment of COVID-19.
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http://dx.doi.org/10.3389/fimmu.2020.574508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7550455PMC
November 2020

SR-BI mediates neutral lipid sorting from LDL to lipid droplets and facilitates their formation.

PLoS One 2020 15;15(10):e0240659. Epub 2020 Oct 15.

Clinical Center, The National Institutes of Health, Bethesda, Maryland, United States of America.

SR-BI binds various lipoproteins, including HDL, LDL as well as VLDL, and mediates selective cholesteryl ester (CE) uptake. HDL derived CE accumulates in cellular lipid droplets (LDs), which also store triacylglycerol (TAG). We hypothesized that SR-BI could significantly facilitate LD formation, in part, by directly transporting LDL derived neutral lipids (NL) such as CE and TAG into LDs without lipolysis and de novo lipid synthesis. SR-BI overexpression greatly increased LDL uptake and LD formation in stably transfected HeLa cells (SR-BI-HeLa). LDs isolated from SR-BI-HeLa contained 4- and 7-times more CE and TAG, respectively, than mock-transfected HeLa (Mock-HeLa). In contrast, LDL receptor overexpression in HeLa (LDLr-HeLa) greatly increased LDL uptake, degradation with moderate 1.5- and 2-fold increases of CE and TAG, respectively. Utilizing CE and TAG analogs, BODIPY-TAG (BP-TAG) and BODIPY-CE (BP-CE), for tracking LDL NL, we found that after initial binding of LDL to SR-BI-HeLa, apoB remained at the cell surface, while BP-CE and BP-TAG were sorted and simultaneously transported together to LDs. Both lipids demonstrated limited internalization to lysosomes or endoplasmic reticulum in SR-BI-HeLa. In LDLr-HeLa, NLs demonstrated clear lysosomal sequestration without their sorting to LDs. An inhibition of TAG and CE de novo synthesis by 90-95% only reduced TAG and CE LD content by 45-50%, and had little effect on BP-CE and BP-TAG transport to LDs in SR-BI HeLa. Furthermore, intravenous infusion of 1-2 mg of LDL increased liver LDs in normal (WT) but not in SR-BI KO mice. Mice transgenic for human SR-BI demonstrated higher liver LD accumulation than WT mice. Finally, Electro Spray Infusion Mass Spectrometry (ESI-MS) using deuterated d-CE found that LDs accumulated up to 40% of unmodified d-CE LDL. We conclude that SR-BI mediates LDL-induced LD formation in vitro and in vivo. In addition to cytosolic NL hydrolysis and de novo lipid synthesis, this process includes selective sorting and transport of LDL NL to LDs with limited lysosomal NL sequestration and the transport of LDL CE, and TAG directly to LDs independently of de novo synthesis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240659PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7561250PMC
December 2020

Hypertriglyceridemia: new approaches in management and treatment.

Curr Opin Lipidol 2020 12;31(6):331-339

Lipoprotein Metabolism Laboratory, Translational Vascular Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.

Purpose Of Review: Hypertriglyceridemia (HTG), a form of dyslipidemia characterized by elevated plasma of triglycerides (TG), is associated with an increased risk for acute pancreatitis. Moreover, HTG has recently been shown to be linked to the development of atherosclerotic cardiovascular disease (ASCVD); therefore, there is a great interest in better understanding the pathophysiology of HTG and improving its clinical management. In this review, we briefly describe TG metabolism, recent guidelines for the clinical management of HTG and provide an overview of the current and potential new therapies for HTG.

Recent Findings: Screening patients for HTG is valuable for not only identifying patients with extreme TG elevations, who are at risk for pancreatitis, but also for managing ASCVD risk in patients with more moderate forms of HTG. Therefore, the most recent USA guidelines for cardiovascular diseases recommend using TG as a risk enhancer test, leading to a more aggressive treatment of patients with intermediate risk. Currently, there are several available approaches for reducing plasma TG, which include lifestyle changes, fibrates and omega-3 fatty acid treatment. The addition of eicosapentaenoic acid (EPA) on top of statins has recently been shown to significantly reduce ASCVD events. Nevertheless, there is an unmet need for more effective treatment options. Several new therapies based on newly identified targets in TG metabolism, such as apolipoprotein C-III and angiopoietin-like 3 protein, are currently under development.

Summary: The clinical management of HTG is important in the prevention and treatment of acute pancreatitis and also impacts on how ASCVD risk is managed. More work needs to be done to establish the mechanism for the ability of how EPA lowers ASCVD and how to best integrate it with other lipid-lowering therapies. The efficacy and safety of the novel therapies for HTG should be established soon in the ongoing late-stage clinical trials.
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http://dx.doi.org/10.1097/MOL.0000000000000710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770610PMC
December 2020

Apolipoprotein A-I in mouse cerebrospinal fluid derives from the liver and intestine via plasma high-density lipoproteins assembled by ABCA1 and LCAT.

FEBS Lett 2021 03 20;595(6):773-788. Epub 2020 Oct 20.

Lipoprotein Metabolism Section, Translational Vascular Medicine Branch, NHLBI, NIH, Bethesda, MD, USA.

Apolipoprotein (apo) A-I, the major structural protein of high-density lipoprotein (HDL), is present in human and mouse cerebrospinal fluid (CSF) despite its lack of expression in brain cells. To identify the origin of apoA-I in CSF, we generated intestine-specific and liver-specific Apoa1 knockout mice (Apoa1 and Apoa1 mice, respectively). Lipoprotein profiles of Apoa1 and Apoa1 mice resembled those of control littermates, whereas knockout of Apoa1 in both intestine and liver (Apoa1 ) resulted in a 60-percent decrease in HDL-cholesterol levels, thus strongly mimicking the Apoa1 mice. Immunoassays revealed that mouse apoA-I was not present in the CSF of the Apoa1 mice. Furthermore, apoA-I levels in CSF were highly correlated with plasma spherical HDL levels, which were regulated by ABCA1 and LCAT. Collectively, these results suggest that apoA-I protein in CSF originates in liver and small intestine and is taken up from the plasma.
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http://dx.doi.org/10.1002/1873-3468.13950DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987658PMC
March 2021

Accuracy of New Equation to Calculate Low-Density Lipoprotein Cholesterol-Reply.

JAMA Cardiol 2021 Jan;6(1):122-123

Clinical Center, Department of Laboratory Medicine, National Institutes of Health, Bethesda, Maryland.

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http://dx.doi.org/10.1001/jamacardio.2020.4445DOI Listing
January 2021

Modulation of Cardiometabolic Disease Markers by Type I Interferon Inhibition in Systemic Lupus Erythematosus.

Arthritis Rheumatol 2021 03 15;73(3):459-471. Epub 2021 Feb 15.

AstraZeneca, Gaithersburg, Maryland.

Objective: Neutrophil dysregulation and the type I interferon (IFN) axis have been proposed to contribute to premature cardiovascular disease, a leading cause of mortality in patients with systemic lupus erythematosus (SLE). In the present study, we evaluated the ability of anifrolumab, a type I IFN receptor-blocking antibody, to reduce neutrophil extracellular trap (NET) formation and modulate cardiometabolic disease markers in comparison to placebo.

Methods: Study subjects comprised patients with moderate-to-severe SLE who were enrolled in phase IIb of the MUSE trial (A Phase II, Randomized Study to Evaluate the Efficacy and Safety of MEDI-546 in Subjects with Systemic Lupus Erythematosus), with healthy individuals as controls. Blood samples were collected from SLE patients (n = 305) and healthy controls (n = 10-20) before the initiation of treatment (baseline) and from SLE patients after they had been treated with 300 mg of anifrolumab (n = 99) or placebo (n = 102). Baseline IFN gene signature test status was determined, and the IFN gene signature (21-gene panel) was monitored over time. Serum proteins were measured by multiplex immunoassay or ultrasensitive Simoa assay. NET complexes, cholesterol efflux capacity (CEC), and glycoprotein acetylation (GlycA) and other lipid parameters were assessed in plasma.

Results: Formation of NET complexes and levels of tumor necrosis factor (TNF) and interleukin-10 (IL-10) were correlated with extent of type I IFN pathway activity. NET complexes and IL-10 levels were up-regulated in SLE patients compared to healthy controls (P < 0.008). The cardiometabolic disease markers CEC and GlycA were also found to be dysregulated in patients with SLE (P < 0.001 versus healthy controls). Type I IFN receptor inhibition with anifrolumab significantly reduced NET complexes and GlycA and improved CEC compared to baseline (P < 0.05) whereas no improvements were seen with placebo. Levels of TNF and IL-10 were reduced with anifrolumab compared to placebo (P < 0.05).

Conclusion: These data support a key role for type I IFNs in modulating factors contributing to SLE vasculopathy and suggest that inhibition of this pathway could decrease cardiovascular risk in individuals with SLE.
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http://dx.doi.org/10.1002/art.41518DOI Listing
March 2021

Cholesterol transport between red blood cells and lipoproteins contributes to cholesterol metabolism in blood.

J Lipid Res 2020 12 9;61(12):1577-1588. Epub 2020 Sep 9.

Department of Analytical Laboratory Chemistry, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; Life Science Research Center, Nagano Children's Hospital, Azumino, Japan.

Lipoproteins play a key role in transport of cholesterol to and from tissues. Recent studies have also demonstrated that red blood cells (RBCs), which carry large quantities of free cholesterol in their membrane, play an important role in reverse cholesterol transport. However, the exact role of RBCs in systemic cholesterol metabolism is poorly understood. RBCs were incubated with autologous plasma or isolated lipoproteins resulting in a significant net amount of cholesterol moved from RBCs to HDL, while cholesterol from LDL moved in the opposite direction. Furthermore, the bi-directional cholesterol transport between RBCs and plasma lipoproteins was saturable and temperature-, energy-, and time-dependent, consistent with an active process. We did not find LDLR, ABCG1, or scavenger receptor class B type 1 in RBCs but found a substantial amount of ABCA1 mRNA and protein. However, specific cholesterol efflux from RBCs to isolated apoA-I was negligible, and ABCA1 silencing with siRNA or inhibition with vanadate and Probucol did not inhibit the efflux to apoA-I, HDL, or plasma. Cholesterol efflux from and cholesterol uptake by RBCs from and mice were similar, arguing against the role of ABCA1 in cholesterol flux between RBCs and lipoproteins. Bioinformatics analysis identified ABCA7, ABCG5, lipoprotein lipase, and mitochondrial translocator protein as possible candidates that may mediate the cholesterol flux. Together, these results suggest that RBCs actively participate in cholesterol transport in the blood, but the role of cholesterol transporters in RBCs remains uncertain.
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http://dx.doi.org/10.1194/jlr.RA120000635DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7707172PMC
December 2020

Associations of GlycA and high-sensitivity C-reactive protein with measures of lipolysis in adults with obesity.

J Clin Lipidol 2020 Sep - Oct;14(5):667-674. Epub 2020 Aug 4.

Section on Growth and Obesity, Division of Intramural Research (DIR), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, USA; Johns Hopkins Community Physicians at Howard County General Hospital, Johns Hopkins Medicine, Columbia, MD, USA; Department of Endocrinology, Diabetes and Metabolism, Johns Hopkins School of Medicine, Baltimore, MD, USA. Electronic address:

Background: Obesity-associated inflammation promotes metabolic dysfunction. However, it is unclear how different inflammatory biomarkers predict dysregulation in specific tissues/organs, particularly adipose tissue.

Objective: The aim of our study was to examine whether GlycA, a nuclear magnetic resonance-measured biomarker of inflammation, is a better predictor of insulin-suppressible lipolysis and other measures of metabolic dysfunction compared with high-sensitivity C-reactive protein (hsCRP) in human obesity.

Methods: This was a cross-sectional study of 58 nondiabetic adults with obesity (body mass index: 39.8 ± 7.0 kg/m, age 46.5 ± 12.2 years, 67.2% female) who underwent a frequently sampled intravenous glucose tolerance test in the fasted state. Noninsulin-suppressible (l), insulin-suppressible (l), and maximal (l+l) lipolysis rates, as well as insulin sensitivity and acute insulin response to glucose, were calculated by minimal model analysis. Nuclear magnetic resonance was used to measure GlycA. Body composition was determined by dual-energy X-ray absorptiometry.

Results: GlycA was strongly correlated with hsCRP (r = +0.46; P < .001). GlycA and hsCRP were positively associated with l, l+l, and fat mass (Ps < .01). In linear regression models accounting for age, race, sex, and fat mass, GlycA remained significantly associated with l and l+l (Ps < .05), whereas hsCRP did not (Ps ≥ .20). Neither GlycA nor hsCRP was associated with l insulin sensitivity, or acute insulin response to glucose.

Conclusions: GlycA was associated with elevated lipolysis, independent of adiposity, in adults with obesity. Our findings suggest that GlycA and hsCRP have distinct inflammation-mediated metabolic effects, with GlycA having a greater association with adipose tissue dysfunction. Further studies are warranted to investigate the mechanisms underlying these associations.
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http://dx.doi.org/10.1016/j.jacl.2020.07.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642018PMC
August 2020

Effect of niacin monotherapy on high density lipoprotein composition and function.

Lipids Health Dis 2020 Aug 21;19(1):190. Epub 2020 Aug 21.

Translational Vascular Medicine Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD, USA.

Background: Niacin has modest but overall favorable effects on plasma lipids by increasing high density lipoprotein cholesterol (HDL-C) and lowering triglycerides. Clinical trials, however, evaluating niacin therapy for prevention of cardiovascular outcomes have returned mixed results. Recent evidence suggests that the HDL proteome may be a better indicator of HDL's cardioprotective function than HDL-C. The objective of this study was to evaluate the effect of niacin monotherapy on HDL protein composition and function.

Methods: A 20-week investigational study was performed with 11 participants receiving extended-release niacin (target dose = 2 g/day) for 16-weeks followed by a 4-week washout period. HDL was isolated from participants at weeks: 0, 16, and 20. The HDL proteome was analyzed at each time point by mass spectrometry and relative protein quantification was performed by label-free precursor ion intensity measurement.

Results: In this cohort, niacin therapy had typical effects on routine clinical lipids (HDL-C + 16%, q < 0.01; LDL-C - 20%, q < 0.01; and triglyceride - 15%, q = 0.1). HDL proteomics revealed significant effects of niacin on 5 proteins: serum amyloid A (SAA), angiotensinogen (AGT), apolipoprotein A-II (APOA2), clusterin (CLUS), and apolipoprotein L1 (APOL1). SAA was the most prominently affected protein, increasing 3-fold in response to niacin (q = 0.008). Cholesterol efflux capacity was not significantly affected by niacin compared to baseline, however, stopping niacin resulted in a 9% increase in efflux (q < 0.05). Niacin did not impact HDL's ability to influence endothelial function.

Conclusion: Extended-release niacin therapy, in the absence of other lipid-modifying medications, can increase HDL-associated SAA, an acute phase protein associated with HDL dysfunction.
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http://dx.doi.org/10.1186/s12944-020-01350-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7441610PMC
August 2020

Evaluation of Three Commercial Automated Assays for the Detection of Anti-SARS-CoV-2 Antibodies.

Clin Chem 2020 10;66(10):1351-1353

Department of Laboratory Medicine, National Institutes of Health, Bethesda, MD.

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http://dx.doi.org/10.1093/clinchem/hvaa193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454464PMC
October 2020

High-density lipoproteins are a potential therapeutic target for age-related macular degeneration.

J Biol Chem 2020 09 31;295(39):13601-13616. Epub 2020 Jul 31.

Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina, USA; Department of Cell Biology, Duke University Medical Center, Durham, North Carolina, USA. Electronic address:

Strong evidence suggests that dysregulated lipid metabolism involving dysfunction of the retinal pigmented epithelium (RPE) underlies the pathogenesis of age-related macular degeneration (AMD), the leading cause of irreversible blindness in the elderly. A hallmark of AMD is the overproduction of lipid- and protein-rich extracellular deposits that accumulate in the extracellular matrix (Bruch's membrane (BrM)) adjacent to the RPE. We analyzed apolipoprotein A-1 (ApoA-1)-containing lipoproteins isolated from BrM of elderly human donor eyes and found a unique proteome, distinct from high-density lipoprotein (HDL) isolated from donor plasma of the same individuals. The most striking difference is higher concentrations of ApoB and ApoE, which bind to glycosaminoglycans. We hypothesize that this interaction promotes lipoprotein deposition onto BrM glycosaminoglycans, initiating downstream effects that contribute to RPE dysfunction/death. We tested this hypothesis using two potential therapeutic strategies to alter the lipoprotein/protein profile of these extracellular deposits. First, we used short heparan sulfate oligosaccharides to remove lipoproteins already deposited in both the extracellular matrix of RPE cells and aged donor BrM tissue. Second, an ApoA-1 mimetic, 5A peptide, was demonstrated to modulate the composition and concentration of apolipoproteins secreted from primary porcine RPE cells. Significantly, in a mouse model of AMD, this 5A peptide altered the proteomic profile of circulating HDL and ameliorated some of the potentially harmful changes to the protein composition resulting from the high-fat, high-cholesterol diet in this model. Together, these results suggest that targeting HDL interactions with BrM represents a new strategy to slow AMD progression in humans.
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http://dx.doi.org/10.1074/jbc.RA119.012305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7521644PMC
September 2020

COVID-19-Associated dyslipidemia: Implications for mechanism of impaired resolution and novel therapeutic approaches.

FASEB J 2020 08 26;34(8):9843-9853. Epub 2020 Jun 26.

Lipoprotein Metabolism Laboratory, Translational Vascular Medicine Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.

The current coronavirus disease 2019 (COVID-19) pandemic presents a global challenge for managing acutely ill patients and complications from viral infection. Systemic inflammation accompanied by a "cytokine storm," hemostasis alterations and severe vasculitis have all been reported to occur with COVID-19, and emerging evidence suggests that dysregulation of lipid transport may contribute to some of these complications. Here, we aim to summarize the current understanding of the potential mechanisms related to COVID-19 dyslipidemia and propose possible adjunctive type therapeutic approaches that modulate lipids and lipoproteins. Specifically, we hypothesize that changes in the quantity and composition of high-density lipoprotein (HDL) that occurs with COVID-19 can significantly decrease the anti-inflammatory and anti-oxidative functions of HDL and could contribute to pulmonary inflammation. Furthermore, we propose that lipoproteins with oxidized phospholipids and fatty acids could lead to virus-associated organ damage via overactivation of innate immune scavenger receptors. Restoring lipoprotein function with ApoA-I raising agents or blocking relevant scavenger receptors with neutralizing antibodies could, therefore, be of value in the treatment of COVID-19. Finally, we discuss the role of omega-3 fatty acids transported by lipoproteins in generating specialized proresolving mediators and how together with anti-inflammatory drugs, they could decrease inflammation and thrombotic complications associated with COVID-19.
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http://dx.doi.org/10.1096/fj.202001451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7361619PMC
August 2020

Lecithin:cholesterol acyltransferase: symposium on 50 years of biomedical research from its discovery to latest findings.

J Lipid Res 2020 08 1;61(8):1142-1149. Epub 2020 Jun 1.

Department of Nutrition, University of Oslo, Oslo, Norway

LCAT converts free cholesterol to cholesteryl esters in the process of reverse cholesterol transport. Familial LCAT deficiency (FLD) is a genetic disease that was first described by Kaare R. Norum and Egil Gjone in 1967. This report is a summary from a 2017 symposium where Dr. Norum recounted the history of FLD and leading experts on LCAT shared their results. The Tesmer laboratory shared structural findings on LCAT and the close homolog, lysosomal phospholipase A2. Results from studies of FLD patients in Finland, Brazil, Norway, and Italy were presented, as well as the status of a patient registry. Drs. Kuivenhoven and Calabresi presented data from carriers of genetic mutations suggesting that FLD does not necessarily accelerate atherosclerosis. Dr. Ng shared that LCAT-null mice were protected from diet-induced obesity, insulin resistance, and nonalcoholic fatty liver disease. Dr. Zhou presented multiple innovations for increasing LCAT activity for therapeutic purposes, whereas Dr. Remaley showed results from treatment of an FLD patient with recombinant human LCAT (rhLCAT). Dr. Karathanasis showed that rhLCAT infusion in mice stimulates cholesterol efflux and suggested that it could also enhance cholesterol efflux from macrophages. While the role of LCAT in atherosclerosis remains elusive, the consensus is that a continued study of both the enzyme and disease will lead toward better treatments for patients with heart disease and FLD.
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http://dx.doi.org/10.1194/jlr.S120000720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397740PMC
August 2020

Measuring LDL-cholesterol: what is the best way to do it?

Curr Opin Cardiol 2020 07;35(4):405-411

Lipoprotein Metabolism Laboratory, Translational Vascular Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.

Purpose Of Review: Cholesterol on low-density lipoproteins (LDL-C) is one of the main drivers of atherosclerotic cardiovascular disease (ASCVD) and hence its measurement is critical in the management of patients at risk. Although LDL-C has routinely been either calculated by the Friedewald equation or measured with direct assays, these methods have limitations, particularly for patients with dyslipidaemias, low LDL-C, and hypertriglyceridemia. The focus of this review will be recent advances in the measurement of LDL for ASCVD risk management.

Recent Findings: We first describe the recent recommendations on how LDL-C is used in ASCVD risk assessment and management. We then review the current approaches to the measurement of LDL-C and recent developments on new more accurate equations for calculating LDL-C. Finally, we present new and emerging LDL assays that may be superior to LDL-C for risk assessment, such as LDL particle number and small dense LDL-C, and several LDL-based lipid tests in early development.

Summary: LDL-C is valuable in ASCVD risk management but recent improvements in its measurement and the development of other LDL-related tests may further improve its value.
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http://dx.doi.org/10.1097/HCO.0000000000000740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360339PMC
July 2020

The lysosome: A potential juncture between SARS-CoV-2 infectivity and Niemann-Pick disease type C, with therapeutic implications.

FASEB J 2020 06 5;34(6):7253-7264. Epub 2020 May 5.

Lipoprotein Metabolism Section, Translational Vascular Medicine Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.

Drug repurposing is potentially the fastest available option in the race to identify safe and efficacious drugs that can be used to prevent and/or treat COVID-19. By describing the life cycle of the newly emergent coronavirus, SARS-CoV-2, in light of emerging data on the therapeutic efficacy of various repurposed antimicrobials undergoing testing against the virus, we highlight in this review a possible mechanistic convergence between some of these tested compounds. Specifically, we propose that the lysosomotropic effects of hydroxychloroquine and several other drugs undergoing testing may be responsible for their demonstrated in vitro antiviral activities against COVID-19. Moreover, we propose that Niemann-Pick disease type C (NPC), a lysosomal storage disorder, may provide new insights into potential future therapeutic targets for SARS-CoV-2, by highlighting key established features of the disorder that together result in an "unfavorable" host cellular environment that may interfere with viral propagation. Our reasoning evolves from previous biochemical and cell biology findings related to NPC, coupled with the rapidly evolving data on COVID-19. Our overall aim is to suggest that pharmacological interventions targeting lysosomal function in general, and those particularly capable of reversibly inducing transient NPC-like cellular and biochemical phenotypes, constitute plausible mechanisms that could be used to therapeutically target COVID-19.
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http://dx.doi.org/10.1096/fj.202000654RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383733PMC
June 2020

GlycA: A New Biomarker for Systemic Inflammation and Cardiovascular Disease (CVD) Risk Assessment.

J Lab Precis Med 2020 Apr 20;5. Epub 2020 Apr 20.

Lipoprotein Metabolism Section, Translational and Vascular Medicine Branch, National Heart, Lung and Blood Institute (NHLBI), National Institutes of Health, Bethesda, MD, USA.

The GlycA test is a recently developed proton nuclear magnetic resonance (H-NMR) spectroscopy-based assay that has been gaining increased interest as a serum biomarker for systemic inflammation, and consequently, as a potential biomarker for cardiovascular disease (CVD) risk assessment. The test has undergone investigation in several large cohort studies, since its development, to assess its predictive value for incident CVD events, CVD-associated mortality, and all-cause mortality. Despite variation in the generated estimates by these studies, they have all consistently demonstrated moderate-strength positive correlations between baseline GlycA levels, and incident CVD event rates and associated mortality. These correlations withheld testing even after adjusting for several other established CVD risk factors, including notable inflammatory biomarkers such as high-sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL-6). Compared with hsCRP, which is a well-known inflammatory biomarker for CVD risk assessment, GlycA has a comparable predictive value for future CVD-related events. However, the indications to pursue GlycA testing, and its clinical utility in patient care management, are yet to be determined. In this review, we define the GlycA test and what it "measures", and provide a brief summary of the findings of studies showing its association with incident CVD rates, and CVD-related mortality, as well as its correlation with other inflammatory biomarkers, namely hsCRP. Finally, we highlight the analytical advantages of the GlycA test, compared with "traditional" inflammatory biomarkers, while also mentioning its current limitations.
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http://dx.doi.org/10.21037/jlpm.2020.03.03DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7194207PMC
April 2020
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