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Novel Aspects of Lipoprotein Metabolism with Focus on Systemic Inflammation
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Novel Aspects of Lipoprotein Metabolism with Focus on Systemic Inflammation

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Endocrinology & Metabolism".

Deadline for manuscript submissions: closed (31 October 2019) | Viewed by 63101

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editor

Dr. Robin P.F. Dullaart

E-Mail Website
Guest Editor
Department of Endocrinology, University of Groningen and University Medical Center Groningen, 9700 RB Groningen, The Netherlands
Interests: lipoprotein metabolism; diabetes; metabolic syndrome; inflammatory pathways; NAFLD; thyroid function and CVD risk markers

Special Issue Information

Dear colleagues,

Recently developed high-throughput laboratory techniques regarding lipidomics and metabolomics have enabled one to discern novel cross-talk mechanisms between lipid phenotypes and enhanced chronic inflammation. For example, glycoprotein biomarkers of low-grade inflammation predict incident cardiometabolic diseases and may confer reduced life expectancy, whereas lipoprotein subfractions and lipoprotein compositional features enable one to discern new metabolic phenotypes. This Special Issue of the Journal of Clinical Medicine (IF = 5.583), entitled “Novel Aspects of Lipoprotein Metabolism with a Focus on Systemic Inflammation”, welcomes the submission of manuscripts either describing original research or reviewing the scientific literature. Manuscripts should focus on lipoprotein metabolism and inflammation, particularly in relation to obesity, NAFLD, chronic kidney disease, and pharmacological treatment thereof. Potential topics may include but are not limited to the following:

  • Cellular signalling mechanisms in lipoprotein metabolism;
  • Cross-talk between lipoproteins and inflammation;
  • Importance of low-grade autoimmunity for lipoprotein metabolism;
  • Lipoprotein subfractions and CVD risk assessment;
  • The role of PCSK9-related pathways in insulin secretion and action;
  • Determinants of circulating PCSK9;
  • Hormonal regulation of liver fat.

Dr. Robin P.F. Dullaart
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Clinical Medicine is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • cardiometabolic risk markers
  • lipoprotein subfractions
  • lipoprotein autoantibodies
  • low-grade inflammation
  • metabolic syndrome
  • metabolomics
  • NAFLD
  • PCSK9
  • triglyceride metabolism
  • type 2 diabetes

Published Papers (17 papers)

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17 pages, 1888 KiB  
Article
Evidences for Expression and Location of ANGPTL8 in Human Adipose Tissue
by Leonardo Catalano-Iniesta, Virginia Sánchez Robledo, María Carmen Iglesias-Osma, Amparo Galán Albiñana, Sixto Carrero, Enrique J. Blanco, Marta Carretero-Hernández, José Carretero and María José García-Barrado
J. Clin. Med. 2020, 9(2), 512; https://doi.org/10.3390/jcm9020512 - 13 Feb 2020
Cited by 13 | Viewed by 2797
Abstract
The metabolism of triglycerides (TGs) is regulated, among others, by the lipoprotein lipase (LPL) that hydrolyses the TGs on endothelial cells. In turn, LPL is inhibited by the ANGPTLs family of proteins, such as ANGPTL3, 4, and, 8; the latter is the least [...] Read more.
The metabolism of triglycerides (TGs) is regulated, among others, by the lipoprotein lipase (LPL) that hydrolyses the TGs on endothelial cells. In turn, LPL is inhibited by the ANGPTLs family of proteins, such as ANGPTL3, 4, and, 8; the latter is the least known. In this work, we have tried to establish the expression and localisation of the Angiopoietin-like 8 (ANGPTL8) protein in the visceral adipose tissue (VAT) of morbid-obese and non-obese patients. 109 subjects (66 women and 43 men) undergoing laparoscopic surgery participated in this study. A blood sample and a portion of the VAT were obtained, and the patients were classified according to their Body Mass Index (BMI) as non-obese (19.5–30 kg/m2) and morbid-obese (40–50 kg/m2). No significant changes in ANGPTL8 plasma levels were determined by EIA in obese patients. The immunocytochemistry and Western blotting showed the presence of increased ANGPTL8 in morbid-obese patients (p < 0.05). In-situ hybridisation and a real time polymerase chain reaction (RT-PCR) confirmed that the mRNA that encodes ANGPTL8 was present in adipocytes, without differences in their nutritional state (p = 0.89), and even in the endothelial cells. Our data suggests that ANGPT8 plasmatic levels do not change significantly in patients with morbid obesity, although there is a modest difference related to gender. Besides, we demonstrate that in visceral adipose tissue, ANGPTL8 is well defined in the cytoplasm of adipocytes coexisting with perilipin-1 and its mRNA, also is present in endothelial cells. These findings suggest the possibility that among other functions, ANGPTL8 could perform either a paracrine and/or an endocrine role in the adipose tissue. Full article
(This article belongs to the Special Issue Novel Aspects of Lipoprotein Metabolism with Focus on Systemic Inflammation)
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16 pages, 486 KiB  
Article
The Systemic Redox Status Is Maintained in Non-Smoking Type 2 Diabetic Subjects Without Cardiovascular Disease: Association with Elevated Triglycerides and Large VLDL
by Peter R. van Dijk, Amaal Eman Abdulle, Marian L.C. Bulthuis, Frank G. Perton, Margery A. Connelly, Harry van Goor and Robin P.F. Dullaart
J. Clin. Med. 2020, 9(1), 49; https://doi.org/10.3390/jcm9010049 - 24 Dec 2019
Cited by 8 | Viewed by 2187
Abstract
Decreased circulating levels of free thiols (R-SH, sulfhydryl groups) reflect enhanced oxidative stress, which plays an important role in the pathogenesis of cardiometabolic diseases. Since hyperglycemia causes oxidative stress, we questioned whether plasma free thiols are altered in patients with type 2 diabetes [...] Read more.
Decreased circulating levels of free thiols (R-SH, sulfhydryl groups) reflect enhanced oxidative stress, which plays an important role in the pathogenesis of cardiometabolic diseases. Since hyperglycemia causes oxidative stress, we questioned whether plasma free thiols are altered in patients with type 2 diabetes mellitus (T2DM) without cardiovascular disease or renal function impairment. We also determined their relationship with elevated triglycerides and very low density lipoproteins (VLDL), a central feature of diabetic dyslipidemia. Fasting plasma free thiols (colorimetric method), lipoproteins, VLDL (nuclear magnetic resonance spectrometry), free fatty acids (FFA), phospholipid transfer protein (PLTP) activity and adiponectin were measured in 79 adult non-smoking T2DM subjects (HbA1c 51 ± 8 mmol/mol, no use of insulin or lipid lowering drugs), and in 89 non-smoking subjects without T2DM. Plasma free thiols were univariately correlated with glucose (r = 0.196, p < 0.05), but were not decreased in T2DM subjects versus non-diabetic subjects (p = 0.31). Free thiols were higher in subjects with (663 ± 84 µmol/L) versus subjects without elevated triglycerides (619 ± 91 µmol/L; p = 0.002). Age- and sex-adjusted multivariable linear regression analysis demonstrated that plasma triglycerides were positively and independently associated with free thiols (β = 0.215, p = 0.004), FFA (β = 0.168, p = 0.029) and PLTP activity (β = 0.228, p = 0.002), inversely with adiponectin (β = −0.308, p < 0.001) but not with glucose (β = 0.052, p = 0.51). Notably, the positive association of free thiols with (elevated) triglycerides appeared to be particularly evident in men. Additionally, large VLDL were independently associated with free thiols (β = 0.188, p = 0.029). In conclusion, circulating free thiols are not decreased in this cohort of non-smoking and generally well-controlled T2DM subjects. Paradoxically, higher triglycerides and more large VLDL particles are likely associated with higher plasma levels of thiols, reflecting lower systemic oxidative stress. Full article
(This article belongs to the Special Issue Novel Aspects of Lipoprotein Metabolism with Focus on Systemic Inflammation)
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16 pages, 535 KiB  
Article
Higher Sodium Intake Assessed by 24 Hour Urinary Sodium Excretion Is Associated with Non-Alcoholic Fatty Liver Disease: The PREVEND Cohort Study
by Eline H. van den Berg, Eke G. Gruppen, Hans Blokzijl, Stephan J.L. Bakker and Robin P.F. Dullaart
J. Clin. Med. 2019, 8(12), 2157; https://doi.org/10.3390/jcm8122157 - 06 Dec 2019
Cited by 16 | Viewed by 2977
Abstract
A higher sodium intake is conceivably associated with insulin resistant conditions like obesity, but associations of non-alcoholic fatty liver disease (NAFLD) with a higher sodium intake determined by 24 hours (24 h) urine collections are still unclear. Dietary sodium intake was measured by [...] Read more.
A higher sodium intake is conceivably associated with insulin resistant conditions like obesity, but associations of non-alcoholic fatty liver disease (NAFLD) with a higher sodium intake determined by 24 hours (24 h) urine collections are still unclear. Dietary sodium intake was measured by sodium excretion in two complete consecutive 24 h urine collections in 6132 participants of the Prevention of Renal and Vascular End-Stage Disease (PREVEND) cohort. Fatty Liver Index (FLI) ≥60 and Hepatic Steatosis Index (HSI) >36 were used as proxies of suspected NAFLD. 1936 (31.6%) participants had an FLI ≥60, coinciding with the increased prevalence of type 2 diabetes (T2D), metabolic syndrome, hypertension and history of cardiovascular disease. Sodium intake was higher in participants with an FLI ≥60 (163.63 ± 61.81 mmol/24 h vs. 136.76 ± 50.90 mmol/24 h, p < 0.001), with increasing incidence in ascending quartile categories of sodium intake (p < 0.001). Multivariably, an FLI ≥60 was positively associated with a higher sodium intake when taking account for T2D, a positive cardiovascular history, hypertension, alcohol intake, smoking and medication use (odds ratio (OR) 1.54, 95% confidence interval (CI) 1.44–1.64, p < 0.001). Additional adjustment for the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) diminished this association (OR 1.30, 95% CI 1.21–1.41, p < 0.001). HSI >36 showed similar results. Associations remained essentially unaltered after adjustment for body surface area or waist/hip ratio. In conclusion, suspected NAFLD is a feature of higher sodium intake. Insulin resistance-related processes may contribute to the association of NAFLD with sodium intake. Full article
(This article belongs to the Special Issue Novel Aspects of Lipoprotein Metabolism with Focus on Systemic Inflammation)
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9 pages, 690 KiB  
Article
Impaired HDL Metabolism Links GlycA, A Novel Inflammatory Marker, with Incident Cardiovascular Events
by Kayla A. Riggs, Parag H. Joshi, Amit Khera, Kavisha Singh, Oludamilola Akinmolayemi, Colby R. Ayers and Anand Rohatgi
J. Clin. Med. 2019, 8(12), 2137; https://doi.org/10.3390/jcm8122137 - 03 Dec 2019
Cited by 10 | Viewed by 2565
Abstract
High-density lipoproteins (HDL) exert anti-atherosclerotic effects via reverse cholesterol transport, yet this salutary property is impaired in the setting of inflammation. GlycA, a novel integrated glycosylation marker of five acute phase reactants, is linked to cardiovascular (CV) events. We assessed the hypothesis that [...] Read more.
High-density lipoproteins (HDL) exert anti-atherosclerotic effects via reverse cholesterol transport, yet this salutary property is impaired in the setting of inflammation. GlycA, a novel integrated glycosylation marker of five acute phase reactants, is linked to cardiovascular (CV) events. We assessed the hypothesis that GlycA is associated with measures of impaired HDL function and that dysfunctional HDL may contribute to the association between GlycA and incident CV events. Baseline measurements of HDL cholesterol (HDL-C), HDL particle concentration (HDL-P), apoliprotein A1 (Apo A1), cholesterol efflux capacity, GlycA and high-sensitivity C-reactive protein (hs-CRP) were obtained from the Dallas Heart Study, a multi-ethnic cohort of 2643 adults (median 43 years old; 56% women, 50% black) without cardiovascular disease (CVD). GlycA was derived from nuclear magnetic resonance imaging. Participants were followed for first nonfatal MI, nonfatal stroke, coronary revascularization, or CV death over a median of 12.4 years (n = 197). The correlation between GlycA and hs-CRP was 0.58 (p < 0.0001). In multivariate models with HDL-C, GlycA was directly associated with HDL-P and Apo A1 and inversely associated with cholesterol efflux (standardized beta estimates: 0.08, 0.29, -0.06, respectively; all p ≤ 0.0004) GlycA was directly associated with incident CV events (adjusted hazard ratio (HR) for Q4 vs. Q1: 3.33, 95% confidence interval (CI) 1.99, 5.57). Adjustment for cholesterol efflux mildly attenuated this association (HR for Q4 vs. Q1: 3.00, 95% CI 1.75 to 5.13). In a multi-ethnic cohort, worsening inflammation, as reflected by higher GlycA levels, is associated with higher HDL-P and lower cholesterol efflux. Impaired cholesterol efflux likely explains some of the association between GlycA and incident CV events. Further studies are warranted to investigate the impact of inflammation on HDL function and CV disease. Full article
(This article belongs to the Special Issue Novel Aspects of Lipoprotein Metabolism with Focus on Systemic Inflammation)
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20 pages, 3629 KiB  
Article
Anti-ApoA-1 IgGs in Familial Hypercholesterolemia Display Paradoxical Associations with Lipid Profile and Promote Foam Cell Formation
by Sabrina Pagano, Alessandra Magenta, Marco D’Agostino, Francesco Martino, Francesco Barillà, Nathalie Satta, Miguel A. Frias, Annalisa Ronca, François Mach, Baris Gencer, Elda Favari and Nicolas Vuilleumier
J. Clin. Med. 2019, 8(12), 2035; https://doi.org/10.3390/jcm8122035 - 21 Nov 2019
Cited by 9 | Viewed by 2361
Abstract
Aims: Anti-Apolipoprotein A-1 autoantibodies (anti-ApoA-1 IgG) promote atherogenesis via innate immune receptors, and may impair cellular cholesterol homeostasis (CH). We explored the presence of anti-ApoA-1 IgG in children (5–15 years old) with or without familial hypercholesterolemia (FH), analyzing their association with lipid profiles, [...] Read more.
Aims: Anti-Apolipoprotein A-1 autoantibodies (anti-ApoA-1 IgG) promote atherogenesis via innate immune receptors, and may impair cellular cholesterol homeostasis (CH). We explored the presence of anti-ApoA-1 IgG in children (5–15 years old) with or without familial hypercholesterolemia (FH), analyzing their association with lipid profiles, and studied their in vitro effects on foam cell formation, gene regulation, and their functional impact on cholesterol passive diffusion (PD). Methods: Anti-ApoA-1 IgG and lipid profiles were measured on 29 FH and 25 healthy children. The impact of anti-ApoA-1 IgG on key CH regulators (SREBP2, HMGCR, LDL-R, ABCA1, and miR-33a) and foam cell formation detected by Oil Red O staining were assessed using human monocyte-derived macrophages. PD experiments were performed using a validated THP-1 macrophage model. Results: Prevalence of high anti-ApoA-1 IgG levels (seropositivity) was about 38% in both study groups. FH children seropositive for anti-ApoA-1 IgG had significant lower total cholesterol LDL and miR-33a levels than those who were seronegative. On macrophages, anti-ApoA-1 IgG induced foam cell formation in a toll-like receptor (TLR) 2/4-dependent manner, accompanied by NF-kB- and AP1-dependent increases of SREBP-2, LDL-R, and HMGCR. Despite increased ABCA1 and decreased mature miR-33a expression, the increased ACAT activity decreased membrane free cholesterol, functionally culminating to PD inhibition. Conclusions: Anti-ApoA-1 IgG seropositivity is frequent in children, unrelated to FH, and paradoxically associated with a favorable lipid profile. In vitro, anti-ApoA-1 IgG induced foam cell formation through a complex interplay between innate immune receptors and key cholesterol homeostasis regulators, functionally impairing the PD cholesterol efflux capacity of macrophages. Full article
(This article belongs to the Special Issue Novel Aspects of Lipoprotein Metabolism with Focus on Systemic Inflammation)
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14 pages, 990 KiB  
Article
High Betaine, a Trimethylamine N-Oxide Related Metabolite, Is Prospectively Associated with Low Future Risk of Type 2 Diabetes Mellitus in the PREVEND Study
by Erwin Garcia, Maryse C. J. Osté, Dennis W. Bennett, Elias J. Jeyarajah, Irina Shalaurova, Eke G. Gruppen, Stanley L. Hazen, James D. Otvos, Stephan J. L. Bakker, Robin P.F. Dullaart and Margery A. Connelly
J. Clin. Med. 2019, 8(11), 1813; https://doi.org/10.3390/jcm8111813 - 01 Nov 2019
Cited by 28 | Viewed by 3703
Abstract
Background: Gut microbiota-related metabolites, trimethylamine-N-oxide (TMAO), choline, and betaine, have been shown to be associated with cardiovascular disease (CVD) risk. Moreover, lower plasma betaine concentrations have been reported in subjects with type 2 diabetes mellitus (T2DM). However, few studies have explored the association [...] Read more.
Background: Gut microbiota-related metabolites, trimethylamine-N-oxide (TMAO), choline, and betaine, have been shown to be associated with cardiovascular disease (CVD) risk. Moreover, lower plasma betaine concentrations have been reported in subjects with type 2 diabetes mellitus (T2DM). However, few studies have explored the association of betaine with incident T2DM, especially in the general population. The goals of this study were to evaluate the performance of a newly developed betaine assay and to prospectively explore the potential clinical associations of betaine and future risk of T2DM in a large population-based cohort. Methods: We developed a high-throughput, nuclear magnetic resonance (NMR) spectroscopy procedure for acquiring spectra that allow for the accurate quantification of plasma/serum betaine and TMAO. Assay performance for betaine quantification was assessed and Cox proportional hazards regression was employed to evaluate the association of betaine with incident T2DM in 4336 participants in the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study. Results: Betaine assay results were linear (y = 1.02X − 3.75) over a wide range of concentrations (26.0–1135 µM). The limit of blank (LOB), limit of detection (LOD) and limit of quantitation (LOQ) were 6.4, 8.9, and 13.2 µM, respectively. Coefficients of variation for intra- and inter-assay precision ranged from 1.5–4.3% and 2.5–5.5%, respectively. Deming regression analysis of results produced by NMR and liquid chromatography coupled to tandem mass spectrometry(LC-MS/MS) revealed an R2 value of 0.94 (Y = 1.08x – 1.89) and a small bias for higher values by NMR. The reference interval, in a cohort of apparently healthy adult participants (n = 501), was determined to be 23.8 to 74.7 µM (mean of 42.9 ± 12.6 µM). In the PREVEND study (n = 4336, excluding subjects with T2DM at baseline), higher betaine was associated with older age and lower body mass index, total cholesterol, triglycerides, and hsCRP. During a median follow-up of 7.3 (interquartile range (IQR), 5.9–7.7) years, 224 new T2DM cases were ascertained. Cox proportional hazards regression models revealed that the highest tertile of betaine was associated with a lower incidence of T2DM. Hazard ratio (HR) for the crude model was 0.61 (95% CI: 0.44–0.85, p = 0.004). The association remained significant even after adjusting for multiple clinical covariates and T2DM risk factors, including fasting glucose. HR for the fully-adjusted model was 0.50 (95% CI: 0.32–0.80, p = 0.003). Conclusions: The newly developed NMR-based betaine assay exhibits performance characteristics that are consistent with usage in the clinical laboratory. Betaine levels may be useful for assessing the risk of future T2DM. Full article
(This article belongs to the Special Issue Novel Aspects of Lipoprotein Metabolism with Focus on Systemic Inflammation)
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16 pages, 1051 KiB  
Article
Plasma Levels of Retinol Binding Protein 4 Relate to Large VLDL and Small LDL Particles in Subjects with and without Type 2 Diabetes
by Hanna Wessel, Ali Saeed, Janette Heegsma, Margery A. Connelly, Klaas Nico Faber and Robin P. F. Dullaart
J. Clin. Med. 2019, 8(11), 1792; https://doi.org/10.3390/jcm8111792 - 25 Oct 2019
Cited by 26 | Viewed by 4578
Abstract
Background: Retinol binding protein 4 (RBP4) carries retinol in plasma, but is also considered an adipokine, as it is implicated in insulin resistance in mice. Plasma RBP4 correlates with total cholesterol, low density lipoprotein (LDL)-cholesterol and triglycerides, and may confer increased cardiovascular risk. [...] Read more.
Background: Retinol binding protein 4 (RBP4) carries retinol in plasma, but is also considered an adipokine, as it is implicated in insulin resistance in mice. Plasma RBP4 correlates with total cholesterol, low density lipoprotein (LDL)-cholesterol and triglycerides, and may confer increased cardiovascular risk. However, controversy exists about circulating RPB4 levels in type 2 diabetes mellitus (T2DM) and obesity. Here, we analyzed the relationships of RBP4 and retinol with lipoprotein subfractions in subjects with and without T2DM. Methods: Fasting plasma RBP4 (enzyme-linked immunosorbent assay) and retinol (high performance liquid chromatography) were assayed in 41 T2DM subjects and 37 non-diabetic subjects. Lipoprotein subfractions (NMR spectroscopy) were measured in 36 T2DM subjects and 27 non-diabetic subjects. Physical interaction of RBP4 with lipoproteins was assessed by fast protein liquid chromatography (FPLC). Results: Plasma RBP4 and retinol were strongly correlated (r = 0.881, p < 0.001). RBP4, retinol and the RBP4/retinol ratio were not different between T2DM and non-diabetic subjects (all p > 0.12), and were unrelated to body mass index. Notably, RBP4 and retinol were elevated in subjects with metabolic syndrome (p < 0.05), which was attributable to an association with elevated triglycerides (p = 0.013). Large VLDL, total LDL and small LDL were increased in T2DM subjects (p = 0.035 to 0.003). Taking all subjects together, RBP4 correlated with total cholesterol, non-HDL cholesterol, LDL cholesterol, triglycerides and apolipoprotein B in univariate analysis (p < 0.001 for each). Age-, sex- and diabetes status-adjusted multivariable linear regression analysis revealed that RBP4 was independently associated with large VLDL (β = 0.444, p = 0.005) and small LDL particles (β = 0.539, p < 0.001). Its relationship with large VLDL remained after further adjustment for retinol. RBP4 did not co-elute with VLDL nor LDL particles in FPLC analyses. Conclusions: Plasma RBP4 levels are related to but do not physically interact with large VLDL and small LDL particles. Elevated RBP4 may contribute to a proatherogenic plasma lipoprotein profile. Full article
(This article belongs to the Special Issue Novel Aspects of Lipoprotein Metabolism with Focus on Systemic Inflammation)
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12 pages, 1438 KiB  
Article
Low Serum Paraoxonase-1 Activity Associates with Incident Cardiovascular Disease Risk in Subjects with Concurrently High Levels of High-Density Lipoprotein Cholesterol and C-Reactive Protein
by James P. Corsetti, Charles E. Sparks, Richard W. James, Stephan J. L. Bakker and Robin P. F. Dullaart
J. Clin. Med. 2019, 8(9), 1357; https://doi.org/10.3390/jcm8091357 - 01 Sep 2019
Cited by 13 | Viewed by 2232
Abstract
Paroxonase-1 (PON1) is a key enzyme that inhibits low-density lipoprotein oxidation and consequently atherogenesis. Here, we assessed whether low serum PON1 activity associates with incident cardiovascular disease (CVD) in subjects with high levels of high-density cholesterol (HDL-C) and C-reactive protein (CRP), a marker [...] Read more.
Paroxonase-1 (PON1) is a key enzyme that inhibits low-density lipoprotein oxidation and consequently atherogenesis. Here, we assessed whether low serum PON1 activity associates with incident cardiovascular disease (CVD) in subjects with high levels of high-density cholesterol (HDL-C) and C-reactive protein (CRP), a marker of low-grade systemic inflammation. Cox proportional-hazards modeling of incident CVD risk (11 years mean follow-up) adjusted for relevant clinical and biomarker covariates was performed on a population-based study (N = 7766) stratified into three groups: low CRP—(LR; event rate 4.9%); low HDL-C/high CRP—(HR1; event rate 14.4%); and high HDL-C/high CRP—(HR2; event rate 7.6%). Modeling results for PON1 activity in HR2 were significant and robust (hazard ratio/SD unit—0.68, 95% CI 0.55–0.83, p = 0.0003), but not so for LR and HR1. Analyses in HR2 of the interaction of PON1 with HDL-C, apoA-I, apoA-II, and apoE levels were significant only for PON1 with apoE (hazard ratio—1.77, 95% CI 1.29–2.41, p = 0.0003). Subsequent subgroup analysis revealed inverse risk dependence for apoE at low PON1 levels. In conclusion, in a population-based study of subjects with concurrently high HDL-C and CRP levels, low serum PON1 activity associates with incident CVD risk with risk accentuated at low apoE levels. Full article
(This article belongs to the Special Issue Novel Aspects of Lipoprotein Metabolism with Focus on Systemic Inflammation)
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16 pages, 1393 KiB  
Article
Relationship between HDL Cholesterol Efflux Capacity, Calcium Coronary Artery Content, and Antibodies against ApolipoproteinA-1 in Obese and Healthy Subjects
by Nicolas Vuilleumier, Sabrina Pagano, Fabrizio Montecucco, Alessandra Quercioli, Thomas H. Schindler, François Mach, Eleonora Cipollari, Nicoletta Ronda and Elda Favari
J. Clin. Med. 2019, 8(8), 1225; https://doi.org/10.3390/jcm8081225 - 15 Aug 2019
Cited by 12 | Viewed by 3284
Abstract
Aims: To explore the associations between cholesterol efflux capacity (CEC), coronary artery calcium (CAC) score, Framingham risk score (FRS), and antibodies against apolipoproteinA-1 (anti-apoA-1 IgG) in healthy and obese subjects (OS). Methods and Results: ABCA1-, ABCG1-, passive diffusion (PD)-CEC and anti-apoA-1 IgG were [...] Read more.
Aims: To explore the associations between cholesterol efflux capacity (CEC), coronary artery calcium (CAC) score, Framingham risk score (FRS), and antibodies against apolipoproteinA-1 (anti-apoA-1 IgG) in healthy and obese subjects (OS). Methods and Results: ABCA1-, ABCG1-, passive diffusion (PD)-CEC and anti-apoA-1 IgG were measured in sera from 34 controls and 35 OS who underwent CAC score determination by chest computed tomography. Anti-apoA-1 IgG ability to modulate CEC and macrophage cholesterol content (MCC) was tested in vitro. Controls and OS displayed similar ABCG1-, ABCA1-, PD-CEC, CAC and FRS scores. Logistic regression analyses indicated that FRS was the only significant predictor of CAC lesion. Overall, anti-apoA-1 IgG were significantly correlated with ABCA1-CEC (r = 0.48, p < 0.0001), PD-CEC (r = −0.33, p = 0.004), and the CAC score (r = 0.37, p = 0.03). ABCA1-CEC was correlated with CAC score (r = 0.47, p = 0.004) and FRS (r = 0.18, p = 0.29), while PD-CEC was inversely associated with the same parameters (CAC: r = −0.46, p = 0.006; FRS: score r = −0.40, p = 0.01). None of these associations was replicated in healthy controls or after excluding anti-apoA-1 IgG seropositive subjects. In vitro, anti-apoA-1 IgG inhibited PD-CEC (p < 0.0001), increased ABCA1-CEC (p < 0.0001), and increased MCC (p < 0.0001). Conclusions: We report a paradoxical positive association between ABCA1-CEC and the CAC score, with the latter being inversely associated with PD in OS. Corroborating our clinical observations, anti-apoA-1 IgG enhanced ABCA1 while repressing PD-CEC, leading to MCC increase in vitro. These results indicate that anti-apoA-1 IgG have the potential to interfere with CEC and macrophage lipid metabolism, and may underpin paradoxical associations between ABCA1-CEC and cardiovascular risk. Full article
(This article belongs to the Special Issue Novel Aspects of Lipoprotein Metabolism with Focus on Systemic Inflammation)
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11 pages, 820 KiB  
Article
Short-Term Cooling Increases Plasma ANGPTL3 and ANGPTL8 in Young Healthy Lean Men but Not in Middle-Aged Men with Overweight and Prediabetes
by Laura G.M. Janssen, Matti Jauhiainen, Vesa M. Olkkonen, P.A. Nidhina Haridas, Kimberly J. Nahon, Patrick C.N. Rensen and Mariëtte R. Boon
J. Clin. Med. 2019, 8(8), 1214; https://doi.org/10.3390/jcm8081214 - 14 Aug 2019
Cited by 8 | Viewed by 3014
Abstract
Angiopoietin-like proteins (ANGPTLs) regulate triglyceride (TG)-rich lipoprotein distribution via inhibiting TG hydrolysis by lipoprotein lipase in metabolic tissues. Brown adipose tissue combusts TG-derived fatty acids to enhance thermogenesis during cold exposure. It has been shown that cold exposure regulates ANGPTL4, but its effects [...] Read more.
Angiopoietin-like proteins (ANGPTLs) regulate triglyceride (TG)-rich lipoprotein distribution via inhibiting TG hydrolysis by lipoprotein lipase in metabolic tissues. Brown adipose tissue combusts TG-derived fatty acids to enhance thermogenesis during cold exposure. It has been shown that cold exposure regulates ANGPTL4, but its effects on ANGPTL3 and ANGPTL8 in humans have not been elucidated. We therefore investigated the effect of short-term cooling on plasma ANGPTL3 and ANGPTL8, besides ANGPTL4. Twenty-four young, healthy, lean men and 20 middle-aged men with overweight and prediabetes were subjected to 2 h of mild cooling just above their individual shivering threshold. Before and after short-term cooling, plasma ANGPTL3, ANGPTL4, and ANGPTL8 were determined by ELISA. In young, healthy, lean men, short-term cooling increased plasma ANGPTL3 (+16%, p < 0.05), ANGPTL4 (+15%, p < 0.05), and ANGPTL8 levels (+28%, p < 0.001). In middle-aged men with overweight and prediabetes, short-term cooling only significantly increased plasma ANGPTL4 levels (+15%, p < 0.05), but not ANGPTL3 (230 ± 9 vs. 251 ± 13 ng/mL, p = 0.051) or ANGPTL8 (2.2 ± 0.5 vs. 2.3 ± 0.5 μg/mL, p = 0.46). We show that short-term cooling increases plasma ANGPTL4 levels in men, regardless of age and metabolic status, but only overtly increases ANGPTL3 and ANGPTL8 levels in young, healthy, lean men. Full article
(This article belongs to the Special Issue Novel Aspects of Lipoprotein Metabolism with Focus on Systemic Inflammation)
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14 pages, 645 KiB  
Article
Non-Linear Relationship between Anti-Apolipoprotein A-1 IgGs and Cardiovascular Outcomes in Patients with Acute Coronary Syndromes
by Nicolas Vuilleumier, Sabrina Pagano, Christophe Combescure, Baris Gencer, Julien Virzi, Lorenz Räber, David Carballo, Sebastian Carballo, David Nanchen, Nicolas Rodondi, Stephan Windecker, Stanley L. Hazen, Zeneng Wang, Xinmin S. Li, Arnold von Eckardstein, Christian M. Matter, Thomas F. Lüscher, Roland Klingenberg and Francois Mach
J. Clin. Med. 2019, 8(7), 1002; https://doi.org/10.3390/jcm8071002 - 09 Jul 2019
Cited by 10 | Viewed by 2848
Abstract
Autoantibodies against apolipoprotein A-I (anti-apoA-I IgGs) are prevalent in atherosclerosis-related conditions. It remains elusive whether they improve the prognostic accuracy of the Global Registry of Acute Coronary Events (GRACE) score 2.0 (GS) in acute coronary syndromes (ACS). In this prospective multicenter registry, 1713 [...] Read more.
Autoantibodies against apolipoprotein A-I (anti-apoA-I IgGs) are prevalent in atherosclerosis-related conditions. It remains elusive whether they improve the prognostic accuracy of the Global Registry of Acute Coronary Events (GRACE) score 2.0 (GS) in acute coronary syndromes (ACS). In this prospective multicenter registry, 1713 ACS patients were included and followed for 1 year. The primary endpoint (major adverse cardiovascular events (MACE)) was defined as the composite of myocardial infarction, stroke (including transient ischemic attack), or cardiovascular (CV) death with individual events independently adjudicated. Plasma levels of anti-apoA-I IgGs upon study inclusion were assessed using ELISA. The association between anti-apoA-I IgGs and incident MACE was assessed using Cox models with splines and C-statistics. One-year MACE incidence was 8.4% (144/1713). Anti-apoA-I IgG levels were associated with MACE with a non-linear relationship (p = 0.01), which remained unchanged after adjusting for the GS (p = 0.04). The hazard increased progressively across the two first anti-apoA-I IgG quartiles before decreasing thereafter. Anti-apoA-I IgGs marginally improved the prognostic accuracy of the GS (c-statistics increased from 0.68 to 0.70). In this multicenter study, anti-apoA-I IgGs were predictive of incident MACE in ACS independently of the GS but in a nonlinear manner. The practical implications of these findings remain to be defined. Full article
(This article belongs to the Special Issue Novel Aspects of Lipoprotein Metabolism with Focus on Systemic Inflammation)
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11 pages, 606 KiB  
Article
Autoantibodies to Apolipoprotein A-1 as Independent Predictors of Cardiovascular Mortality in Renal Transplant Recipients
by Josephine L.C. Anderson, Sabrina Pagano, Julien Virzi, Robin P.F. Dullaart, Wijtske Annema, Folkert Kuipers, Stephan J.L. Bakker, Nicolas Vuilleumier and Uwe J.F. Tietge
J. Clin. Med. 2019, 8(7), 948; https://doi.org/10.3390/jcm8070948 - 29 Jun 2019
Cited by 9 | Viewed by 2188
Abstract
Renal transplant recipients (RTRs) are known to have a high cardio-vascular disease (CVD) burden only partly explained by traditional CVD risk factors. The aim of this paper was therefore to determine: i) the prognostic value of autoantibodies against apoA-1 (anti-apoA-1 IgG) for incidence [...] Read more.
Renal transplant recipients (RTRs) are known to have a high cardio-vascular disease (CVD) burden only partly explained by traditional CVD risk factors. The aim of this paper was therefore to determine: i) the prognostic value of autoantibodies against apoA-1 (anti-apoA-1 IgG) for incidence of CVD mortality, all-cause mortality and graft failure in RTR. Four hundred and sixty two (462) prospectively included RTRs were followed for 7.0 years. Baseline anti-apoA-1 IgG were determined and associations with incidence of CVD mortality (n = 48), all-cause mortality (n = 92) and graft failure (n = 39) were tested. Kaplan–Meier analyses demonstrated significant associations between tertiles of anti-apoA-1 IgG and CVD mortality (log rank test: p = 0.048). Adjusted Cox regression analysis showed a 54% increase in risk for CVD mortality for each anti-apoA-1 IgG levels standard deviation increase (hazard ratio [HR]: 1.54, 95% Confidence Interval [95%CI]: 1.14–2.05, p = 0.005), and a 33% increase for all-cause mortality (HR: 1.33; 95%CI: 1.06–1.67, p = 0.01), independent of CVD risk factors, renal function and HDL function. The association with all-cause mortality disappeared after excluding cases of CVD specific mortality. The sensitivity, specificity, positive predictive value, and negative predictive value of anti-apoA-1 positivity for CVD mortality were 18.0%, 89.3%, 17.0%, and 90.0%, respectively. HDL functionality was not associated with anti-apoA-1 IgG levels. This prospective study demonstrates that in RTR, anti-apoA-1 IgG are independent predictors of CVD mortality and are not associated with HDL functionality. Full article
(This article belongs to the Special Issue Novel Aspects of Lipoprotein Metabolism with Focus on Systemic Inflammation)
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9 pages, 892 KiB  
Article
Estimating the Level of Carbamoylated Plasma Non-High-Density Lipoproteins Using Infrared Spectroscopy
by Sigurd E. Delanghe, Sander De Bruyne, Linde De Baene, Wim Van Biesen, Marijn M. Speeckaert and Joris R. Delanghe
J. Clin. Med. 2019, 8(6), 774; https://doi.org/10.3390/jcm8060774 - 31 May 2019
Cited by 4 | Viewed by 2396
Abstract
Background: The increased cardiovascular morbidity and mortality observed in chronic kidney disease (CKD) patients can be partly explained by the presence of carbamoylated lipoproteins. Lipid profiles can be determined with infrared spectroscopy. In this paper, the effects of carbamoylation on spectral changes of [...] Read more.
Background: The increased cardiovascular morbidity and mortality observed in chronic kidney disease (CKD) patients can be partly explained by the presence of carbamoylated lipoproteins. Lipid profiles can be determined with infrared spectroscopy. In this paper, the effects of carbamoylation on spectral changes of non-high-density lipoproteins (non-HDL) were studied. Methods: In the present study, fasting serum samples were obtained from 84 CKD patients (CKD stage 3–5: n = 37 and CKD stage 5d (hemodialysis): n = 47) and from 45 healthy subjects. In vitro carbamoylation of serum lipoproteins from healthy subjects was performed using increasing concentrations of potassium cyanate. Lipoprotein-containing pellets were isolated by precipitation of non-HDL. The amount of carbamoylated serum non-HDL was estimated using attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy, followed by soft independent modelling by class analogy analysis. Results: Carbamoylation resulted in a small increase of the amide I band (1714–1589 cm−1) of the infrared spectroscopy (IR) spectrum. A significant difference in the amide II/amide I area under the curves (AUC) ratio was observed between healthy subjects and CKD patients, as well as between the two CKD groups (non-dialysis versus hemodialysis patients). Conclusions: ATR-FTIR spectroscopy can be considered as a novel method to detect non-HDL carbamoylation. Full article
(This article belongs to the Special Issue Novel Aspects of Lipoprotein Metabolism with Focus on Systemic Inflammation)
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Review

Jump to: Research

20 pages, 804 KiB  
Review
The Role of the Gut Microbiota in Lipid and Lipoprotein Metabolism
by Yijing Yu, Fitore Raka and Khosrow Adeli
J. Clin. Med. 2019, 8(12), 2227; https://doi.org/10.3390/jcm8122227 - 17 Dec 2019
Cited by 79 | Viewed by 9301
Abstract
Both environmental and genetic factors contribute to relative species abundance and metabolic characteristics of the intestinal microbiota. The intestinal microbiota and accompanying microbial metabolites differ substantially in those who are obese or have other metabolic disorders. Accumulating evidence from germ-free mice and antibiotic-treated [...] Read more.
Both environmental and genetic factors contribute to relative species abundance and metabolic characteristics of the intestinal microbiota. The intestinal microbiota and accompanying microbial metabolites differ substantially in those who are obese or have other metabolic disorders. Accumulating evidence from germ-free mice and antibiotic-treated animal models suggests that altered intestinal gut microbiota contributes significantly to metabolic disorders involving impaired glucose and lipid metabolism. This review will summarize recent findings on potential mechanisms by which the microbiota affects intestinal lipid and lipoprotein metabolism including microbiota dependent changes in bile acid metabolism which affects bile acid signaling by bile acid receptors FXR and TGR5. Microbiota changes also involve altered short chain fatty acid signaling and influence enteroendocrine cell function including GLP-1/GLP-2-producing L-cells which regulate postprandial lipid metabolism. Full article
(This article belongs to the Special Issue Novel Aspects of Lipoprotein Metabolism with Focus on Systemic Inflammation)
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12 pages, 867 KiB  
Review
Cross-Talk between Lipoproteins and Inflammation: The Role of Microvesicles
by Gemma Chiva-Blanch and Lina Badimon
J. Clin. Med. 2019, 8(12), 2059; https://doi.org/10.3390/jcm8122059 - 22 Nov 2019
Cited by 16 | Viewed by 5622
Abstract
Atherothrombosis is the principal underlying cause of cardiovascular disease (CVD). Microvesicles (MV) are small blebs originated by an outward budding at the cell plasma membranes, which are released in normal conditions. However, MV release is increased in pathophysiologic conditions such as CVD. Low [...] Read more.
Atherothrombosis is the principal underlying cause of cardiovascular disease (CVD). Microvesicles (MV) are small blebs originated by an outward budding at the cell plasma membranes, which are released in normal conditions. However, MV release is increased in pathophysiologic conditions such as CVD. Low density lipoprotein (LDL) and MV contribute to atherothrombosis onset and progression by promoting inflammation and leukocyte recruitment to injured endothelium, as well as by increasing thrombosis and plaque vulnerability. Moreover, (oxidized)LDL induces MV release and vice-versa, perpetuating endothelium injury leading to CVD progression. Therefore, MV and lipoproteins exhibit common features, which should be considered in the interpretation of their respective roles in the pathophysiology of CVD. Understanding the pathways implicated in this process will aid in developing novel therapeutic approaches against atherothrombosis. Full article
(This article belongs to the Special Issue Novel Aspects of Lipoprotein Metabolism with Focus on Systemic Inflammation)
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Graphical abstract

18 pages, 1116 KiB  
Review
IL-1β and Statin Treatment in Patients with Myocardial Infarction and Diabetic Cardiomyopathy
by Luca Liberale, Federico Carbone, Giovanni G. Camici and Fabrizio Montecucco
J. Clin. Med. 2019, 8(11), 1764; https://doi.org/10.3390/jcm8111764 - 23 Oct 2019
Cited by 22 | Viewed by 3206
Abstract
Statins are effective lipid-lowering drugs with a good safety profile that have become, over the years, the first-line therapy for patients with dyslipidemia and a real cornerstone of cardiovascular (CV) preventive therapy. Thanks to both cholesterol-related and “pleiotropic” effects, statins have a beneficial [...] Read more.
Statins are effective lipid-lowering drugs with a good safety profile that have become, over the years, the first-line therapy for patients with dyslipidemia and a real cornerstone of cardiovascular (CV) preventive therapy. Thanks to both cholesterol-related and “pleiotropic” effects, statins have a beneficial impact against CV diseases. In particular, by reducing lipids and inflammation statins, they can influence the pathogenesis of both myocardial infarction and diabetic cardiomyopathy. Among inflammatory mediators involved in these diseases, interleukin (IL)-1β is a pro-inflammatory cytokine that recently been shown to be an effective target in secondary prevention of CV events. Statins are largely prescribed to patients with myocardial infarction and diabetes, but their effects on IL-1β synthesis and release remain to be fully characterized. Of interest, preliminary studies even report IL-1β secretion to rise after treatment with statins, with a potential impact on the inflammatory microenvironment and glycemic control. Here, we will summarize evidence of the role of statins in the prevention and treatment of myocardial infarction and diabetic cardiomyopathy. In accordance with the dual lipid-lowering and anti-inflammatory effect of these drugs and in light of the important results achieved by IL-1β inhibition through canakinumab in CV secondary prevention, we will dissect the current evidence linking statins with IL-1β and outline the possible benefits of a potential double treatment with statins and canakinumab. Full article
(This article belongs to the Special Issue Novel Aspects of Lipoprotein Metabolism with Focus on Systemic Inflammation)
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21 pages, 857 KiB  
Review
HDL and LDL: Potential New Players in Breast Cancer Development
by Lídia Cedó, Srinivasa T. Reddy, Eugènia Mato, Francisco Blanco-Vaca and Joan Carles Escolà-Gil
J. Clin. Med. 2019, 8(6), 853; https://doi.org/10.3390/jcm8060853 - 14 Jun 2019
Cited by 85 | Viewed by 7039
Abstract
Breast cancer is the most prevalent cancer and primary cause of cancer-related mortality in women. The identification of risk factors can improve prevention of cancer, and obesity and hypercholesterolemia represent potentially modifiable breast cancer risk factors. In the present work, we review the [...] Read more.
Breast cancer is the most prevalent cancer and primary cause of cancer-related mortality in women. The identification of risk factors can improve prevention of cancer, and obesity and hypercholesterolemia represent potentially modifiable breast cancer risk factors. In the present work, we review the progress to date in research on the potential role of the main cholesterol transporters, low-density and high-density lipoproteins (LDL and HDL), on breast cancer development. Although some studies have failed to find associations between lipoproteins and breast cancer, some large clinical studies have demonstrated a direct association between LDL cholesterol levels and breast cancer risk and an inverse association between HDL cholesterol and breast cancer risk. Research in breast cancer cells and experimental mouse models of breast cancer have demonstrated an important role for cholesterol and its transporters in breast cancer development. Instead of cholesterol, the cholesterol metabolite 27-hydroxycholesterol induces the proliferation of estrogen receptor-positive breast cancer cells and facilitates metastasis. Oxidative modification of the lipoproteins and HDL glycation activate different inflammation-related pathways, thereby enhancing cell proliferation and migration and inhibiting apoptosis. Cholesterol-lowering drugs and apolipoprotein A-I mimetics have emerged as potential therapeutic agents to prevent the deleterious effects of high cholesterol in breast cancer. Full article
(This article belongs to the Special Issue Novel Aspects of Lipoprotein Metabolism with Focus on Systemic Inflammation)
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