ABCC6 deficiency promotes dyslipidemia and atherosclerosis

AbstractABCC6 deficiency promotes ectopic calcification; however, circumstantial evidence suggested that ABCC6 may also influence atherosclerosis. The present study addressed the role of ABCC6 in atherosclerosis using Ldlr−/− mice and pseudoxanthoma elasticum (PXE) patients. Mice lacking the Abcc6 and Ldlr genes were fed an atherogenic diet for 16 weeks before intimal calcification, aortic plaque formation and lipoprotein profile were evaluated. Cholesterol efflux and the expression of several inflammation, atherosclerosis and cholesterol homeostasis-related genes were also determined in murine liver and bone marrow-derived macrophages. Furthermore, we examined plasma lipoproteins, vascular calcification, carotid intima-media thickness and atherosclerosis in a cohort of PXE patients with ABCC6 mutations and compared results to dysmetabolic subjects with increased cardiovascular risk. We found that ABCC6 deficiency causes changes in lipoproteins, with decreased HDL cholesterol in both mice and humans, and induces atherosclerosis. However, we found that the absence of ABCC6 does not influence overall vascular mineralization induced with atherosclerosis. Decreased cholesterol efflux from macrophage cells and other molecular changes such as increased pro-inflammation seen in both humans and mice are likely contributors for the phenotype. However, it is likely that other cellular and/or molecular mechanisms are involved. Our study showed a novel physiological role for ABCC6, influencing plasma lipoproteins and atherosclerosis in a haploinsufficient manner, with significant penetrance.

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ABCA1 increases extracellular ATP to mediate cholesterol efflux to ApoA-I

AJP Cell Physiology ◽

10.1152/ajpcell.00042.2011 ◽

2011 ◽

Vol 301 (4) ◽

pp. C886-C894 ◽

Cited By ~ 13

Author(s):

Jee Yeon Lee ◽

Joel Karwatsky ◽

Loretta Ma ◽

Xiaohui Zha

Keyword(s):

Plasma Membrane ◽

Cholesterol Efflux ◽

Molecular Mechanisms ◽

Physiological Role ◽

Extracellular Atp ◽

The Body ◽

Cholesterol Homeostasis ◽

Atp Levels ◽

Membrane Bound

ATP-binding cassette protein A1 (ABCA1) is a key plasma membrane protein required for the efflux of cellular cholesterol to extracellular acceptors, particularly to apolipoprotein A-I (apoA-I). This process is essential to maintain cholesterol homeostasis in the body. The detailed molecular mechanisms, however, are still insufficiently understood. Also, the molecular identity of ABCA1, i.e., channel, pump, or flippase, remains unknown. In this study we analyzed extracellular ATP levels in the medium of ABCA1-expressing BHK cells and RAW macrophages and compared them to the medium of nonexpressing cells. We found that extracellular ATP concentrations are significantly elevated when cells express ABCA1. Importantly, a dysfunctional ABCA1 mutant (A937V), when expressed similarly as wild-type ABCA1, is unable to raise extracellular ATP concentration, which suggests a casual relationship between functional ABCA1 and elevated extracellular ATP. To explore the physiological role of extracellular ATP, we analyzed ABCA1-mediated cholesterol efflux under conditions where extracellular ATP levels were modulated. We found that increasing extracellular ATP within the physiological range, i.e., <μM, promotes cholesterol efflux to apoA-I. On the other hand, removing extracellular ATP, either by adding apyrase to the medium or by expressing a plasma membrane-bound ectonucleotidase, CD39, abolishes cholesterol efflux to apoA-I. On the basis of these results, we conclude that, through direct or indirect mechanisms, ABCA1 functions to raise ATP levels in the medium. This elevated extracellular ATP is required for ABCA1-mediated cholesterol efflux to apoA-I.

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Rheumatoid Arthritis Impacts on the Independent Relationships between Circulating Adiponectin Concentrations and Cardiovascular Metabolic Risk

Mediators of Inflammation ◽

10.1155/2013/461849 ◽

2013 ◽

Vol 2013 ◽

pp. 1-9 ◽

Cited By ~ 5

Author(s):

Patrick H. Dessein ◽

Gavin R. Norton ◽

Margaret Badenhorst ◽

Angela J. Woodiwiss ◽

Ahmed Solomon

Keyword(s):

Rheumatoid Arthritis ◽

Risk Factors ◽

Blood Pressure ◽

Cardiovascular Risk ◽

Hdl Cholesterol ◽

Intima Media Thickness ◽

Carotid Intima Media Thickness ◽

Metabolic Risk ◽

Black African ◽

Pressure Independent

Adiponectin and leptin are likely involved in the pathophysiology of rheumatoid arthritis (RA) and therefore potential new therapeutic targets. Adiponectin inhibition could be expected to enhance cardiovascular metabolic risk. However, it is unknown whether RA changes the influence of adipokines on cardiovascular metabolic risk. We determined whether RA impacts on the independent relationships of circulating leptin and adiponectin concentrations with cardiovascular risk factors and carotid intima-media thickness (cIMT) in 277 black African subjects from a developing population; 119 had RA. RA impacted on the relationships of adiponectin concentrations with lipid concentrations and blood pressure, independent of confounders including adiposity (interactionP<0.05). This translated into an association of adiponectin concentrations with more favorable lipid variables including HDL cholesterol (P=0.0005), non-HDL cholesterol (P=0.007), and triglyceride (P=0.005) concentrations, total cholesterol-HDL cholesterol (P=0.0002) and triglycerides-HDL cholesterol (P=0.0003) ratios, and higher systolic (P=0.0006), diastolic (P=0.0004), and mean blood pressure (P=0.0007) in RA but not non-RA subjects. Leptin was not associated with metabolic risk after adjustment for adiposity. The cIMT did not differ by RA status, and adipokine concentrations were unrelated to atherosclerosis. This study suggests that leptin and adiponectin inhibition may not alter overall cardiovascular risk and disease in RA.

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Evaluation of Clinical Variables Associated with Increased Carotid Intima-Media Thickness in Middle-Aged Hypertensive Women

International Journal of Hypertension ◽

10.1155/2012/257501 ◽

2012 ◽

Vol 2012 ◽

pp. 1-6 ◽

Cited By ~ 1

Author(s):

Michelle Trindade ◽

Renata Brum Martucci ◽

Adriana K. Burlá ◽

Wille Oigman ◽

Mario Fritsch Neves ◽

...

Keyword(s):

Blood Pressure ◽

Systolic Blood Pressure ◽

Pulse Pressure ◽

Ldl Cholesterol ◽

Hdl Cholesterol ◽

Intima Media Thickness ◽

Carotid Intima Media Thickness ◽

Independent Variables ◽

Vascular Ultrasound ◽

Media Thickness

It has been previously documented that carotid intima-media thickness (cIMT) is a predictor of cardiovascular disease. The aim of this study was to identify clinical parameters associated with an increased cIMT treated hypertensive women. Female patients (n=116) with essential hypertension, aged 40–65 years, were included in this study. Vascular ultrasound was performed and the patients were divided into two groups according to the values of cIMT (< or ≥0.9 mm). Patients with greater cIMT presented significantly higher systolic blood pressure and pulse pressure. Serum HDL-cholesterol was significantly lower and CRP was significantly higher in the same group. There was a significant correlation between cIMT and age (r=0.25,P=0.007), systolic blood pressure (r=0.19,P=0.009), pulse pressure (r=0.30,P=0.001), and LDL-cholesterol (r=0.19,P=0.043). cIMT was correlated to CRP (r=0.31,P=0.007) and negatively correlated to HDL-cholesterol (r=0.33,P=0.001). In logistic regression, only HDL-cholesterol, CRP, and pulse pressure were shown to be independent variables associated to increased cIMT. In conclusion, pulse pressure, HDL-cholesterol, and CRP are variables correlated with cIMT in treated hypertensive women.

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Abstract 17913: Inhibition of CETP by Dalcetrapib Results in a Modest Increase in Cholesterol Efflux Capacity Associated With an Increase in Large HDL Particles, but Does Not Impact Carotid Intima-Media Thickness in a dal-PLAQUE-2 Substudy

Circulation ◽

10.1161/circ.130.suppl_2.17913 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

David Rhainds ◽

Marie Boule ◽

Sonia Alem ◽

Mathieu R Brodeur ◽

Daniel Charpentier ◽

...

Keyword(s):

Cardiovascular Risk ◽

Cholesterol Efflux ◽

Hdl Cholesterol ◽

Intima Media Thickness ◽

Phase Iii ◽

Plaque Burden ◽

Cholesterol Efflux Capacity ◽

Media Thickness ◽

One Year ◽

Neutral Effect

Inhibition of cholesteryl ester transfer protein (CETP) is an approach aiming at raising HDL-cholesterol levels and reducing cardiovascular risk. The dal-PLAQUE-2 phase III study recruited 988 subjects with stable coronary artery disease. Its primary objective was to evaluate the effect of dalcetrapib on the progression of carotid atherosclerotic disease measured by intima-media thickness after one year of therapy. As dalcetrapib showed a neutral effect on cardiovascular risk in the dal-OUTCOMES study, our objective was to evaluate its effect on cIMT and markers of HDL mass, lipoprotein subclass distribution and HDL function. All subjects from dal-PLAQUE-2 who had provided serum samples at baseline and one year were included in our substudy of 193 subjects on placebo and 186 subjects on dalcetrapib. Comparisons between groups at one year were made by ANCOVA after adjustment for baseline levels. No significant differences between groups for all variables considered were observed at baseline. Dalcetrapib reduced CETP activity as measured by a fluorescent method by 30% after 1 year (p<0.001), which resulted in increases in HDL-cholesterol and apoA-I levels by 32% and 11%, respectively (both p<0.001). Dalcetrapib markedly increased the concentration of large HDL particles measured by NMR profiling (+59%, p<0.001), at the expense of small HDL particles (-9.5%, p<0.001). Cholesterol efflux capacity of serum was measured from J774 macrophages under basal conditions and after cAMP stimulation. Dalcetrapib increased basal and stimulated efflux by 7.1% and 5.5% (both p<0.001), but was without effect on the ABCA1-dependent component (p=0.26). Despite these effects, dalcetrapib had no impact on mean and maximal cIMT (p=0.98 and p=0.85). While the change in cIMT was inversely correlated with basal cholesterol efflux in the placebo group (Spearman r=-0.163, p<0.05), such a relationship was not found in the dalcetrapib group. Moreover, the change in total HDL particles concentration was inversely correlated with change in cIMT (r=0.181, p<0.05) in the placebo arm only. In conclusion, dalcetrapib raised HDL-C and larger HDL, but this had minimal effects on cholesterol efflux capacity of patients’ serum and had a neutral effect on carotid artery plaque burden.

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Abstract 14477: Adolescent Lipoprotein Subclass Profile: Reference Ranges, Comparison to Adult, and Association With Carotid Intima-media Thickness

Circulation ◽

10.1161/circ.142.suppl_3.14477 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Raimund Pechlaner ◽

Nele Friedrich ◽

Anna Staudt ◽

Nina Gande ◽

Benoît Bernar ◽

...

Keyword(s):

Early Life ◽

Hdl Cholesterol ◽

Intima Media Thickness ◽

Carotid Intima Media Thickness ◽

Life Assessment ◽

Reference Ranges ◽

Lipoprotein Subclass ◽

Lipoprotein Subclasses ◽

Media Thickness ◽

Triglyceride Content

Introduction: Atherosclerosis begins in early life. Assessment of comprehensive lipoprotein subclass profiles in adolescents and their relation to atherosclerosis may enhance our understanding of the development of dyslipidemia in early life and inform early vascular prevention Hypothesis: Lipoprotein subclass profiles in adolescents are distinct from those in adults and associate with carotid intima-media thickness (cIMT). Methods: Content of lipids (cholesterol, free cholesterol, triglycerides, phospholipids) and apolipoproteins (apoB-100, apoA1, apoA2) of 17 lipoprotein subclasses (from least dense to densest: VLDL1-6, IDL, LDL1-6, HDL1-4) was measured in plasma of n=1776 14- to 19-year olds (56.6% female) and of n=3217 adults (51.5% female) by nuclear magnetic resonance. cIMT was ascertained by sonography in adolescents. Results: Adolescents compared to adults featured lower triglycerides, total, LDL, and non-HDL cholesterol, and apoB, and higher HDL cholesterol. They showed 27.2 to 60.5% lower triglyceride content of all lipoprotein subclasses and 21.7 to 50.0% lower VLDL lipid content. Concentrations of LDL-4 and LDL-5 were 40.7 to 47.3% lower, with markedly lower levels also of LDL-6 and LDL-3, but 24.3% higher HDL-1 ApoA1. In adolescents, LDL-3, LDL-4, and LDL-5 subclasses were associated with cIMT (difference in cIMT for a 1-SD higher concentration, 4.76 to 5.93μm), whereas no significant association with cIMT was observed for VLDL or HDL. Conclusions: Adolescents showed a markedly different and more favorable lipoprotein profile compared to adults. Dense LDL subclasses were the only subclasses associated with cIMT, implicating them as the potential preferred therapeutic target for primary prevention of cardiovascular disease in adolescents.

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Abstract 441: Gamma-glutamyltransferase and Markers of Subclinical Atherosclerosis in Patients with Psoriasis

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.36.suppl_1.441 ◽

2016 ◽

Vol 36 (suppl_1) ◽

Author(s):

Kenan Demircioglu ◽

Feyza Aksu ◽

Mustafa Caliskan ◽

Yusuf Yilmaz

Keyword(s):

Subclinical Atherosclerosis ◽

Density Lipoprotein ◽

Hdl Cholesterol ◽

High Sensitivity ◽

Intima Media Thickness ◽

Carotid Intima Media Thickness ◽

Control Group ◽

Gamma Glutamyltransferase ◽

Glucose Levels ◽

Hs Crp

Introduction: Gamma-glutamyltransferase(GGT) plays a catalytic role in degradation of glutathione. Serum GGT is accepted as a marker of oxidative stress.The aim of this study is to investigate the relationship between serum GGT levels and epicardial adipose tissue (EFT) thickness, carotid intima media thickness (CIMT) measurements in patients with psoriasis. Methods: The study population included 89 patients with psoriasis and 79 healthy volunteers. After overnight fasting, blood samples were taken for to determine blood glucose levels and establishing cholesterol profiles including TG, TC, LDL cholesterol and high-density lipoprotein (HDL) cholesterol; GGT; and high- sensitivity C-reaktive protein (hs-CRP) levels. A high-resolution B-mode ultrasound machine (Toshiba, aplio XU) with a 7.5 MHz linear transducer used for examing CIMT.The right common carotid artery (CCA), approximately 1 cm proximal to the bifurcation, was longitudinally selected and CIMT was defined as the distance between the intima and the media. Results: 89 patients with psoriasis (age:41.7±10.9 years;41 women, 48 men), and 71 healthy control subjects (age:40.4±8.2 years;39 women, 32 men) were included. There were no significant variation for age and sex between two groups(p>0.05).The hs-CRP and GGT values were significantly higher in psoriasis, compared with the controls (hs-CRP:1.35(0.9-3.6)mg/l for psoriasis group, 0.45(0.29-0.79)mg/l for control group, p<0.001; GGT:20.6±9.6 U/l for psoriasis group, 16.7±8.0 U/l for control group, p=0.02. In psoriatic patients, CIMT and EFT were significantly inreased (0.60(0.50-0.68)mm vs. 0.50 (0.40-0.60)mm;p=0.007, 0.67±0.20cm; 0.27±0.12cm; p<0.001, respectively) compared with the control group. CIMT significantly positively correlated with EFT, age, BMI, diastolic BP and GGT.EFT significantly positively correlated with GGT, CIMT, age, hs-CRP, systolic BP and TG and negatively correlated with HDL cholesterol. Discussion: The pathophysiology of atherosclerosis in psoriasis is not fully explained.GGT may be used as an indicator of subclinical atherosclerosis like CRP.

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LDL-cholesterol to HDL-cholesterol ratio discordance with lipid parameters and carotid intima-media thickness: a cohort study in China

Lipids in Health and Disease ◽

10.1186/s12944-020-01324-5 ◽

2020 ◽

Vol 19 (1) ◽

Author(s):

Yanmei Lou ◽

Xue Li ◽

Liming Cao ◽

Pei Qin ◽

Jing Shi ◽

...

Keyword(s):

Cohort Study ◽

Ldl Cholesterol ◽

Hdl Cholesterol ◽

Intima Media Thickness ◽

Carotid Intima Media Thickness ◽

Cholesterol Ratio ◽

Media Thickness ◽

Lipid Parameters

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Peroxisome Proliferator Activated Receptors and Lipoprotein Metabolism

PPAR Research ◽

10.1155/2008/132960 ◽

2008 ◽

Vol 2008 ◽

pp. 1-11 ◽

Cited By ~ 59

Author(s):

Sander Kersten

Keyword(s):

Lipoprotein Metabolism ◽

Physiological Role ◽

Density Lipoprotein ◽

Hdl Cholesterol ◽

Molecular Target ◽

Plasma Triglyceride ◽

Dietary Fatty Acids ◽

Plasma Lipoproteins ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptors

Plasma lipoproteins are responsible for carrying triglycerides and cholesterol in the blood and ensuring their delivery to target organs. Regulation of lipoprotein metabolism takes place at numerous levels including via changes in gene transcription. An important group of transcription factors that mediates the effect of dietary fatty acids and certain drugs on plasma lipoproteins are the peroxisome proliferator activated receptors (PPARs). Three PPAR isotypes can be distinguished, all of which have a major role in regulating lipoprotein metabolism. PPARαis the molecular target for the fibrate class of drugs. Activation of PPARαin mice and humans markedly reduces hepatic triglyceride production and promotes plasma triglyceride clearance, leading to a clinically significant reduction in plasma triglyceride levels. In addition, plasma high-density lipoprotein (HDL)-cholesterol levels are increased upon PPARαactivation in humans. PPARγis the molecular target for the thiazolidinedione class of drugs. Activation of PPARγin mice and human is generally associated with a modest increase in plasma HDL-cholesterol and a decrease in plasma triglycerides. The latter effect is caused by an increase in lipoprotein lipase-dependent plasma triglyceride clearance. Analogous to PPARα, activation of PPARβ/δleads to increased plasma HDL-cholesterol and decreased plasma triglyceride levels. In this paper, a fresh perspective on the relation between PPARs and lipoprotein metabolism is presented. The emphasis is on the physiological role of PPARs and the mechanisms underlying the effect of synthetic PPAR agonists on plasma lipoprotein levels.

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