Genetic Determination of Plasma Cholesterol Efflux Capacity Is Gender-Specific and Independent of HDL-Cholesterol Levels

Background: Studies have shown that low HDL-cholesterol levels may be associated with the progression of aortic valvular calcium and aortic valvular stenosis (AVS), but whether patients with AVS have impaired cholesterol efflux capacities is unknown. Methods and results: We have measured four parameters of cholesterol efflux capacity in apolipoprotein B-depleted serum samples from 48 patients with (aortic jet velocity ≥2.5 m/s, mean age = 72 ± 7 years and 72.7% men) and 51 patients without AVS (aortic jet velocity ≤ 1.7 m/s, mean age 71 ± 7 years and 70.6% men). Cholesterol efflux capacity was measured using J774 macrophages with and without stimulation of ABCA1 expression by cAMP (non-stimulated efflux, total efflux and ABCA1-mediated efflux), and HepG2 hepatocytes to measure SR-BI-mediated efflux. Mean HDL-cholesterol and apolipoprotein A-I levels as well as efflux are shown in the table for patients with vs. without AVS. The Pearson correlation coefficient between HDL-cholesterol levels and SR-B1-dependent efflux was 0.39 (p=0.007) in patients with AVS and 0.68 (<0.0001) in controls (P-value for the difference between the correlation coefficients obtained with Fisher’s test = 0.04). Conclusions: This study provides evidence that serum from patients with AVS may have impaired cholesterol efflux capacities, especially through the SR-B1 pathway. Table. Mean HDL-cholesterol and apolipoprotein A-I levels as well as non-stimulated-, total-, ABCA1-, and SR-B1-dependent cholesterol efflux obtained from patients’ serum with vs. without AVS. Data is shown as mean ± SD. Differences between categories were assessed using a Student unpaired t-test.

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A loss-of-function variant in OSBPL1A predisposes to low plasma HDL cholesterol levels and impaired cholesterol efflux capacity

Atherosclerosis ◽

10.1016/j.atherosclerosis.2016.04.005 ◽

2016 ◽

Vol 249 ◽

pp. 140-147 ◽

Cited By ~ 12

Author(s):

Mahdi M. Motazacker ◽

Juho Pirhonen ◽

Julian C. van Capelleveen ◽

Marion Weber-Boyvat ◽

Jan Albert Kuivenhoven ◽

...

Keyword(s):

Cholesterol Efflux ◽

Hdl Cholesterol ◽

Loss Of Function ◽

Cholesterol Efflux Capacity ◽

Cholesterol Levels

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A loss-of-function variant in OSBPL1A predisposes to low plasma HDL cholesterol levels and impaired cholesterol efflux capacity

Atherosclerosis ◽

10.1016/j.atherosclerosis.2016.07.088 ◽

2016 ◽

Vol 252 ◽

pp. e259-e260

Author(s):

J. van Capelleveen ◽

J. Pirhonen ◽

M.M. Motazacker ◽

M. Weber-Boyvat ◽

M. Jauhiainen ◽

...

Keyword(s):

Cholesterol Efflux ◽

Hdl Cholesterol ◽

Loss Of Function ◽

Cholesterol Efflux Capacity ◽

Cholesterol Levels

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INHERITANCE OF PLASMA CHOLESTEROL LEVELS IN MICE

Genetics ◽

10.1093/genetics/73.2.303 ◽

1973 ◽

Vol 73 (2) ◽

pp. 303-312

Author(s):

Robert S Weibust

Keyword(s):

Age Differences ◽

Plasma Cholesterol ◽

Inbred Strains ◽

Genetic Determination ◽

Cholesterol Levels ◽

Strain Data ◽

Cumulative Selection ◽

Selection For ◽

Sex And Age Differences

ABSTRACT Mean plasma cholesterol levels were determined at two ages in mice from eight unrelated inbred strains (BALB/cJ, BDP/J, CBA/J, C57BL/6J, LP/J, RF/J, SJL/J, and 129/J). Significant strain, sex, and age differences were observed. Estimates of the degree of genetic determination of the trait obtained from an analysis of the strain data averaged 58 ± 4% for the males and 54 ± 8% for the females.—Selection for high and low plasma cholesterol levels produced two significantly different and distinct lines. Selection was initiated in a genetically heterogeneous population derived from an eight-way cross of the inbred strains listed above. After five generations of selection the divergence of the high and low lines amounted to 4 phenotypic standard deviations of the foundation population. Realized heritability estimated from the regression of divergence on the combined cumulative selection differential was 51 ± 5% for the males and 50 ± 3% for the females. The results indicate that genetic factors are important in controlling plasma cholesterol levels in the mouse and that the majority of these factors act additively.

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Abstract 433: Liver Disease Alters HDL Metabolism and Function

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.36.suppl_1.433 ◽

2016 ◽

Vol 36 (suppl_1) ◽

Author(s):

Markus Trieb ◽

Angela Horvath ◽

Vanessa Stadlbauer ◽

Ulrike Taschler ◽

Sanja Curcic ◽

...

Keyword(s):

Gel Electrophoresis ◽

Cholesterol Efflux ◽

Hdl Cholesterol ◽

Paraoxonase Activity ◽

Cholesterol Efflux Capacity ◽

Cholesterol Levels ◽

Hdl Function ◽

Cirrhotic Patients ◽

Native Gel ◽

Hdl Metabolism

Background/Aims: High-density lipoproteins (HDLs) are important endogenous inhibitors of inflammatory responses. Dysfunctional HDL might contribute to the serious complications experienced by patients with acute and chronic liver failure, but the effect of cirrhosis on several metrics of HDL function is not understood. Methods: We measured metrics of HDL function in an explorative cross sectional study of 59 patients with compensated cirrhosis, 21 patients with acutely decompensated cirrhosis and 20 healthy controls. HDL particle size was assessed using native gel electrophoresis. HDL cholesterol efflux potential was assessed using [ 3 H]-cholesterol labeled macrophages. Paraoxonase activity was determined by photometry using phenylacetate as substrate. Nuclear factor-κB activation in monocytes and cytokines were assessed by flow cytometry. Endothelial regenerative activity was determined using an electric cell-substrate impedance sensing system. Results: Sera of cirrhotic patients showed low HDL-cholesterol levels and profoundly suppressed activities of several serum enzymes involved in HDL maturation and metabolism. Native gel electrophoresis analyses revealed that cirrhotic HDL shifts toward the larger HDL 2 subclass. We observed that (i) HDL cholesterol efflux capability, (ii) paraoxonase activity, (iii) the ability to inhibit monocyte production of pro-inflammatory cytokines and (iv) endothelial regenerative activities were significantly reduced in stable cirrhotic patients, and markedly suppressed in acutely decompensated patients. Of particular interest, HDL cholesterol efflux capacity appeared to be strongly associated with mortality of cirrhotic patients, independently of HDL cholesterol levels. Conclusion: Cirrhosis affects HDL metabolism and several metrics of HDL function. HDL cholesterol efflux capacity appears to predict 1-year mortality independent of HDL-cholesterol levels.

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High Density Lipoprotein Cholesterol Efflux Capacity and Atherosclerosis in Cardiovascular Disease: Pathophysiological Aspects and Pharmacological Perspectives

Cells ◽

10.3390/cells10030574 ◽

2021 ◽

Vol 10 (3) ◽

pp. 574

Author(s):

Maria Pia Adorni ◽

Nicoletta Ronda ◽

Franco Bernini ◽

Francesca Zimetti

Keyword(s):

High Density Lipoprotein ◽

Cholesterol Efflux ◽

Current Knowledge ◽

Density Lipoprotein ◽

Hdl Cholesterol ◽

High Density ◽

Current Evidence ◽

Endocrine Disorders ◽

Lifestyle Modifications ◽

Cholesterol Efflux Capacity

Over the years, the relationship between high-density lipoprotein (HDL) and atherosclerosis, initially highlighted by the Framingham study, has been revealed to be extremely complex, due to the multiple HDL functions involved in atheroprotection. Among them, HDL cholesterol efflux capacity (CEC), the ability of HDL to promote cell cholesterol efflux from cells, has emerged as a better predictor of cardiovascular (CV) risk compared to merely plasma HDL-cholesterol (HDL-C) levels. HDL CEC is impaired in many genetic and pathological conditions associated to high CV risk such as dyslipidemia, chronic kidney disease, diabetes, inflammatory and autoimmune diseases, endocrine disorders, etc. The present review describes the current knowledge on HDL CEC modifications in these conditions, focusing on the most recent human studies and on genetic and pathophysiologic aspects. In addition, the most relevant strategies possibly modulating HDL CEC, including lifestyle modifications, as well as nutraceutical and pharmacological interventions, will be discussed. The objective of this review is to help understanding whether, from the current evidence, HDL CEC may be considered as a valid biomarker of CV risk and a potential pharmacological target for novel therapeutic approaches.

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Antibodies Against the C-Terminus of ApoA-1 Are Inversely Associated with Cholesterol Efflux Capacity and HDL Metabolism in Subjects with and without Type 2 Diabetes Mellitus

International Journal of Molecular Sciences ◽

10.3390/ijms20030732 ◽

2019 ◽

Vol 20 (3) ◽

pp. 732 ◽

Cited By ~ 4

Author(s):

Robin Dullaart ◽

Sabrina Pagano ◽

Frank Perton ◽

Nicolas Vuilleumier

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Apolipoprotein B ◽

Cholesterol Efflux ◽

Hdl Cholesterol ◽

Enzyme Linked Immunosorbent Assay ◽

Cholesterol Efflux Capacity ◽

C Terminus

Background: We determined relationships of cholesterol efflux capacity (CEC), plasma cholesterol esterification (EST) and cholesteryl ester transfer (CET) with anti-c-terminus apoA-1 (Ac-terAA1) and anti-apolipoprotein (apo)-1 (AAA1) autoantibodies in subjects with and without Type 2 diabetes mellitus (T2D). Methods: In 75 T2D subjects and 75 nondiabetic subjects, Ac-terAA1 and AAA1 plasma levels were measured by enzyme-linked immunosorbent assay. CEC was measured as [3H]-cholesterol efflux from human cultured fibroblasts to diluted individual subject plasma. Plasma EST and CET were assayed by isotope methods. Results: Ac-terAA1 and AAA1 levels and were similar between T2D and control subjects. Univariate regression analysis (n = 150) demonstrated that Ac-terAA1 levels were inversely correlated with CEC, EST, CET, total cholesterol, non-HDL cholesterol, triglycerides and apolipoprotein B, (p < 0.05 to p < 0.01), but not with glucose and HbA1c. In separate multivariable linear regression models, CEC, EST and CET were inversely associated with Ac-terAA1 levels independently of age, sex, T2D and drug use (β = −0.186, p = 0.026; β = −0.261, p < 0.001; and β = −0.321, p < 0.001; respectively). These associations were lost after additional adjustment for non-HDL cholesterol and triglycerides. No associations were observed for AAA1. Conclusions: CEC, plasma EST and CET are inversely associated with Ac-terAA1 autoantibodies, conceivably attributable to an inverse relationship of these autoantibodies with apolipoprotein B-containing lipoproteins.

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Impaired hdl cholesterol efflux capacity during development of pacing-induced heart failure in minipig

Atherosclerosis ◽

10.1016/j.atherosclerosis.2015.04.118 ◽

2015 ◽

Vol 241 (1) ◽

pp. e32

Author(s):

F. Bigazzi ◽

M.P. Adorni ◽

M. Puntoni ◽

F. Sbrana ◽

V. Lionetti ◽

...

Keyword(s):

Heart Failure ◽

Cholesterol Efflux ◽

Hdl Cholesterol ◽

Cholesterol Efflux Capacity

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A Novel Mutant, ApoA-I Nichinan (Glu235→0), Is Associated With Low HDL Cholesterol Levels and Decreased Cholesterol Efflux From Cells

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/01.atv.19.6.1447 ◽

1999 ◽

Vol 19 (6) ◽

pp. 1447-1455 ◽

Cited By ~ 25

Author(s):

Hua Han ◽

Jun Sasaki ◽

Akira Matsunaga ◽

Hideki Hakamata ◽

Wei Huang ◽

...

Keyword(s):

Cholesterol Efflux ◽

Hdl Cholesterol ◽

Cholesterol Levels ◽

Low Hdl

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Abstract 226: Serum Amyloid A Isoforms and the Capacity to Mediate Cholesterol Efflux

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.34.suppl_1.226 ◽

2014 ◽

Vol 34 (suppl_1) ◽

Author(s):

Hussein Yassine ◽

Olgica Trenchevska ◽

Chad Borges ◽

Dobrin Nedelkov ◽

Randall W Nelson ◽

...

Keyword(s):

Cholesterol Efflux ◽

Serum Amyloid A ◽

Hdl Cholesterol ◽

Acute Phase Reactant ◽

Serum Amyloid ◽

Amyloid A ◽

Cholesterol Levels ◽

Acute Phase Reactant Protein

Serum Amyloid A (SAA) is an acute phase reactant protein that exists in multiple isoforms, can form HDL, and participates in cholesterol efflux. In vitro studies suggest that the SAA 2.1 isoform has an increased capacity to mediate cholesterol efflux compared to the other isoforms. We examined SAA isoforms using a novel mass spectrometric immunoassay (MSIA) and HDL’s cholesterol efflux capacity (via ABCA-1 and SR-BI) in samples from 59 subjects with (n=33) and without type 2 diabetes (n=26). SAA 1.1 levels were detectable in 58, SAA 2.1 in 14 and SAA 2.2 in 36 of the 59 subjects. SAA 2.1 levels significantly correlated with SR-BI cholesterol efflux (r=0.71, p=0.01, n=14), but not ABCA-1 mediated efflux (r=0.1, P=0.1). This correlation was not explained by changes in HDL phospholipids, Apo A-I or HDL cholesterol levels. In contrast, SAA 2.2 or 1.1 levels did not correlate with changes in SR-BI or ABCA-1 mediated efflux. Although the SAA 2.1 isoform is less frequently detected in plasma, our data confirm that it is closely linked with HDL mediated cholesterol efflux, particularly that is SR-BI mediated.

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