Evidence for the presence of lipid-free monomolecular apolipoprotein A-1 in plasma

Miyazaki, Osamu; Ogihara, Jun; Fukamachi, Isamu; Kasumi, Takafumi

doi:10.1194/jlr.m041038

Cited by 35 publications

(28 citation statements)

References 50 publications

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“…These factors might inadvertently introduce changes in HDL composition. However, HDL obtained by ultracentrifugation also has its limitations — for example, ultracentrifugation methods that limit HDL density to 1.21 g/ml will not accurately represent the contribution of pre-β HDL (HDL-VS) that is found in the density range 1.21–1.25 g/ml 84 . No data are available to suggest that one assay might be more physiologically relevant or better than the other for assessing the cellular cholesterol efflux activity of HDL.…”

Section: Hdl Functionality and Atherosclerosismentioning

confidence: 99%

Dysfunctional HDL and atherosclerotic cardiovascular disease

et al. 2015

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High-density lipoproteins (HDLs) protect against atherosclerosis by removing excess cholesterol from macrophages through the ATP-binding cassette transporter A1 (ABCA1) and ATP-binding cassette transporter G1 (ABCG1) pathways involved in reverse cholesterol transport. Factors that impair the availability of functional apolipoproteins or the activities of ABCA1 and ABCG1 could, therefore, strongly influence atherogenesis. HDL also inhibits lipid oxidation, restores endothelial function, exerts anti-inflammatory and antiapoptotic actions, and exerts anti-inflammatory actions in animal models. Such properties could contribute considerably to the capacity of HDL to inhibit atherosclerosis. Systemic and vascular inflammation has been proposed to convert HDL to a dysfunctional form that has impaired antiatherogenic effects. A loss of anti-inflammatory and antioxidative proteins, perhaps in combination with a gain of proinflammatory proteins, might be another important component in rendering HDL dysfunctional. The proinflammatory enzyme myeloperoxidase induces both oxidative modification and nitrosylation of specific residues on plasma and arterial apolipoprotein A-I to render HDL dysfunctional, which results in impaired ABCA1 macrophage transport, the activation of inflammatory pathways, and an increased risk of coronary artery disease. Understanding the features of dysfunctional HDL or apolipoprotein A-I in clinical practice might lead to new diagnostic and therapeutic approaches to atherosclerosis.

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Section: Hdl Functionality and Atherosclerosismentioning

confidence: 99%

Dysfunctional HDL and atherosclerotic cardiovascular disease

et al. 2015

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“…Nearly 95% of all circulating apoA-I is bound to HDL, yet a small fraction is released in a transient lipid-poor/free state (termed free for brevity) that can carry several lipid molecules and is labile to aggregation [8-11]. Free apoA-I can rapidly bind to the existing HDL or generate HDL de novo ; alternatively, free apolipoprotein can be either catabolized or get misfolded in amyloid [3,8,9].…”

Section: Introductionmentioning

confidence: 99%

Triglyceride increase in the core of high-density lipoproteins augments apolipoprotein dissociation from the surface: Potential implications for treatment of apolipoprotein deposition diseases

Jayaraman

Sánchez-Quesada²,

Gursky

2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Lipids in the body are transported via lipoproteins that are nanoparticles comprised of lipids and amphipathic proteins termed apolipoproteins. This family of lipid surface-binding proteins is over-represented in human amyloid diseases. In particular, all major proteins of high-density lipoproteins (HDL), including apoA-I, apoA-II and serum amyloid A, can cause systemic amyloidoses in humans upon protein mutations, post-translational modifications or overproduction. Here, we begin to explore how the HDL lipid composition influences amyloid deposition by apoA-I and related proteins. First, we summarize the evidence that, in contrast to lipoproteins that are stabilized by kinetic barriers, free apolipoproteins are labile to misfolding and proteolysis. Next, we report original biochemical and biophysical studies showing that increase in triglyceride content in the core of plasma or reconstituted HDL destabilizes the lipoprotein assembly, making it more labile to various perturbations (oxidation, thermal and chemical denaturation and enzymatic hydrolysis), and promotes apoA-I release in a lipid-poor/free aggregation-prone form. Together, the results suggest that decreasing plasma levels of triglycerides will shift the dynamic equilibrium from the lipid-poor/free (labile) to the HDL-bound (protected) apolipoprotein state, thereby decreasing the generation of the protein precursor of amyloid. This prompts us to propose that triglyceride-lowering therapies may provide a promising strategy to alleviate amyloid diseases caused by the deposition of HDL proteins.

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“…A speculative mechanism for the increase in pre-β1-HDL is outlined in Figure 7, suggesting that on fusion of MDCO-216 with the small HDL particles a substantial part of apoA-I WT is displaced from the fusion partners and seems as free apoA-I or pre-β1-HDL. As described by Miyazaki et al, 16 the Mab, developed for quantitation of pre-β1-HDL as used in this study, likely reacts with free apoA-I. These changes also occur when MDCO-216 is incubated at 37°C with plasma or serum in vitro, 14 suggesting that they are completely physicochemical in nature.…”

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confidence: 99%

High-Density Lipoprotein Subfractions and Cholesterol Efflux Capacities After Infusion of MDCO-216 (Apolipoprotein A-IMilano/Palmitoyl-Oleoyl-Phosphatidylcholine) in Healthy Volunteers and Stable Coronary Artery Disease Patients

Kempen

Asztalos

Moerland

et al. 2016

ATVB

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More recently this complex (now called MDCO-216 after improvements related to purity and yield in the manufacturing process) was shown to strongly enhance ATP-binding cassette transporter A1 (ABCA1)-mediated cholesterol efflux capacity after drug infusion in cynomolgus monkeys 12 and in humans. Objective-To determine effects of single ascending doses of MDCO-216 on high-density lipoprotein (HDL) subfractions in relation to changes in cholesterol efflux capacity in healthy volunteers and in patients with stable angina pectoris. Approach and Results-Doses of 5-(in volunteers only), 10-, 20-, 30-, and 40-mg/kg MDCO-216 were infused during 2 hours, and plasma and serum were collected during 30 days. Plasma levels of HDL subfractions were assessed by 2-dimensional gel electrophoresis, immunoblotting, and image analysis. Lipoprotein particle concentrations and sizes were also assessed by proton nuclear magnetic resonance ( 1 H-NMR). There was a rapid dose-dependent increase of total apolipoprotein A-I (apoA-I) in pre-β1, α-1, and α-2 HDL levels and decrease in α-3 and α-4 HDL. Using a selective antibody apoA-IMilano was detected in the large α-1 and α-2 HDL on all doses and at each time point. ApoA-IMilano was also detected at the α-4 position but only at high doses. 1 H-NMR analysis similarly showed a rapid and dosedependent shift from small-to large-sized HDL particles. The increase of basal and ATP-binding cassette transporter A1-mediated efflux capacities reported previously correlated strongly and independently with the increase in pre-β1-HDL and α-1 HDL, but not with that in α-2 HDL. Conclusions-On infusion, MDCO-216 rapidly eliminates small HDL and leads to formation of α-1 and α-2 HDL containing both wild-type apoA-I and apoA-IMilano. In this process, endogenous apoA-I is liberated appearing as pre-β1-HDL. In addition to pre-β1-HDL, the newly formed α-1 HDL particle containing apoA-I Milano may have a direct effect on cholesterol efflux capacity. Kempen et al HDL Remodeling and Cholesterol Efflux Capacity 737We recently demonstrated that short incubation of MDCO-216 with whole human serum or plasma at 37°C led to a rapid increase in pre-β1, α-1, and α-2 HDL and a decrease in α-3 and α-4 HDL. In parallel, ABCA1-mediated cholesterol efflux capacity was synergistically increased, that is, the increase was greater than the sum of the increases caused by MDCO-216 alone or by serum alone. 14 This article reports the effects on HDL subfractions after MDCO-216 infusion in healthy volunteers and in patients with coronary artery disease (CAD), measured by immunoblotting after 2-dimensional (2D)-PAGE as well as by proton nuclear magnetic resonance ( 1 H-NMR). A marked and prompt increase of pre-β1-HDL was found by 2D-PAGE, whereas both methods showed an increase in larger (α-1 and α-2) HDL particle concentration and decrease in smaller (α-3 and α-4) HDL particles, similar to what was seen after in vitro incubation.14 The increase in pre-β1 and α-1 HDL both correlated independently with the increase in basal and ABCA1-me...

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Evidence for the presence of lipid-free monomolecular apolipoprotein A-1 in plasma

Cited by 35 publications

References 50 publications

Dysfunctional HDL and atherosclerotic cardiovascular disease

Dysfunctional HDL and atherosclerotic cardiovascular disease

Triglyceride increase in the core of high-density lipoproteins augments apolipoprotein dissociation from the surface: Potential implications for treatment of apolipoprotein deposition diseases

High-Density Lipoprotein Subfractions and Cholesterol Efflux Capacities After Infusion of MDCO-216 (Apolipoprotein A-IMilano/Palmitoyl-Oleoyl-Phosphatidylcholine) in Healthy Volunteers and Stable Coronary Artery Disease Patients

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