Apolipoprotein A-I(R151C)Paris is defective in activation of lecithin:cholesterol acyltransferase but not in initial lipid binding, formation of reconstituted lipoproteins, or promotion of cholesterol efflux

1999 ◽  
Vol 77 (8) ◽  
pp. 614-622 ◽  
Author(s):  
Ulrike Daum ◽  
Claus Langer ◽  
Nicolas Duverger ◽  
Florence Emmanuel ◽  
Patrick Benoit ◽  
...  
Keyword(s):  
Cholesterol Efflux ◽  
Lipid Binding ◽  
Lecithin:Cholesterol Acyltransferase ◽  
Apolipoprotein A

N-homocysteinylation of apolipoprotein A-I impairs the protein’s antioxidant ability but not its cholesterol efflux capacity

2014 ◽  
Vol 395 (6) ◽  
pp. 641-648 ◽  
Author(s):  
Akari Miyazaki ◽  
Nozomi Sagae ◽  
Yoko Usami ◽  
Megumi Sato ◽  
Takahiro Kameda ◽  
...  
Keyword(s):  
Cholesterol Efflux ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipid Binding ◽  
Binding Activity ◽  
Antioxidant Ability ◽  
Wild Type ◽  
Cholesterol Efflux Capacity ◽  
Apolipoprotein A ◽  
Significant Difference

Abstract A high homocysteine (Hcy) level is a risk factor for atherosclerosis. Hcy can be added to proteins through a process known as N-homocysteinylation. This is thought to be a potential cause of atherosclerosis induction. We previously reported that N-homocysteinylated apolipoprotein A-I (N-Hcy-apoA-I) was identified in normal human plasma. In this study, the effect of N-homocysteinylation on the functions of apoA-I was examined. A kinetic study using dimyristoyl phosphatidylcholine (DMPC) liposomes indicated that N-Hcy-apoA-I showed increased lipid-binding activity compared to wild-type apoA-I. Two reconstituted high-density lipoprotein (rHDL) particles of different sizes (approximately 8.2 nm and 7.6 nm in diameter) were produced by mixing apoA-I and 1-palmitoyl-2-oleoyl phosphatidylcholine (POPC). However, an increased ratio of large to small particles was found in rHDL prepared with N-Hcy-apoA-I. The normal apoA-I antioxidant ability, estimated by the suppression of conjugated diene formation in low-density lipoprotein (LDL) induced by copper sulfate oxidation, was considerably impaired when using N-Hcy-apoA-I. Although N-Hcy-apoA-I functioned as an oxidant, no significant difference was observed in the cholesterol efflux capacity from THP-1 macrophages between wild-type apoA-I and N-Hcy-apoA-I. These results suggest that N-Hcy-apoA-I might be proatherogenic due to its oxidative behavior but not an attenuation of cholesterol efflux capacity.

scholarly journals Structure-function studies of apoA-I variants

2002 ◽  
Vol 43 (8) ◽  
pp. 1283-1292 ◽  
Author(s):  
Dmitri Sviridov ◽  
Anh Hoang ◽  
Wei Huang ◽  
Jun Sasaki
Keyword(s):  
Central Region ◽  
Binding Sites ◽  
Cholesterol Efflux ◽  
Lipid Binding ◽  
Binding Properties ◽  
Apolipoprotein A ◽  
Self Association ◽  
Rate Limiting ◽  
Lower Capacity ◽  
Combined Data

Five mutants of apolipoprotein A-I (apoA-I), apoA-I(Δ63–73), apoA-I(Δ140–150), apoA-I(63–73@140–150), apoA-I(R149V), and apoA-I(P143A) were compared with human plasma apoA-I for their ability to promote cholesterol and phospholipid efflux from HepG2 cells. A significantly lower capacity to promote cholesterol and phospholipid efflux was observed with lipid-free apoA-I(Δ63–73), while mutations apoA-I(Δ140–150) and apoA-I(P143A) affected phospholipid efflux only. When added as apoA-I/palmitoyloleoyl phosphatidylcholine (POPC) complex, mutations apoA-I(63–73@140–150) and apoA-I(Δ140–150) affected cholesterol efflux. None of the mutations affected α-helicity of the lipid-free mutants or their self-association. Five natural mutations of apoA-I, apoA-I(A95D), apoA-I (Y100H), apoA-I(E110K), apoA-I(V156E), and apoA-I (H162Q) were studied for their ability to bind lipids and promote cholesterol efflux. None of the mutations affected lipid-binding properties, cholesterol efflux, or α-helicity of lipid-free mutants. Two mutations affected self-association of apoA-I: apoA-I(A95D) was more prone to self-association, while apoA-I(E100H) did not self-associate.The following conclusions could be made from the combined data: i) regions 210–243 and 63–100 are the lipid-binding sites of apoA-I and are also required for the efflux of lipids to lipid-free apoA-I, suggesting that initial lipidation of apoA-I is rate limiting in efflux; ii) in addition to the lipid-binding regions, the central region is important for cholesterol efflux to lipidated apoA-I, suggesting its possible involvement in interaction with cells.

scholarly journals First eight residues of apolipoprotein A-I mediate the C-terminus control of helical bundle unfolding and its lipidation

2019 ◽  
Author(s):  
Gregory Brubaker ◽  
Shuhui W. Lorkowski ◽  
Kailash Gulshan ◽  
Stanley L. Hazen ◽  
Valentin Gogonea ◽  
...  
Keyword(s):  
Cholesterol Efflux ◽  
Thermal Denaturation ◽  
Point Mutations ◽  
Lipid Binding ◽  
Site Directed Mutagenesis ◽  
Amino Terminus ◽  
Helical Bundle ◽  
Apolipoprotein A ◽  
C Terminus ◽  
Bundle Structure

AbstractThe crystal structure of a C-terminal deletion of apolipoprotein A-I (apoA1) shows a large helical bundle structure in the amino half of the protein, from residues 8 to 115. Using site directed mutagenesis, guanidine or thermal denaturation, cell free liposome clearance, and cellular ABCA1-mediated cholesterol efflux assays, we demonstrate that apoA1 lipidation can occur when the barrier to this bundle unfolding is lowered. The absence of the C-terminus renders the bundle harder to unfold resulting in loss of apoA1 lipidation that can be reversed by point mutations, such as Trp8Ala, and by truncations as short as 8 residues in the amino terminus, both of which lower the barrier to helical bundle unfolding. Locking the bundle via a disulfide bond leads to loss of apoA1 lipidation. We propose a model in which the C-terminus acts on the N-terminus to destabilize helical bundle. Upon lipid binding to the C-terminus, Trp8 is displaced from its interaction with Phe57, Arg61, Leu64, Val67, Phe71, and Trp72 to destabilize the bundle. However, when the C-terminus is deleted, Trp8 cannot be displaced, the bundle cannot unfold, and apoA1 cannot be lipidated.

scholarly journals Cholesterol Efflux-Independent Modification of Lipid Rafts by AIBP (Apolipoprotein A-I Binding Protein)

2020 ◽  
Vol 40 (10) ◽  
pp. 2346-2359
Author(s):  
Hann Low ◽  
Nigora Mukhamedova ◽  
Luciano dos Santos Aggum Capettini ◽  
Yining Xia ◽  
Irena Carmichael ◽  
...  
Keyword(s):  
Lipid Rafts ◽  
Nicotinamide Adenine Dinucleotide ◽  
Metabolic Pathways ◽  
Cholesterol Efflux ◽  
Binding Protein ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Underlying Mechanism ◽  
Atp Binding Cassette Transporter ◽  
Apolipoprotein A ◽  
Phosphatidylinositol 3

Objective: AIBP (apolipoprotein A-I binding protein) is an effective and selective regulator of lipid rafts modulating many metabolic pathways originating from the rafts, including inflammation. The mechanism of action was suggested to involve stimulation by AIBP of cholesterol efflux, depleting rafts of cholesterol, which is essential for lipid raft integrity. Here we describe a different mechanism contributing to the regulation of lipid rafts by AIBP. Approach and Results: We demonstrate that modulation of rafts by AIBP may not exclusively depend on the rate of cholesterol efflux or presence of the key regulator of the efflux, ABCA1 (ATP-binding cassette transporter A-I). AIBP interacted with phosphatidylinositol 3-phosphate, which was associated with increased abundance and activation of Cdc42 and rearrangement of the actin cytoskeleton. Cytoskeleton rearrangement was accompanied with reduction of the abundance of lipid rafts, without significant changes in the lipid composition of the rafts. The interaction of AIBP with phosphatidylinositol 3-phosphate was blocked by AIBP substrate, NADPH (nicotinamide adenine dinucleotide phosphate), and both NADPH and silencing of Cdc42 interfered with the ability of AIBP to regulate lipid rafts and cholesterol efflux. Conclusions: Our findings indicate that an underlying mechanism of regulation of lipid rafts by AIBP involves PIP-dependent rearrangement of the cytoskeleton.

scholarly journals The mechanism of activation of lecithin:cholesterol acyltransferase by apolipoprotein A-I and an amphiphilic peptide.

1980 ◽  
Vol 255 (15) ◽  
pp. 7333-7339
Author(s):  
S. Yokoyama ◽  
D. Fukushima ◽  
J.P. Kupferberg ◽  
F.J. Kézdy ◽  
E.T. Kaiser
Keyword(s):  
Lecithin:Cholesterol Acyltransferase ◽  
Apolipoprotein A ◽  
Amphiphilic Peptide

Site-specific glycations of apolipoprotein A-I lead to differentiated functional effects on lipid-binding and on glucose metabolism

2018 ◽  
Vol 1864 (9) ◽  
pp. 2822-2834 ◽  
Author(s):  
Joan Domingo-Espín ◽  
Oktawia Nilsson ◽  
Katja Bernfur ◽  
Rita Del Giudice ◽  
Jens O. Lagerstedt
Keyword(s):  
Glucose Metabolism ◽  
Lipid Binding ◽  
Site Specific ◽  
Apolipoprotein A

Abstract 104: Serum from Patients with Aortic Valvular Stenosis Shows Decreased Cholesterol Efflux Capacities Despite Similar High-Density Lipoprotein Cholesterol Levels

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Benoit J Arsenault ◽  
Mathieu R Brodeur ◽  
David Rhainds ◽  
Anne-Elen Kernaleguen ◽  
Véronique Lavoie ◽  
...  
Keyword(s):  
Cholesterol Efflux ◽  
Pearson Correlation ◽  
Hdl Cholesterol ◽  
P Value ◽  
Aortic Valvular Stenosis ◽  
Cholesterol Efflux Capacity ◽  
Cholesterol Levels ◽  
Apolipoprotein A ◽  
Valvular Stenosis ◽  
Jet Velocity

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.

Non enzymatic glycation of apolipoprotein A-I. Effects on its self-association and lipid binding properties

1988 ◽  
Vol 153 (3) ◽  
pp. 1060-1067 ◽  
Author(s):  
Carlos Calvo ◽  
Corinne Talussot ◽  
Gabriel Ponsin ◽  
Francois Berthézène
Keyword(s):  
Lipid Binding ◽  
Binding Properties ◽  
Apolipoprotein A ◽  
Self Association
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