Apolipoprotein A-1 binding protein promotes macrophage cholesterol efflux by facilitating apolipoprotein A-1 binding to ABCA1 and preventing ABCA1 degradation

2016 ◽  
Vol 248 ◽  
pp. 149-159 ◽  
Author(s):  
Min Zhang ◽  
Liang Li ◽  
Wei Xie ◽  
Jian-Feng Wu ◽  
Feng Yao ◽  
...  
Keyword(s):  
Cholesterol Efflux ◽  
Binding Protein ◽  
Apolipoprotein A ◽  
Macrophage Cholesterol Efflux

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.

Abstract 260: Apolipoprotein A-I Binding Protein Regulates Macrophage Polarization in Atherosclerosis

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Dina A Schneider ◽  
Longhou Fang ◽  
Yury I Miller
Keyword(s):  
Lipid Rafts ◽  
Lipid Accumulation ◽  
Cholesterol Efflux ◽  
Binding Protein ◽  
Macrophage Polarization ◽  
Atherosclerotic Lesion ◽  
Negative Regulator ◽  
High Cholesterol Diet ◽  
Apolipoprotein A ◽  
M1 Macrophage

Our laboratory recently demonstrated that Apolipoprotein A-I Binding Protein (AIBP), an evolutionarily conserved intracellular and secreted protein, mediates cholesterol efflux from endothelial cells, which in turn disrupts lipid rafts and limits angiogenic signaling. Since lipid rafts are implicated in multiple cell signal cascades, to better understand the in vivo role of AIBP our laboratory has generated Apoa1bp -/- mice. The Apoa1bp -/- mice exhibit increased levels of inflammatory cytokines, and have an increased content of M1 macrophages in white adipose tissue in comparison to wild type mice when challenged with a high fat diet. Since AIBP accelerates cholesterol efflux from macrophages to HDL, and vascular lipid accumulation and inflammation are key factors in atherosclerosis, we hypothesized that AIBP is atheroprotective by suppressing macrophage lipid accumulation and inflammatory M1 macrophage polarization. Immunohistochemistry shows that AIBP is present in atherosclerotic lesion macrophages. However, elicited macrophages lacking AIBP expression do not exhibit any impairment in their ability to polarize to M1, suggesting that deficiency in secreted extracellular AIBP may be responsible for the M1 phenotype observed in Apoa1bp -/- mice. Indeed, treating macrophages with recombinant AIBP prior to polarization resulted in suppression of M1 polarization. In a high-cholesterol diet feeding experiment, Apoa1bp -/- Ldlr -/- mice had increased M1 macrophage content in their aorta and aortic root atherosclerotic lesions, as determined by FACS and immunohistochemistry, respectively. In conclusion, AIBP is an important negative regulator of macrophage polarization and lipid accumulation. A better understanding of AIBP’s regulatory functions in the context of atherosclerosis will provide new mechanistic insights and targeted therapies.

scholarly journals Biochemical and Structural Characterization of Apolipoprotein A-I Binding Protein, a Novel Phosphoprotein with a Potential Role in Sperm Capacitation

Endocrinology ◽  
2008 ◽  
Vol 149 (5) ◽  
pp. 2108-2120 ◽  
Author(s):  
Kula N. Jha ◽  
Igor A. Shumilin ◽  
Laura C. Digilio ◽  
Olga Chertihin ◽  
Heping Zheng ◽  
...  
Keyword(s):  
Cholesterol Efflux ◽  
Reproductive Tract ◽  
Binding Protein ◽  
Protein A ◽  
Density Lipoprotein ◽  
Female Reproductive Tract ◽  
Apolipoprotein A ◽  
The Media

The physiological changes that sperm undergo in the female reproductive tract rendering them fertilization-competent constitute the phenomenon of capacitation. Cholesterol efflux from the sperm surface and protein kinase A (PKA)-dependent phosphorylation play major regulatory roles in capacitation, but the link between these two phenomena is unknown. We report that apolipoprotein A-I binding protein (AI-BP) is phosphorylated downstream to PKA activation, localizes to both sperm head and tail domains, and is released from the sperm into the media during in vitro capacitation. AI-BP interacts with apolipoprotein A-I, the component of high-density lipoprotein involved in cholesterol transport. The crystal structure demonstrates that the subunit of the AI-BP homodimer has a Rossmann-like fold. The protein surface has a large two compartment cavity lined with conserved residues. This cavity is likely to constitute an active site, suggesting that AI-BP functions as an enzyme. The presence of AI-BP in sperm, its phosphorylation by PKA, and its release during capacitation suggest that AI-BP plays an important role in capacitation possibly providing a link between protein phosphorylation and cholesterol efflux.

The Anti-Atherogenic Properties of Sesamin are Mediated via Improved Macrophage Cholesterol Efflux Through PPARγ1-LXRα and MAPK Signaling

2014 ◽  
Vol 84 (1-2) ◽  
pp. 79-91 ◽  
Author(s):  
Amin F. Majdalawieh ◽  
Hyo-Sung Ro
Keyword(s):  
Cholesterol Efflux ◽  
Transcriptional Activity ◽  
Molecular Mechanisms ◽  
Foam Cell ◽  
Mapk Signaling ◽  
Luciferase Reporter ◽  
Foam Cell Formation ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Macrophage Cholesterol Efflux

Background: Foam cell formation resulting from disrupted macrophage cholesterol efflux, which is triggered by PPARγ1 and LXRα, is a hallmark of atherosclerosis. Sesamin and sesame oil exert anti-atherogenic effects in vivo. However, the exact molecular mechanisms underlying such effects are not fully understood. Aim: This study examines the potential effects of sesamin (0, 25, 50, 75, 100 μM) on PPARγ1 and LXRα expression and transcriptional activity as well as macrophage cholesterol efflux. Methods: PPARγ1 and LXRα expression and transcriptional activity are assessed by luciferase reporter assays. Macrophage cholesterol efflux is evaluated by ApoAI-specific cholesterol efflux assays. Results: The 50 μM, 75 μM, and 100 μM concentrations of sesamin up-regulated the expression of PPARγ1 (p< 0.001, p < 0.001, p < 0.001, respectively) and LXRα (p = 0.002, p < 0.001, p < 0.001, respectively) in a concentration-dependent manner. Moreover, 75 μM and 100 μM concentrations of sesamin led to 5.2-fold (p < 0.001) and 6.0-fold (p<0.001) increases in PPAR transcriptional activity and 3.9-fold (p< 0.001) and 4.2-fold (p < 0.001) increases in LXR transcriptional activity, respectively, in a concentration- and time-dependent manner via MAPK signaling. Consistently, 50 μM, 75 μM, and 100 μM concentrations of sesamin improved macrophage cholesterol efflux by 2.7-fold (p < 0.001), 4.2-fold (p < 0.001), and 4.2-fold (p < 0.001), respectively, via MAPK signaling. Conclusion: Our findings shed light on the molecular mechanism(s) underlying sesamin’s anti-atherogenic effects, which seem to be due, at least in part, to its ability to up-regulate PPARγ1 and LXRα expression and transcriptional activity, improving macrophage cholesterol efflux. We anticipate that sesamin may be used as a therapeutic agent for treating atherosclerosis.

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