scholarly journals Proteasomal Inhibition Promotes ATP-Binding Cassette Transporter A1 (ABCA1) and ABCG1 Expression and Cholesterol Efflux From Macrophages In Vitro and In Vivo

2011 ◽  
Vol 31 (9) ◽  
pp. 1980-1987 ◽  
Author(s):  
Masatsune Ogura ◽  
Makoto Ayaori ◽  
Yoshio Terao ◽  
Tetsuya Hisada ◽  
Maki Iizuka ◽  
...  
Keyword(s):  
Cholesterol Efflux ◽  
Atp Binding ◽  
Atp Binding Cassette Transporter ◽  
Proteasomal Inhibition ◽  
Atp Binding Cassette

Study of ATP-binding Cassette Transporter A1 (ABCA1)-mediated Cellular Cholesterol Efflux in Diabetic Golden Hamsters

2007 ◽  
Vol 35 (4) ◽  
pp. 508-516 ◽  
Author(s):  
Y Zhu ◽  
H-J Wang ◽  
L-F Chen ◽  
Q Fang ◽  
X-W Yan
Keyword(s):  
Cholesterol Efflux ◽  
Adenosine Monophosphate ◽  
Peritoneal Macrophages ◽  
Atp Binding ◽  
Cellular Cholesterol ◽  
Golden Hamsters ◽  
Atp Binding Cassette Transporter ◽  
Cellular Cholesterol Efflux ◽  
Atp Binding Cassette

The effects of cyclic adenosine monophosphate (cAMP) and atorvastatin on macrophage adenosine triphosphate (ATP)-binding cassette transporter A1 (ABCA1)-mediated cholesterol efflux were investigated in a diabetic animal model. Golden hamsters were fed a high-fat diet which resulted in insulin resistance. Diabetes was induced by a single intraperitoneal injection of streptozotocin (30 mg/kg). Normal golden hamsters were used as controls. Peritoneal macrophages were incubated with apolipoprotein A-1 (apoA-1), 8-bromoadenosine-3′,5′-cyclic monophosphate (8-br-cAMP), and atorvastatin in vitro Intracellular cholesterol accumulation was greater in the diabetic animals than in the insulin-resistant animals. Expression of ABCA1 mRNA in macrophages from diabetic animals was upregulated by 8-br-cAMP and atorvastatin. ApoA-1 caused a time-dependent cellular cholesterol efflux. Both atorvastatin and 8-br-cAMP significantly facilitated ABCA1-mediated cellular cholesterol efflux, with the maximal cholesterol efflux rate observed in the macrophages from diabetic animals. Accumulation of cholesterol in the macrophages of diabetic animals can be significantly alleviated by atorvastatin or 8-br-cAMP through improving ABCA1-mediated cellular cholesterol efflux.

scholarly journals ATP-binding cassette transporter Abcg2 lineage contributes to the cardiac vasculature after oxidative stress

2014 ◽  
Vol 306 (12) ◽  
pp. H1610-H1618 ◽  
Author(s):  
Travis J. Maher ◽  
Yi Ren ◽  
Qinglu Li ◽  
Elizabeth Braunlin ◽  
Mary G. Garry ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Immunohistochemical Analysis ◽  
Atp Binding ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Systemic Oxidative Stress ◽  
Atp Binding Cassette Transporter ◽  
Atp Binding Cassette

Due to their specialized location, stem and progenitor cells are often exposed to oxidative stress. Although ATP-binding cassette transporter subfamily G member 2 (Abcg2)-expressing cells have been implicated in cardiac protective mechanisms involving oxidative stress, there remains a lack of understanding regarding the behavior of cardiac Abcg2-expressing cells when exposed to ROS. The aim of the present study was to characterize the response of the cardiac Abcg2 lineage to oxidative stress. In vitro analysis demonstrated that the antioxidant program regulated by Abcg2 is dependent on a functional transporter. Delivery of paraquat dichloride (PQ), a systemic oxidative stress-inducing agent, to mice confirmed that Abcg2 provides a survival benefit. When exposed to PQ, reporter mice showed an increase in the Abcg2 lineage. Transcriptional and immunohistochemical analysis of Abcg2 lineage-positive cells revealed an enhanced vascular commitment after stress. Finally, preconditioning with PQ demonstrated a reduction in scar size and an increase in angiogenesis after permanent left coronary artery ligation. In conclusion, the data suggest that Abcg2 plays a cytoprotective role in response to in vivo oxidative stress. The contribution of the Abcg2 lineage to the vasculature in the heart is increased after PQ delivery.

scholarly journals A Selective ATP-Binding Cassette Subfamily G Member 2 Efflux Inhibitor Revealed via High-Throughput Flow Cytometry

2012 ◽  
Vol 18 (1) ◽  
pp. 26-38 ◽  
Author(s):  
J. Jacob Strouse ◽  
Irena Ivnitski-Steele ◽  
Hadya M. Khawaja ◽  
Dominique Perez ◽  
Jerec Ricci ◽  
...  
Keyword(s):  
Molecular Probes ◽  
Atp Binding ◽  
Specific Substrate ◽  
Tumor Resistance ◽  
Drug Concentrations ◽  
Efflux Inhibition ◽  
Substrate Inhibitor ◽  
Atp Binding Cassette

Chemotherapeutics tumor resistance is a principal reason for treatment failure, and clinical and experimental data indicate that multidrug transporters such as ATP-binding cassette (ABC) B1 and ABCG2 play a leading role by preventing cytotoxic intracellular drug concentrations. Functional efflux inhibition of existing chemotherapeutics by these pumps continues to present a promising approach for treatment. A contributing factor to the failure of existing inhibitors in clinical applications is limited understanding of specific substrate/inhibitor/pump interactions. We have identified selective efflux inhibitors by profiling multiple ABC transporters against a library of small molecules to find molecular probes to further explore such interactions. In our primary screening protocol using JC-1 as a dual-pump fluorescent reporter substrate, we identified a piperazine-substituted pyrazolo[1,5-a]pyrimidine substructure with promise for selective efflux inhibition. As a result of a focused structure-activity relationship (SAR)–driven chemistry effort, we describe compound 1 (CID44640177), an efflux inhibitor with selectivity toward ABCG2 over ABCB1. Compound 1 is also shown to potentiate the activity of mitoxantrone in vitro as well as preliminarily in vivo in an ABCG2-overexpressing tumor model. At least two analogues significantly reduce tumor size in combination with the chemotherapeutic topotecan. To our knowledge, low nanomolar chemoreversal activity coupled with direct evidence of efflux inhibition for ABCG2 is unprecedented.

scholarly journals The Role of Apolipoprotein A-I Helix 10 in Apolipoprotein-mediated Cholesterol Efflux via the ATP-binding Cassette Transporter ABCA1

2002 ◽  
Vol 277 (42) ◽  
pp. 39477-39484 ◽  
Author(s):  
Stacey E. Panagotopulos ◽  
Scott R. Witting ◽  
Erica M. Horace ◽  
David Y. Hui ◽  
J. Nicholas Maiorano ◽  
...  
Keyword(s):  
Cholesterol Efflux ◽  
Atp Binding ◽  
Atp Binding Cassette Transporter ◽  
Apolipoprotein A ◽  
Atp Binding Cassette

scholarly journals Dichlorodiphenyltrichloroethane Impairs Amyloid Beta Clearance by Decreasing Liver X Receptor α Expression

2021 ◽  
Vol 13 ◽  
Author(s):  
Dongmei Wu ◽  
Yang Hu ◽  
Min Song ◽  
Gongbo Li
Keyword(s):  
Amyloid Beta ◽  
Critical Role ◽  
Liver X Receptor ◽  
Dynamics Simulation ◽  
Atp Binding ◽  
Atp Binding Cassette Transporter ◽  
Liver X Receptor Α ◽  
Aβ Clearance ◽  
Atp Binding Cassette

Abnormal amyloid beta (Aβ) clearance is a distinctive pathological mechanism for Alzheimer’s disease (AD). ATP-binding cassette transporter A1 (ABCA1), which mediates the lipidation of apolipoprotein E, plays a critical role in Aβ clearance. As an environmental factor for AD, dichlorodiphenyltrichloroethane (DDT) can decrease ATP-binding cassette transporter A1 (ABCA1) expression and disrupt Aβ clearance. Liver X receptor α (LXRα) is an autoregulatory transcription factor for ABCA1 and a target of some environmental pollutants, such as organophosphate pesticides. In this study, we aimed to investigate whether DDT could affect Aβ clearance by targeting LXRα. The DDT-pretreated H4 human neuroglioma cells and immortalized astrocytes were incubated with exogenous Aβ to evaluate Aβ consumption. Meanwhile, cytotoxicity and LXRα expression were determined in the DDT-treated cells. Subsequently, the antagonism of DDT on LXRα agonist T0901317 was determined in vitro. The interaction between DDT and LXRα was predicted by molecular docking and molecular dynamics simulation technology. We observed that DDT could inhibit Aβ clearance and decrease the levels of LXRα mRNA and LXRα protein. Moreover, DDT is supposed to strongly bind to LXRα and exert antagonistic effects on LXRα. In conclusion, this study firstly presented that DDT could inhibit LXRα expression, which would contribute to Aβ clearance decline in vitro. It provides an experimental basis to search for potential therapeutic targets of AD.

scholarly journals Liver-X-receptor-mediated increase in ATP-binding cassette transporter A1 expression is attenuated by fatty acids in CaCo- cells: effect on cholesterol efflux to high-density lipoprotein

2004 ◽  
Vol 377 (3) ◽  
pp. 545-552 ◽  
Author(s):  
Shubha MURTHY ◽  
Ella BORN ◽  
Satya N. MATHUR ◽  
F. Jeffrey FIELD
Keyword(s):  
Fatty Acids ◽  
Oleic Acid ◽  
Cholesterol Efflux ◽  
Atp Binding ◽  
Transcriptional Level ◽  
Mrna Levels ◽  
Atp Binding Cassette Transporter ◽  
Arachidonic Acids ◽  
Docosahexaenoic Acids ◽  
Atp Binding Cassette

The effect of fatty acids on LXR (liver X receptors)-mediated enhancement of ABCA1 (ATP-binding cassette transporter A1) expression and cholesterol efflux was investigated in human intestinal cells CaCo-2. LXR activation by T0901317 increased basolateral cholesterol efflux to lipoprotein particles isolated at a density of 1.21 g/ml or higher. Oleic and arachidonic acids attenuated the amount of cholesterol isolated from these particles. Stearic, linoleic and docosahexaenoic acids also decreased cholesterol efflux from basolateral membranes, with the polyunsaturated fatty acids being the most potent. Although oleic, arachidonic and docosahexaenoic acids modestly decreased ABCA1 mRNA levels in response to LXR activation, stearic and linoleic acids did not. Except for oleic acid, all fatty acids substantially attenuated an increase in ABCA1 mass secondary to LXR activation. Inhibiting acyl-CoA:cholesterol acyltransferase activity prevented the decrease in cholesterol efflux caused by oleic acid. Thus, in response to LXR activation, all fatty acids decreased the efflux of cholesterol from the basolateral membrane of CaCo-2 cells. Although modest suppression of ABCA1 gene expression by oleic, arachidonic and docosahexaenoic acids cannot be completely excluded as a mechanism, the predominant effect of fatty acids on ABCA1 expression and cholesterol efflux is at a post-transcriptional level.

Sign in / Sign up

Export Citation Format

Share Document