Down‐regulation of ATP‐binding cassette transporter A1 (ABCA1) and ABCG1 expression by unsaturated fatty acids in vivo and in vitro

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.

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Unsaturated fatty acids repress expression of ATP binding cassette transporter A1 and G1 in RAW 264.7 macrophages

The Journal of Nutritional Biochemistry ◽

10.1016/j.jnutbio.2011.07.007 ◽

2012 ◽

Vol 23 (10) ◽

pp. 1271-1276 ◽

Cited By ~ 17

Author(s):

Chai Siah Ku ◽

Youngki Park ◽

Sara L. Coleman ◽

Jiyoung Lee

Keyword(s):

Fatty Acids ◽

Unsaturated Fatty Acids ◽

Atp Binding ◽

Raw 264.7 ◽

Raw 264.7 Macrophages ◽

Atp Binding Cassette Transporter ◽

Atp Binding Cassette

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

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.111.228478 ◽

2011 ◽

Vol 31 (9) ◽

pp. 1980-1987 ◽

Cited By ~ 54

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

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

CrossRef Listing of Deleted DOIs ◽

10.1177/1087057112456875 ◽

2012 ◽

Vol 18 (1) ◽

pp. 26-38 ◽

Cited By ~ 15

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.

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

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.634948 ◽

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.

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