DNA topoisomerase II inhibitors induce macrophage ABCA1 expression and cholesterol efflux—An LXR-dependent mechanism

Zhang, Ling; Jiang, Meixiu; Shui, Yongsheng; Chen, Yuanli; Wang, Qixue; Hu, Wenquan; Ma, Xingzhe; Li, Xiaoju; Liu, Xin; Cao, Xingyue; Li, Mengyang; Duan, Yajun; Han, Jihong

doi:10.1016/j.bbalip.2013.02.007

Cited by 21 publications

(16 citation statements)

References 37 publications

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“…NS, not significant. docking study," we determined a much weaker interaction between etoposide or teniposide and amino acid residues within the ligand binding pocket of LXR than T0901317 (14). In this study both etoposide and teniposide induce CETP expression, which is also associated with activation of LXR pathway.…”

Section: Discussionmentioning

confidence: 82%

“…Altogether, these results indicate that etoposide and teniposide activate the LXR pathway by multiple mechanisms which might distinguish the ligands with full LXR activities. Indeed, in our previous study we observed that teniposide demonstrates a greater effect than T0901317 on induction of macrophage ABCA1 expression at the same concentration (14). Although the interaction between LXR and Topo II protein and the involved precise mechanisms by which to influence LXR activity require more investigation, we anticipate that this interaction may suppress LXR activity.…”

Section: Discussionmentioning

confidence: 99%

“…6E shows that teniposide increased RCT in both wild type and CETPtg mice. The increased RCT in wild type mice should be due to the induction of ABCA1 expression by teniposide (14). However, the overall induction of RCT by teniposide was greater in CETPtg mice than in wild type mice, which should be contributed by induction of CETP expression.…”

Section: Administration Of Teniposide Induces Liver Cetp Expression Amentioning

confidence: 99%

“…Etoposide has been reported to reduce atherosclerosis in hypercholesterolemia rabbits with un-fully elucidated mechanisms (12)(13)(14). Meanwhile, high expressing CETP can reduce atherosclerosis in the animal models (15)(16)(17), indicating that the anti-atherogenic properties of Topo II inhibitors are related to regulation of cholesterol metabolism, such as hepatic CETP expression.…”

Section: Cholesteryl Ester Transfer Protein (Cetp) Transfers Cholestementioning

confidence: 99%

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Regulation of Hepatic Cholesteryl Ester Transfer Protein Expression and Reverse Cholesterol Transport by Inhibition of DNA Topoisomerase II

Chen

Zhang³

et al. 2015

Journal of Biological Chemistry

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Background: CETP expression mediates cholesterol metabolism and the development of atherosclerosis. Results: Inhibition of Topo II activates CETP expression in HepG2 cells and CETP transgenic mouse liver, which was associated with increased reverse cholesterol transport in vivo. Conclusion: Topo II inhibitors induced CETP expression and RCT by activating LXR pathway. Significance: We found an important function of Topo II inhibition in regulating cholesterol metabolism.

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Section: Discussionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Section: Administration Of Teniposide Induces Liver Cetp Expression Amentioning

confidence: 99%

Section: Cholesteryl Ester Transfer Protein (Cetp) Transfers Cholestementioning

confidence: 99%

See 2 more Smart Citations

Regulation of Hepatic Cholesteryl Ester Transfer Protein Expression and Reverse Cholesterol Transport by Inhibition of DNA Topoisomerase II

Chen

Zhang³

et al. 2015

Journal of Biological Chemistry

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“…Apart from this, the activation of PKC can also modulate ABCA1 gene transcription and expression 36. PKC-mediated activation of PI3K and Ras/MAPK pathways35 could also activate PPARα,32 PPARγ,37 and LXR38 through phosphorylation and can further up- or downregulate ABCA1 expression. The binding of ApoA-I to ABCA1 has also been shown to promote cAMP production, thereby activating protein kinase A and further increasing ABCA1 mRNA expression in mouse macrophages 35.…”

Section: Discussionmentioning

confidence: 99%

β<sub>3</sub>-Adrenoceptor activation upregulates apolipoprotein A-I expression in HepG2 cells, which might further promote cholesterol efflux from macrophage foam cells

Gao

Jiang

2017

DDDT

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ObjectiveThe aim of this study was to explore the effects of β3-adrenoceptor (β3-AR) activation on HepG2 cells and its influence on cholesterol efflux from macrophage foam cells.Materials and methodsHepG2 cells were cultured and treated with the β3-AR agonist, BRL37344, and antagonist, SR52390A, and the expression of apolipoprotein (Apo) A-I, ApoA-II, ApoB, and β3-AR in the supernatants and cells was determined. The expression of peroxisome proliferator-activated receptor (PPAR) γ and PPARα in the HepG2 cells was also assessed. Next, using the RAW264.7 macrophage foam cell model, we also assessed the influence of the HepG2 cell supernatants on lipid efflux. The cholesterol content of the foam cells was also measured, and the cholesterol efflux from the macrophages was examined by determining 3H-labeled cholesterol levels. Expression of ATP-binding cassette transporter (ABC) A1 and ABCG1 of the macrophage foam cells was also assessed.Resultsβ3-AR activation increased ApoA-I expression in both the HepG2 cells and the supernatants; PPARγ expression was upregulated, but PPARα expression was not. Treatment with GW9662 abolished the increased expression of ApoA-I induced by the β3-AR agonist. The HepG2 cell supernatants decreased the lipid accumulation and increased the cholesterol efflux from the macrophage foam cells. ABCA1 expression, but not ABCG1 expression, increased in the macrophage foam cells treated with BRL37344-treated HepG2 cell supernatants.ConclusionActivation of β3-AR in HepG2 cells upregulates ApoA-I expression, which might further promote cholesterol efflux from macrophage foam cells. PPARγ might be required for the induction of ApoA-I expression.

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Analysis of Low Molecular Weight Substances and Related Processes Influencing Cellular Cholesterol Efflux

2019

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Cholesterol efflux is the key process protecting the vascular system from the development of atherosclerotic lesions. Various extracellular and intracellular events affect the ability of the cell to efflux excess cholesterol. To explore the possible pathways and processes that promote or inhibit cholesterol efflux, we applied a combined cheminformatic and bioinformatic approach. We performed a comprehensive analysis of published data on the various substances influencing cholesterol efflux and found 153 low molecular weight substances that are included in the Chemical Entities of Biological Interest (ChEBI) database. Pathway enrichment was performed for substances identified within the Reactome database, and 45 substances were selected in 93 significant pathways. The most common pathways included the energy-dependent processes related to active cholesterol transport from the cell, lipoprotein metabolism and lipid transport, and signaling pathways. The activators and inhibitors of cholesterol efflux were non-uniformly distributed among the different pathways: the substances influencing 'biological oxidations' activate cholesterol efflux and the substances influencing 'Signaling by GPCR and PTK6' inhibit efflux. This analysis may be used in the search and design of efflux effectors for therapies targeting structural and functional high-density lipoprotein deficiency. Key Points We performed a comprehensive analysis of the various substances influencing cholesterol efflux, with pathway enrichment using the Reactome database. The activators and inhibitors of cholesterol efflux are non-uniformly distributed among different pathways. The substances influencing biological oxidation activate cholesterol efflux, and the substances influencing signaling by G protein-coupled receptors (GPCR) and nonreceptor tyrosine kinase (PTK6) inhibit efflux.

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DNA topoisomerase II inhibitors induce macrophage ABCA1 expression and cholesterol efflux—An LXR-dependent mechanism

Cited by 21 publications

References 37 publications

Regulation of Hepatic Cholesteryl Ester Transfer Protein Expression and Reverse Cholesterol Transport by Inhibition of DNA Topoisomerase II

Regulation of Hepatic Cholesteryl Ester Transfer Protein Expression and Reverse Cholesterol Transport by Inhibition of DNA Topoisomerase II

β<sub>3</sub>-Adrenoceptor activation upregulates apolipoprotein A-I expression in HepG2 cells, which might further promote cholesterol efflux from macrophage foam cells

Analysis of Low Molecular Weight Substances and Related Processes Influencing Cellular Cholesterol Efflux

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DNA topoisomerase II inhibitors induce macrophage ABCA1 expression and cholesterol efflux—An LXR-dependent mechanism

Cited by 21 publications

References 37 publications

Regulation of Hepatic Cholesteryl Ester Transfer Protein Expression and Reverse Cholesterol Transport by Inhibition of DNA Topoisomerase II

Regulation of Hepatic Cholesteryl Ester Transfer Protein Expression and Reverse Cholesterol Transport by Inhibition of DNA Topoisomerase II

&beta;<sub>3</sub>-Adrenoceptor activation upregulates apolipoprotein A-I expression in HepG2 cells, which might further promote cholesterol efflux from macrophage foam cells

Analysis of Low Molecular Weight Substances and Related Processes Influencing Cellular Cholesterol Efflux

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β<sub>3</sub>-Adrenoceptor activation upregulates apolipoprotein A-I expression in HepG2 cells, which might further promote cholesterol efflux from macrophage foam cells