RAPAMYCIN DECREASES CHOLESTEROL EFFLUX AND ABCA1 PROTEIN EXPRESSION WITHIN THP-1 MACROPHAGES

Endothelial ABCA1 expression protects against atherosclerosis and this atheroprotective effect is partially attributed to enhancing apoAI-mediated cholesterol efflux. ABCA1 is a target gene for LXR and RXR; therefore, treating endothelial cells with LXR and/or RXR agonists may increase ABCA1 expression. We tested whether treating cultured immortalized mouse aortic endothelial cells (iMAEC) with the endogenous LXR agonist 22(R)-hydroxycholesterol, synthetic LXR agonist GW3965, endogenous RXR agonist 9-cis-retinoic acid, or synthetic RXR agonist SR11237 increases ABCA1 protein expression. We observed a significant increase in ABCA1 protein expression in iMAEC treated with either GW3965 or SR11237 alone, but no significant increase in ABCA1 protein was observed in iMAEC treated with either 22(R)-hydroxycholesterol or 9-cis-retionic acid alone. However, we observed significant increases in both ABCA1 protein expression and apoAI-mediated cholesterol efflux when iMAEC were treated with a combination of either 22(R)-hydroxycholesterol and 9-cis-retinoic acid or GW3965 and SR11237. Furthermore, treating iMAEC with either 22(R)-hydroxycholesterol and 9-cis-retinoic acid or GW3965 and SR11237 did not trigger an inflammatory response, based on VCAM-1, ICAM-1, CCL2, and IL-6 mRNA expression. Based on our findings, delivering LXR and RXR agonists precisely to endothelial cells may be a promising atheroprotective approach.

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Effect of Apolipoprotein A-I on ATP Binding Cassette Transporter A1 Degradation and Cholesterol Efflux in THP-1 Macrophage-derived Foam Cells

Acta Biochimica et Biophysica Sinica ◽

10.1093/abbs/36.3.218 ◽

2004 ◽

Vol 36 (3) ◽

pp. 218-226 ◽

Cited By ~ 26

Author(s):

Chao-Ke Tang ◽

Guo-Hua Tang ◽

Guang-Hui Yi ◽

Zuo Wang ◽

Lu-Shan Liu ◽

...

Keyword(s):

Protease Inhibitors ◽

Cholesterol Efflux ◽

Foam Cells ◽

Atp Binding ◽

Thiol Protease ◽

Atp Binding Cassette Transporter ◽

Apolipoprotein A ◽

Abca1 Protein ◽

Abca1 Mrna ◽

Atp Binding Cassette

Abstract Cholesterol-loaded macrophage foam cells are a central component of atherosclerotic lesions. ATP binding cassette transporter A1 (ABCA1), the defective molecule in Tangier disease, mediates the efflux of phospholipid and cholesterol from cells to apolipoprotein A-I (apoA-I), reversing foam cell formation. This study investigated the effect of apoA-I on ABCA1 degradation and cholesterol efflux in THP-1 macrophage-derived foam cells. After exposure of the cultured THP-1 macrophage-derived foam cells to apoA-I for different time, cholesterol efflux, ABCA1 mRNA and protein levels were determined by FJ-2107P type liquid scintillator, RT-PCR and Western blot, respectively. The mean ABCA1 fluorescence intensity on THP-1 macrophage-derived foam cells was detected by flow cytometry. Results showed that apoA-I markedly increased ABCA1-mediated cholesterol efflux from THP-1 macrophage-derived foam cells. This was accompanied by an increase in the content of ABCA1. ApoA-I did not alter ABCA1 mRNA abundance. Significantly, thiol protease inhibitors increased the level of ABCA1 protein and slowed its decay in THP-1 macrophage-derived foam cells, whereas none of the proteosome-specific inhibitor lactacystin, other protease inhibitors, or the lysosomal inhibitor NH4Cl showed such effects. The apoA-I-mediated cellular cholesterol efflux was enhanced by thiol protease inhibitors. Our results suggested that thiol protease inhibitors might provide an alternative way to upregulate ABCA1 protein. This strategy is especially appealing since it may mimic the stabilizing effect of the natural ligands apoA-I.

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Abstract 616: Interleukin 22 Downregulates ABCG1 and Impairs Cholesterol Efflux in Macrophages

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.34.suppl_1.616 ◽

2014 ◽

Vol 34 (suppl_1) ◽

Author(s):

Marion Hofmann Bowman ◽

Bijoy Chellan ◽

Ling Yan ◽

Timothy Sonntag ◽

Catherine Reardon

Keyword(s):

Protein Expression ◽

Barrier Function ◽

Cholesterol Efflux ◽

Peritoneal Macrophages ◽

Mouse Serum ◽

Epithelial Barrier ◽

Dependent Manner ◽

Epithelial Barrier Function ◽

Cholesterol Uptake ◽

Mrna And Protein Expression

IL22 belongs to the IL10 cytokine family and is expressed by T helper cells. IL22 functions on epithelial cells and has been shown to improve epithelial barrier function in inflammatory bowel disease, asthma, and psoriasis; autoimmune diseases associated with elevated serum IL22. Patients with psoriasis have increased coronary artery disease and it was previously shown that macrophages from patients with psoriasis have impaired cholesterol efflux. The function of IL-22 on macrophage cholesterol metabolism is not known. Methods: ABCA1, ABCG1 and CD36 mRNA and protein expression, cholesterol uptake and efflux were studied in murine macrophages and human THP-1 macrophages. C57BL6/J mice with transgenic expression of hS100A12 and hS100A8/9 in myeloid cells were generated by using a bacterial artificial chromosome (hBAC/S100 mice). hBAC/S100 and WT littermate mice were breed into mice lacking the receptor for advanced glycation endproducts, RAGE. Results: Peritoneal macrophages from hBAC/S100 mice have reduced ABCG1 mRNA and protein expression, increased cholesterol uptake, and reduced cholesterol efflux compared to WT. This was abolished in hBAC/S100 mice lacking RAGE, the receptor for S100/calgranulin. Recombinant S100A12 or S100A8 protein (2.5 μg/ml) had no effect on ABCG1 expression in WT peritoneal macrophages or human THP-1 cells, suggesting other systemic intermediary products in hBAC/S100 mice. Serum IL22 and mRNA in splenic T cells were significantly increased in hBAC/S100 mice, and this was abolished in hBAC/S100 mice lacking RAGE. Moreover, r S100A12 increased IL22 mRNA by 2-fold in cultured human THP-1. Importantly, THP-1 macrophages treated with r IL22 (100 ng/ml) had reduced expression of ABCG1 and impaired cholesterol efflux to mouse serum, but not to Apoa1. Up regulation of ABCG1 and ABCA1 in response to LXR agonist TO901317 in THP-1 cells abolished the detrimental effects of IL22 on cholesterol efflux. Conclusion: S100/calgranulin induces IL22 in a RAGE dependent manner. IL22 down regulates ABCG1 and impairs cholesterol efflux in macrophages. This raises the hypothesis that IL22-mediated down regulation of cellular cholesterol efflux may be linked to improved epithelial barrier function, but may also augment atherosclerosis.

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LXR Driven Induction of HDL-Cholesterol is Independent of Intestinal Cholesterol Absorption and ABCA1 Protein Expression

Lipids ◽

10.1007/s11745-013-3853-8 ◽

2013 ◽

Vol 49 (1) ◽

pp. 71-83 ◽

Cited By ~ 10

Author(s):

Kristina Kannisto ◽

Mats Gåfvels ◽

Zhao-Yan Jiang ◽

Katharina Slätis ◽

Xiaoli Hu ◽

...

Keyword(s):

Protein Expression ◽

Hdl Cholesterol ◽

Cholesterol Absorption ◽

Intestinal Cholesterol Absorption ◽

Abca1 Protein

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Inhibition of ABCA1 protein degradation promotes HDL cholesterol efflux capacity and RCT and reduces atherosclerosis in mice

The Journal of Lipid Research ◽

10.1194/jlr.m054742 ◽

2015 ◽

Vol 56 (5) ◽

pp. 986-997 ◽

Cited By ~ 37

Author(s):

LinZhang Huang ◽

BaoYan Fan ◽

Ang Ma ◽

Philip W. Shaul ◽

HaiBo Zhu

Keyword(s):

Protein Degradation ◽

Cholesterol Efflux ◽

Hdl Cholesterol ◽

Cholesterol Efflux Capacity ◽

Abca1 Protein

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Novel Effect of Paeonol on the Formation of Foam Cells: Promotion of LXRα-ABCA1–Dependent Cholesterol Efflux in Macrophages

The American Journal of Chinese Medicine ◽

10.1142/s0192415x13500730 ◽

2013 ◽

Vol 41 (05) ◽

pp. 1079-1096 ◽

Cited By ~ 25

Author(s):

Jin-Feng Zhao ◽

Shr-Jeng Jim Leu ◽

Song-Kun Shyue ◽

Kuo-Hui Su ◽

Jeng Wei ◽

...

Keyword(s):

Protein Expression ◽

Cholesterol Efflux ◽

Nuclear Translocation ◽

Cholesterol Metabolism ◽

Inflammatory Diseases ◽

Oxidized Ldl ◽

Neutralizing Antibody ◽

Foam Cells ◽

Underlying Mechanism ◽

Cholesterol Accumulation

Paeonol, a phenolic component purified from Paeonia suffruticosa (Cortex Moutan), is used in traditional Chinese medicine to treat inflammatory diseases. However, little is known about the effect of paeonol on cholesterol metabolism. We investigated the efficacy of paeonol on cholesterol metabolism and the underlying mechanism in macrophages and apolipoprotein E deficient (apoE-/-) mice. Treatment with paeonol markedly attenuated cholesterol accumulation induced by oxidized LDL in macrophages, which was due to increased cholesterol efflux. Additionally, paeonol enhanced the mRNA and protein expression of ATP-binding membrane cassette transport protein A1 (ABCA1) but did not alter the protein level of ABCG1 or other scavenger receptors. Inhibition of ABCA1 activity with a pharmacological inhibitor, neutralizing antibody or small interfering RNA (siRNA), negated the effects of paeonol on cholesterol efflux and cholesterol accumulation. Furthermore, paeonol induced the nuclear translocation of liver X receptor α (LXRα) by increasing its activity. siRNA knockdown of LXRα abolished the paeonol-induced upregulation of ABCA1, promotion of cholesterol efflux and suppression of cholesterol accumulation. Moreover, atherosclerotic lesions, hyperlipidemia and systemic inflammation were reduced and the protein expression of ABCA1 was increased in aortas of paeonol-treated apoE-/- mice. Paeonol may alleviate the formation of foam cells by enhancing LXRα-ABCA1–dependent cholesterol efflux.

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