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Urolithin A attenuated ox-LDL-induced cholesterol accumulation in macrophages partly through regulating miR-33a and ERK/AMPK/SREBP1 signaling pathways.
Food & Function ( IF 6.1 ) Pub Date : 2020-04-01 , DOI: 10.1039/c9fo02471a
Qi-An Han 1 , Dongfang Su , Chao Shi , Peifeng Liu , Yue Wang , Beiwei Zhu , Xiaodong Xia
Affiliation  

Promoting cholesterol efflux from foam cells represents one of the therapeutic strategies for ameliorating atherosclerosis. Urolithin A (UA) has been shown before to attenuate ox-LDL induced endothelial dysfunction in endothelial cells with its anti-inflammatory properties. The aim of this study was to investigate whether UA could promote cholesterol efflux via modulating related microRNA (miR) and signaling pathways. RAW264.7 cells were treated with 50 μg mL-1 ox-LDL to induce foam cell formation. After treatment with UA at different concentrations, intercellular and extracellular cholesterol levels were determined. Expression of Erk1/2, AMPKα and their phosphorylation forms, and SREBP1, was analyzed by western-blotting. The effect of UA on miR-33a expression and the involvement of miR-33a in cholesterol efflux regulation were also investigated. UA reduced ox-LDL induced cholesterol accumulation in macrophage cells and promoted cholesterol efflux from cells. Compared with ox-LDL treated cells, UA treatment reduced the level of phosphorylated ERK1/2, increased the expression of phosphorylated AMPKα and decreased the SREBP1 expression. Moreover, UA decreased the miR-33a expression at the transcriptional level but increased the transcriptional expression of ATP-binding cassette transporter A1 (ABCA1) and ABCG1, two genes contributing to reverse cholesterol transport. Furthermore, pre-miR-33a attenuated cholesterol efflux induced by UA. Collectively, UA promoted the reverse cholesterol transport in macrophage-derived foam cells and interfered with cholesterol metabolism possibly through regulating the miRNA-33 expression and interaction with the ERK/AMPKα/SREBP1 signaling pathway.

中文翻译:

尿石素A可以部分通过调节miR-33a和ERK / AMPK / SREBP1信号通路来减轻ox-LDL诱导的胆固醇在巨噬细胞中的蓄积。

从泡沫细胞促进胆固醇外流代表减轻动脉粥样硬化的治疗策略之一。尿石素A(UA)之前已被证明具有抗炎特性,可减轻ox-LDL诱导的内皮细胞内皮功能障碍。这项研究的目的是调查UA是否可以通过调节相关的microRNA(miR)和信号通路来促进胆固醇外流。RAW264.7细胞用50μgmL-1 ox-LDL处理以诱导泡沫细胞形成。用不同浓度的UA处理后,测定细胞间和细胞外胆固醇水平。通过Western印迹分析Erk1 / 2,AMPKα及其磷酸化形式和SREBP1的表达。还研究了UA对miR-33a表达的影响以及miR-33a参与胆固醇外排的调节。UA减少了ox-LDL诱导巨噬细胞中胆固醇的积累,并促进了胆固醇从细胞中的流出。与ox-LDL处理的细胞相比,UA处理降低了磷酸化的ERK1 / 2的水平,增加了磷酸化的AMPKα的表达,并降低了SREBP1的表达。此外,UA在转录水平上降低了miR-33a的表达,但增加了ATP结合盒转运蛋白A1(ABCA1)和ABCG1的转录表达,这两个基因有助于胆固醇的逆向转运。此外,pre-miR-33a减弱了UA诱导的胆固醇外流。UA可能通过调节miRNA-33的表达以及与ERK /AMPKα/ SREBP1信号通路的相互作用,共同促进巨噬细胞源性泡沫细胞中胆固醇的逆向转运,并干扰胆固醇的代谢。
更新日期:2020-04-24
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