Enhanced cellular cholesterol efflux by naringenin is mediated through inhibiting endoplasmic reticulum stress - ATF6 activity in macrophages.
Enhanced cellular cholesterol efflux by naringenin is mediated through inhibiting endoplasmic reticulum stress - ATF6 activity in macrophages.
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DOI：
10.1016/j.bbalip.2019.06.005
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发表时间：
2019-06
期刊：
影响因子：
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通讯作者：
Xiaoting Xu;T. Lei;Wenchao Li;H. Ou
中科院分区：
文献类型：
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作者：
Xiaoting Xu;T. Lei;Wenchao Li;H. Ou
柚皮素改善脂蛋白谱，预防心血管疾病。ATF 6是一种内质网（ER）应激传感器，具有与固醇调节剂SREBP相同的激活过程。临床数据显示，ATF 6表达与血浆胆固醇水平相关。在这里，我们研究了柚皮素是否参与胆固醇流出的调节，并测试了ER应激-ATF 6在柚皮素功能中的作用。结果表明，柚皮素可增加巨噬细胞胆固醇向apoA-I和HDL的流出，并增加ABCA 1、ABCG 1和LXRα基因的表达。柚皮素抑制切割的ATF 6核转位及其靶GRP 78和XBP-1的表达。ER应激抑制剂4-苯基丁酸、诱导剂衣霉素和ATF 6过表达均可调节RAW 264. 7和/或THP-1细胞中柚皮素诱导的胆固醇流出，提示柚皮素的功能可能是通过抑制ER应激-ATF 6通路实现的。接下来，我们发现补充有柚皮素的高脂饮食（HFD）使apoE−/−小鼠的原代腹膜巨噬细胞的胆固醇流出能力比仅HFD喂养的小鼠增加>1.2倍。衣霉素处理显著降低了这种增加。柚皮素降低腹主动脉和腹腔巨噬细胞GRP 78、XBP-1和核ATF 6水平，减轻主动脉根部粥样硬化病变，但被衣霉素逆转。这些证实了ER应激-ATF 6参与柚皮素功效。最后，我们发现柚皮素促进AKT磷酸化; PI 3 K抑制剂LY 294002处理增加了核ATF 6，降低了柚皮素增强的ABCA 1表达和胆固醇流出。结论：柚皮素是胆固醇流出的调节因子，其调节作用是通过内质网应激的ATF 6分支和PI 3 K/AKT通路介导的。
Naringenin improves lipoprotein profile and protects against cardiovascular disease. ATF6 is an endoplasmic reticulum (ER) stress sensor with the same activation processes with sterol regulator SREBPs. Clinical data revealed that ATF6 expression was associated with plasma cholesterol level. Here, we investigated whether naringenin was involved in the regulation of cholesterol efflux and tested the role of ER stress-ATF6 in the naringenin function. Results showed that naringenin increased cholesterol efflux to both apoA-I and HDL and gene expressions in ABCA1, ABCG1 and LXRα in RAW264.7 macrophages. Naringenin inhibited the cleaved ATF6 nuclear translocation and its target GRP78 and XBP-1 expressions. Naringenin-induced cholesterol efflux was modulated by treatment with ER stress inhibitor 4-phenylbutyric acid, inducer tunicamycin and ATF6 overexpression in RAW264.7 and/or THP-1 cells, which suggested the naringenin functions were mediated through inhibiting ER stress-ATF6 pathway. Next, we found high-fat diet (HFD) supplemented with naringenin increased by >1.2-fold in cholesterol efflux capacity in primary peritoneal macrophage in apoE−/− mice compared to only HFD-fed mice. The increase was significantly reduced by tunicamycin treatment. Naringenin decreased GRP78, XBP-1 and nuclear ATF6 levels in peritoneal macrophage and aorta and reduced atherosclerotic lesion at aortic root, but reversed by tunicamycin. These confirmed participation of ER stress-ATF6 in naringenin efficacy. Finally, we found naringenin promoted AKT phosphorylation; PI3K inhibitor LY294002 treatment increased nuclear ATF6 and reduced naringenin-enhanced ABCA1 expression and cholesterol efflux. We concluded naringenin as a regulator for cholesterol efflux, and the regulation was mediated by ATF6 branch of ER stress and PI3K/AKT pathway.