Vitamin D Protects Against Atherosclerosis via Regulation of Cholesterol Efflux and Macrophage Polarization in Hypercholesterolemic Swine.
Vitamin D Protects Against Atherosclerosis via Regulation of Cholesterol Efflux and Macrophage Polarization in Hypercholesterolemic Swine.
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维生素 D 通过调节高胆固醇血症猪的胆固醇流出和巨噬细胞极化来预防动脉粥样硬化
DOI：
10.1161/atvbaha.115.306132
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发表时间：
2015-11
期刊：
影响因子：
--
通讯作者：
Agrawal DK
中科院分区：
文献类型：
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作者：
Yin K;You Y;Swier V;Tang L;Radwan MM;Pandya AN;Agrawal DK
维生素 D 缺乏的普遍性及其与心血管疾病风险的关系促使我们评估维生素 D 状态对高胆固醇血症小型猪脂质代谢和动脉粥样硬化的影响。尤卡坦微型猪饲喂缺乏维生素 D (0IU/天)、维生素 D 充足 (1,000IU/天) 或补充维生素 D (3,000IU/天) 的高胆固醇饮食，为期 48 周。每两周测量一次血清脂质和 25(OH)-胆钙化醇水平。分析肝脏和动脉的组织学和生化参数。在人 HepG2 和 THP-1 巨噬细胞衍生的泡沫细胞中检查了 1,25(OH)2D3 对胆固醇代谢的影响。维生素 D 缺乏会降低高胆固醇血症小型猪的血浆 HDL 水平、肝脏 X 受体 (LXR)、ATP 结合盒转运蛋白 A1 (ABCA1) 和 ABCG1 的表达，并促进胆固醇积累和动脉粥样硬化。维生素 D 通过 ABCA1 介导的胆固醇流出促进 HepG2 细胞中新生 HDL 的形成。 CYP27B1 和 VDR 主要存在于冠状动脉斑块中 CD206 + M2 巨噬细胞泡沫细胞聚集的核心中。 1,25(OH)2D3 增加了 THP-1 巨噬细胞衍生的泡沫细胞中 LXR、ABCA1、ABCG1 的表达，并促进胆固醇流出。在 LPS 刺激下，1,25(OH)2D3 降低细胞内游离胆固醇并将巨噬细胞极化为 M2 表型，同时降低 TNF-α、IL-1β、IL-6 的表达。 1,25(OH)2D3 通过 VDR 依赖性 JNK1/2 信号通路显着诱导 CYP27A1 表达，并增加 27-羟基胆固醇水平，从而诱导 LXR、ABCA1 和 ABCG1 表达，刺激 THP-1 巨噬细胞衍生的泡沫细胞中被 VDR 拮抗剂和 JNK1/2 信号抑制剂抑制的胆固醇流出。维生素 D 通过增加 CYP27A1 激活来控制胆固醇流出和巨噬细胞极化，从而预防高胆固醇血症猪的动脉粥样硬化。
Prevalence of vitamin D-deficiency and its association with the risk of cardiovascular disease prompted us to evaluate the effect of vitamin D status on lipid metabolism and atherosclerosis in hypercholesterolemic microswine. Yucatan microswine were fed with vitamin D-deficient (0IU/d), vitamin D-sufficient (1,000IU/d) or vitamin D-supplemented (3,000IU/d) high cholesterol diet for 48 weeks. Serum lipids and 25(OH)-cholecalciferol levels were measured biweekly. Histology and biochemical parameters of liver and arteries were analyzed. Effect of 1,25(OH)2D3 on cholesterol metabolism was examined in human HepG2 and THP-1 macrophage-derived foam cells. Vitamin D-deficiency decreased plasma HDL levels, expression of liver-X-receptors (LXRs), ATP binding cassette transporter A1 (ABCA1) and ABCG1, and promoted cholesterol accumulation and atherosclerosis in hypercholesterolemic microswine. Vitamin D promoted nascent HDL formation in HepG2 cells via ABCA1-mediated cholesterol efflux. CYP27B1 and VDR were predominantly present in the CD206 + M2 macrophage foam cell-accumulated cores in coronary artery plaques. 1,25(OH)2D3 increased the expression of LXRs, ABCA1, ABCG1, and promoted cholesterol efflux in THP-1 macrophage-derived foam cells. 1,25(OH)2D3 decreased intracellular free cholesterol and polarized macrophages to M2-phenotype with decreased expression of TNF-α, IL-1β, IL-6 under LPS-stimulation. 1,25(OH)2D3 markedly induced CYP27A1 expression via a VDR-dependent JNK1/2 signaling pathway and increased 27-hydroxycholesterol levels, which induced LXRs, ABCA1 and ABCG1 expression, stimulated cholesterol efflux that was inhibited by VDR antagonist and JNK1/2 signaling inhibitor in THP-1 macrophage-derived foam cell. Vitamin D protects against atherosclerosis in hypercholesterolemic swine via controlling cholesterol efflux and macrophage polarization via increased CYP27A1 activation.