Homocysteine accelerates atherosclerosis via inhibiting LXRα-mediated ABCA1/ABCG1-dependent cholesterol efflux from macrophages
Homocysteine accelerates atherosclerosis via inhibiting LXRα-mediated ABCA1/ABCG1-dependent cholesterol efflux from macrophages
复制标题
同型半胱氨酸通过抑制 LXRα 介导的 ABCA1/ABCG1 依赖性胆固醇从巨噬细胞流出来加速动脉粥样硬化
DOI：
10.1016/j.lfs.2018.10.060
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发表时间：
2018-12-01
期刊：
影响因子：
6.1
通讯作者：
Jia, Shaobin
中科院分区：
文献类型：
--
作者：
Jin, Ping;Bian, Yitong;Jia, Shaobin
目的：巨噬细胞衍生泡沫细胞的形成在动脉粥样硬化的发展中起着至关重要的作用，肝X受体α (LXR α)是巨噬细胞脂质代谢的关键调节因子。同型半胱氨酸（Hcy）是动脉粥样硬化的独立危险因素；然而，Hcy对巨噬细胞脂质代谢的调控及LXR α的作用尚不清楚。本研究旨在探讨Hcy在脂质代谢紊乱和动脉粥样硬化病变中的潜在作用，特别是Hcy对巨噬细胞胆固醇外排的影响及其可能的机制。主要方法：体外观察Hcy干预下THP-1巨噬细胞的脂质积累和胆固醇外排。采用实时荧光定量PCR和western blot检测各组mRNA和蛋白水平。在体内，通过蛋氨酸饮食诱导的ApoE（-/-）小鼠高同型半胱氨酸血症（HHcy）来评估动脉粥样硬化病变和脂质谱。LXR α激动剂T0901317用于验证LXR α在hhcy加速动脉粥样硬化中的作用。关键发现：Hcy促进THP-1巨噬细胞脂质积累，抑制胆固醇外排。HHcy小鼠病变面积增大，斑块内脂质堆积。体外和体内两项研究均显示ATP结合盒转运蛋白A1 （ABCA1）和G1 （ABCG1）的表达降低。T0901317使ABCA1和ABCG1水平升高；逆转THP-1巨噬细胞中巨噬细胞衍生泡沫细胞的形成，并减少ApoE（-/-）小鼠的动脉粥样硬化病变。意义：抑制LXR α介导的ABCA1/ abcg1依赖性胆固醇从巨噬细胞流出是hcy加速动脉粥样硬化的新机制。
Aims: Macrophage-derived foam-cell formation plays a crucial role in the development of atherosclerosis, and liver X receptor alpha (LXR alpha) is a key regulator of lipid metabolism in macrophages. Homocysteine (Hcy) is an independent risk factor of atherosclerosis; however, the regulation of lipid metabolism and role of LXR alpha induced by Hcy in macrophages is still unknown. The present study aimed to investigate the potential role of Hcy in disordered lipid metabolism and atherosclerotic lesions, especially the effects of Hcy on cholesterol efflux in macrophages and the possible mechanisms.Main methods: In vitro, lipid accumulation and cholesterol efflux were evaluated in THP-1 macrophages with Hcy intervention. Real-time quantitative PCR and western blot analyses were used to assess mRNA and protein levels. In vivo, atherosclerotic lesions and lipid profiles were evaluated by methionine diet-induced hyperhomocysteinemia (HHcy) in ApoE(-/-) mice. The LXR alpha agonist T0901317 was used to verify the role of LXR alpha in HHcy-accelerated atherosclerosis.Key findings: Hcy promoted lipid accumulation and inhibited cholesterol efflux in THP-1 macrophages. HHcy mice showed increased lesion area and lipid accumulation in plaque. Both studies in vitro and in vivo showed decreased expression of ATP binding cassette transporter A1 (ABCA1) and G1 (ABCG1). T0901317 treatment increased ABCA1 and ABCG1 levels; reversed macrophage-derived foam-cell formation in THP-1 macrophages and reduced atherosclerotic lesions in ApoE(-/-) mice.Significance: Inhibition of LXR alpha-mediated ABCA1/ABCG1-dependent cholesterol efflux from macrophages is a novel mechanism in Hcy-accelerated atherosclerosis.