Liu Zhaoyu, Zhu Huaiping, Dai Xiaoyan, Wang Cheng, Ding Ye, Song Ping, Zou Ming-Hui
From the Center for Molecular and Translational Medicine, Georgia State University, Atlanta.
Circ Res. 2017 Oct 13;121(9):1047-1057. doi: 10.1161/CIRCRESAHA.117.311546. Epub 2017 Aug 21.
LKB1 (liver kinase B1) is a serine/threonine kinase and tumor suppressor, which regulates the homeostasis of hematopoietic cells and immune responses. Macrophages transform into foam cells upon taking-in lipids. No role for LKB1 in foam cell formation has previously been reported.
We sought to establish the role of LKB1 in atherosclerotic foam cell formation.
LKB1 expression was examined in human carotid atherosclerotic plaques and in western diet-fed atherosclerosis-prone Ldlr and ApoE mice. LKB1 expression was markedly reduced in human plaques when compared with nonatherosclerotic vessels. Consistently, time-dependent reduction of LKB1 levels occurred in atherosclerotic lesions in western diet-fed Ldlr and ApoE mice. Exposure of macrophages to oxidized low-density lipoprotein downregulated LKB1 in vitro. Furthermore, LKB1 deficiency in macrophages significantly increased the expression of SRA (scavenger receptor A), modified low-density lipoprotein uptake and foam cell formation, all of which were abolished by blocking SRA. Further, we found LKB1 phosphorylates SRA resulting in its lysosome degradation. To further investigate the role of macrophage LKB1 in vivo, ApoELKB1LysM and ApoELKB1 mice were fed with western diet for 16 weeks. Compared with ApoELKB1 wild-type control, ApoELKB1LysM mice developed more atherosclerotic lesions in whole aorta and aortic root area, with markedly increased SRA expression in aortic root lesions.
We conclude that macrophage LKB1 reduction caused by oxidized low-density lipoprotein promotes foam cell formation and the progression of atherosclerosis.
肝脏激酶B1（LKB1）是一种丝氨酸/苏氨酸激酶和肿瘤抑制因子，可调节造血细胞的稳态和免疫反应。巨噬细胞摄取脂质后会转变为泡沫细胞。此前尚无关于LKB1在泡沫细胞形成中作用的报道。
我们试图确定LKB1在动脉粥样硬化泡沫细胞形成中的作用。
检测了LKB1在人类颈动脉粥样硬化斑块以及喂食西方饮食的易患动脉粥样硬化的Ldlr和ApoE小鼠中的表达。与非动脉粥样硬化血管相比，人类斑块中LKB1的表达明显降低。同样，在喂食西方饮食的Ldlr和ApoE小鼠的动脉粥样硬化病变中，LKB1水平随时间下降。体外实验中，巨噬细胞暴露于氧化型低密度脂蛋白会下调LKB1的表达。此外，巨噬细胞中LKB1的缺失显著增加了清道夫受体A（SRA）的表达、修饰型低密度脂蛋白的摄取以及泡沫细胞的形成，而通过阻断SRA，所有这些变化均被消除。此外，我们发现LKB1使SRA磷酸化，导致其在溶酶体中降解。为了进一步研究巨噬细胞LKB1在体内的作用，给ApoELKB1LysM和ApoELKB1小鼠喂食西方饮食16周。与ApoELKB1野生型对照相比，ApoELKB1LysM小鼠在整个主动脉和主动脉根部区域出现了更多的动脉粥样硬化病变，主动脉根部病变中SRA的表达明显增加。
我们得出结论，氧化型低密度脂蛋白导致的巨噬细胞LKB1减少会促进泡沫细胞的形成和动脉粥样硬化的进展。
