Inhibition of ABCA1 protein degradation promotes HDL cholesterol efflux capacity and RCT and reduces atherosclerosis in mice
Inhibition of ABCA1 protein degradation promotes HDL cholesterol efflux capacity and RCT and reduces atherosclerosis in mice
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DOI：
10.1194/jlr.m054742
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发表时间：
2015-05-01
影响因子：
6.5
通讯作者：
Zhu, HaiBo
中科院分区：
文献类型：
--
作者：
Huang, LinZhang;Fan, BaoYan;Zhu, HaiBo
ABCA1在apoa - 1的初始脂化中起关键作用，apoa - 1产生循环中的高密度脂蛋白胆固醇。虽然已知ABCA1的转录上调促进HDL的形成和逆向胆固醇转运（RCT），但尚不清楚ABCA1蛋白降解的抑制如何影响HDL的功能。利用小分子三乙酰-3-羟基苯基腺苷（IMM-H007），我们确定了ABCA1蛋白降解的衰减如何影响HDL胆固醇外排能力、RCT和动脉粥样硬化病变形成。脉冲追踪分析显示IMM-H007抑制ABCA1降解并促进其在巨噬细胞中的细胞表面定位，另外在巨噬细胞中的研究表明IMM-H007从而促进胆固醇外排。IMM-H007处理Paigen饮食喂养小鼠引起循环HDL水平升高，增加HDL的胆固醇外排能力，增强巨噬细胞到血浆、肝脏和粪便的体内RCT。此外，IMM-H007抑制ABCA1降解可减少apoE（-/-）小鼠动脉粥样硬化斑块的形成。因此，通过对ABCA1表达细胞和循环HDL功能的影响，IMM-H007抑制ABCA1蛋白降解可促进HDL胆固醇外流能力和RCT，并减轻动脉粥样硬化。IMM-H007可能是开发增强HDL功能药物的先导化合物。
ABCA1 plays a key role in the initial lipidation of apoA-I, which generates circulating HDL cholesterol. Whereas it is known that the transcriptional upregulation of ABCA1 promotes HDL formation and reverse cholesterol transport (RCT), it is not known how the inhibition of ABCA1 protein degradation impacts HDL function. Employing the small molecule triacetyl-3-hydroxyphenyladenosine (IMM-H007), we determined how the attenuation of ABCA1 protein degradation affects HDL cholesterol efflux capacity, RCT, and atherosclerotic lesion formation. Pulse-chase analysis revealed that IMM-H007 inhibits ABCA1 degradation and facilitates its cell-surface localization in macrophages, and additional studies in macrophages showed that IMM-H007 thereby promotes cholesterol efflux. IMM-H007 treatment of Paigen diet-fed mice caused an increase in circulating HDL level, it increased the cholesterol efflux capacity of HDL, and it enhanced in vivo RCT from macrophages to the plasma, liver, and feces. Furthermore, ABCA1 degradation suppression by IMM-H007 reduced atherosclerotic plaque formation in apoE(-/-) mice. Thus, via effects on both ABCA1-expressing cells and circulating HDL function, the inhibition of ABCA1 protein degradation by IMM-H007 promotes HDL cholesterol efflux capacity and RCT and attenuates atherogenesis. IMM-H007 potentially represents a lead compound for the development of agents to augment HDL function.