MEK1/2 inhibitors activate macrophage ABCG1 expression and reverse cholesterol transport An anti-atherogenic function of ERK1/2 inhibition
MEK1/2 inhibitors activate macrophage ABCG1 expression and reverse cholesterol transport An anti-atherogenic function of ERK1/2 inhibition
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MEK1/2 抑制剂激活巨噬细胞 ABCG1 表达并逆转胆固醇转运 - ERK1/2 抑制的抗动脉粥样硬化功能。
DOI：
10.1016/j.bbalip.2016.06.017
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发表时间：
2016
影响因子：
4.8
通讯作者：
Han Jihong
中科院分区：
文献类型：
--
作者：
Zhang Ling;Chen Yuanli;Yang Xiaoxiao;Yang Jie;Cao Xingyue;Li Xiaoju;Li Luyuan;Miao Qing Robert;Hajjar David P.;Duan Yajun;Han Jihong
肝X受体（LXR）可激活atp结合盒转运蛋白G1 （ABCG1）的表达，ABCG1是一种促进胆固醇外泄到HDL的分子。在本研究中，我们研究了抑制ERK1/2是否可以激活巨噬细胞ABCG1的表达和功能。MEK1/2抑制剂PD98059和U0126增加了ABCG1 mRNA和蛋白的表达，激活了ABCG1天然启动子，但没有激活LXR响应元件缺失的启动子。ABCG1 siRNA抑制ABCG1表达确实增强了巨噬细胞/泡沫细胞的形成，减弱了MEK1/2抑制剂对泡沫细胞形成的抑制作用。MEK1/2抑制剂激活巨噬细胞向HDLin的胆固醇外排，并增强体内胆固醇逆向转运（RCT）。接受U0126治疗的ApoE缺陷（ApoE−/−）小鼠主动脉根部窦性病变减少，这与病变区域活化的巨噬细胞ABCG1表达有关。MEK1/2抑制剂协同RXR激动剂，而不是LXR激动剂，诱导ABCG1表达。此外，MEK1/2抑制剂诱导ABCG1表达与SIRT1 （LXR活性的正调节因子）的激活以及SULT2B1和RIP140 （LXR活性的负调节因子）的失活有关。综上所述，我们的研究表明，MEK1/2抑制剂激活巨噬细胞ABCG1表达/RCT，并通过多种机制抑制泡沫细胞形成和病变发展，支持ERK1/2抑制抗动脉粥样硬化的概念。
Expression of ATP-binding cassette transporter G1 (ABCG1), a molecule facilitating cholesterol efflux to HDL, is activated by liver X receptor (LXR). In this study, we investigated if inhibition of ERK1/2 can activate macrophage ABCG1 expression and functions. MEK1/2 inhibitors, PD98059 and U0126, increased ABCG1 mRNA and protein expression, and activated the natural ABCG1 promoter but not the promoter with the LXR responsive element (LXRE) deletion. Inhibition of ABCG1 expression by ABCG1 siRNA did enhance the formation of macrophage/foam cells and it attenuated the inhibitory effect of MEK1/2 inhibitors on foam cell formation. MEK1/2 inhibitors activated macrophage cholesterol efflux to HDLin vitro, and they enhanced reverse cholesterol transport (RCT)in vivo. ApoE deficient (apoE−/−) mice receiving U0126 treatment had reduced sinus lesions in the aortic root which was associated with activated macrophage ABCG1 expression in the lesion areas. MEK1/2 inhibitors coordinated the RXR agonist, but not the LXR agonist, to induce ABCG1 expression. Furthermore, induction of ABCG1 expression by MEK1/2 inhibitors was associated with activation of SIRT1, a positive regulator of LXR activity, and inactivation of SULT2B1 and RIP140, two negative regulators of LXR activity. Taken together, our study suggests that MEK1/2 inhibitors activate macrophage ABCG1 expression/RCT, and inhibit foam cell formation and lesion development by multiple mechanisms, supporting the concept that ERK1/2 inhibition is anti-atherogenic.