抑制细胞外信号调节激酶1/2（ERK1/2）并激活肝X受体（LXR）可协同减少载脂蛋白E缺陷小鼠的动脉粥样硬化病变。
Inhibition of ERK1/2 and activation of LXR synergistically reduce atherosclerotic lesions in ApoE-deficient mice.
作者信息
Chen Yuanli, Duan Yajun, Yang Xiaoxiao, Sun Lei, Liu Mengyang, Wang Qixue, Ma Xingzhe, Zhang Wenwen, Li Xiaoju, Hu Wenquan, Miao Robert Q, Xiang Rong, Hajjar David P, Han Jihong
机构信息
From the State Key Laboratory of Medicinal Chemical Biology (Y.C., Y.D., J.H.), Collaborative Innovation Center of Biotherapy (Y.C., Y.D., R.X., J.H.), College of Life Sciences (Y.D., X.Y., L.S., M.L., Q.W., X.M., W.Z., X.L., J.H.), Nankai University, Tianjin, China; Department of Surgery, Medical College of Wisconsin, Milwaukee (W.H., R.Q.M.); and Department of Pathology, Weill Medical College of Cornell University, New York, NY (D.P.H.).
出版信息
Arterioscler Thromb Vasc Biol. 2015 Apr;35(4):948-59. doi: 10.1161/ATVBAHA.114.305116. Epub 2015 Feb 19.
OBJECTIVE
Activation of liver X receptor (LXR) inhibits atherosclerosis but induces hypertriglyceridemia. In vitro, it has been shown that mitogen-activated protein kinase kinase 1/2 (MEK1/2) inhibitor synergizes LXR ligand-induced macrophage ABCA1 expression and cholesterol efflux. In this study, we determined whether MEK1/2 (U0126) and LXR ligand (T0901317) can have a synergistic effect on the reduction of atherosclerosis while eliminating LXR ligand-induced fatty livers and hypertriglyceridemia. We also set out to identify the cellular mechanisms of the actions.
APPROACH AND RESULTS
Wild-type mice were used to determine the effect of U0126 on a high-fat diet or high-fat diet plus T0901317-induced transient dyslipidemia and liver injury. ApoE deficient (apoE(-/-)) mice or mice with advanced lesions were used to determine the effect of the combination of T0901317 and U0126 on atherosclerosis and hypertriglyceridemia. We found that U0126 protected animals against T0901317-induced transient or long-term hepatic lipid accumulation, liver injury, and hypertriglyceridemia. Meanwhile, the combination of T0901317 and U0126 inhibited the development of atherosclerosis in a synergistic manner and reduced advanced lesions. Mechanistically, in addition to synergistic induction of macrophage ABCA1 expression, the combination of U0126 and T0901317 maintained arterial wall integrity, inhibited macrophage accumulation in aortas and formation of macrophages/foam cells, and activated reverse cholesterol transport. The inhibition of T0901317-induced lipid accumulation by the combined U0126 might be attributed to inactivation of lipogenesis and activation of lipolysis/fatty acid oxidation pathways.
CONCLUSIONS
Our study suggests that the combination of mitogen-activated protein kinase kinase 1/2 inhibitor and LXR ligand can function as a novel therapy to synergistically reduce atherosclerosis while eliminating LXR-induced deleterious effects.
目的
肝X受体（LXR）的激活可抑制动脉粥样硬化，但会诱发高甘油三酯血症。在体外实验中，有研究表明丝裂原活化蛋白激酶激酶1/2（MEK1/2）抑制剂可增强LXR配体诱导的巨噬细胞ABCA1表达及胆固醇外流。在本研究中，我们探究了MEK1/2（U0126）与LXR配体（T0901317）联合使用时，能否在消除LXR配体所致脂肪肝和高甘油三酯血症的同时，对动脉粥样硬化的减轻产生协同作用。我们还着手确定这些作用的细胞机制。
方法与结果
利用野生型小鼠来确定U0126对高脂饮食或高脂饮食加T0901317诱导的短暂性血脂异常和肝损伤的影响。使用载脂蛋白E缺陷（apoE(-/-)）小鼠或患有晚期病变的小鼠来确定T0901317与U012结6合对动脉粥样硬化和高甘油三酯血症的影响。我们发现，U0保护动物免受T0901317诱导的短暂或长期肝脏脂质蓄积、肝损伤及高甘油三酯血症。同时，T0901317与U0126联合使用以协同方式抑制动脉粥样硬化的发展并减轻晚期病变。从机制上来说，除了协同诱导巨噬细胞ABCA1表达外，U0126与T0901317联合使用可维持动脉壁完整性，抑制巨噬细胞在主动脉中的积聚以及巨噬细胞/泡沫细胞的形成，并激活逆向胆固醇转运。联合使用U0126对T0901317诱导的脂质蓄积的抑制作用可能归因于脂肪生成的失活以及脂解/脂肪酸氧化途径的激活。
结论
我们的研究表明，丝裂原活化蛋白激酶激酶1/2抑制剂与LXR配体联合使用可作为一种新型疗法，在消除LXR诱导的有害作用的同时，协同减轻动脉粥样硬化。
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