Combination of MEK1/2 inhibitor and LXR ligand synergistically inhibit atherosclerosis in LDLR deficient mice
Combination of MEK1/2 inhibitor and LXR ligand synergistically inhibit atherosclerosis in LDLR deficient mice
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MEK1/2抑制剂与LXR配体的组合协同抑制LDLR缺陷小鼠的动脉粥样硬化
DOI：
10.1016/j.bbrc.2019.11.115
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发表时间：
2020
影响因子：
3.1
通讯作者：
Chen Yuanli
中科院分区：
文献类型：
--
作者：
Yang Jie;Liu Lipei;Yang Xiaoxiao;Duan Yajun;Zeng Peng;Yang Shu;Ma Chuanrui;Li Xiaoju;Han Jihong;Chen Yuanli
LXR配体(T0901317)和MEK1/2抑制剂(U0126)联合应用不仅能减轻载脂蛋白E缺陷小鼠的动脉粥样硬化，而且能阻断LXR配体诱导的脂肪肝和高甘油三酯血症。然而，在LDLR缺陷(LDLR-/-)小鼠中，T0901317和U0126的联合作用值得进一步研究，因为LDLR缺陷而不是apoE缺陷在人类中发生的频率很高。在此，我们验证了这种联合治疗对LDLR-/-小鼠动脉粥样硬化形成的有效性，以展示其在临床上的潜在应用。我们发现，尽管T0901317或U0126单独减少了高脂饲料喂养的LDLR-/-小鼠面部和主动脉根部的动脉粥样硬化斑块，但它们的联合应用以协同方式抑制了病变。联合使用U0126和T0901317对血清总胆固醇水平没有影响。T0901317降低了高密度脂蛋白-胆固醇水平，由联合U0126恢复。同时，U0126可减轻T0901317引起的甘油三酯蓄积，而T0901317的主要不良反应限制了其临床应用。机制上，U0126通过抑制肝脏脂肪酸合成酶(FASN)的表达来减少脂肪酸的新合成，从而纠正T0901317诱导的甘油三酯过量产生。总之，我们的研究表明，MEK1/2抑制剂和LXR配体联合使用可以协同减轻LDLR缺陷小鼠的动脉粥样硬化，而不会产生造脂副作用。
Combined LXR ligand (T0901317) and MEK1/2 inhibitor (U0126) not only reduces atherosclerosis in apoE deficient mice, but also blocks LXR ligand-induced fatty liver and hypertriglyceridemia. However, the atheroprotective function of combined T0901317 and U0126 should be further investigated in LDLR deficient (LDLR-/-) mice since deficiency of LDLR not apoE can occur to humans with a high frequency. Herein, we validated the effectiveness of this combinational therapy on the development of atherosclerosis in LDLR-/-mice to demonstrate its potential application in clinic. We found although T0901317 or U0126 alone reduced atherosclerotic plaques inen faceand aortic root areas in HFD-fed LDLR-/-mice, their combination inhibited lesions in a synergistic manner. Combined U0126 and T0901317 had no effect on serum total cholesterol levels. T0901317 deceased HDL-cholesterol levels, which was restored by combined U0126. Meanwhile, U0126 alleviated T0901317-induced triglyceride accumulation, the major adverse effect of T0901317 which limits its clinical utility. Mechanistically, U0126 reduced fatty acidde novosynthesis by inhibiting hepatic fatty acid synthase (FASN) expression, thereby correcting T0901317-induced triglyceride overproduction. In conclusion, our study demonstrates that combination of MEK1/2 inhibitor and LXR ligand can synergistically reduce atherosclerosis in LDLR deficient mice without lipogenic side effects.