Effects of ezetimibe and/or simvastatin on LDL receptor protein expression and on LDL receptor and HMG-CoA reductase gene expression: A randomized trial in healthy men
Effects of ezetimibe and/or simvastatin on LDL receptor protein expression and on LDL receptor and HMG-CoA reductase gene expression: A randomized trial in healthy men
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DOI：
10.1016/j.atherosclerosis.2007.09.034
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发表时间：
2008-05-01
期刊：
影响因子：
5.3
通讯作者：
Krone, Wilhelm
中科院分区：
文献类型：
--
作者：
Gouni-Berthold, Ioanna;Berthold, Heiner K.;Krone, Wilhelm
目的：辛伐他汀（一种HMG-CoA还原酶抑制剂）和依折麦布（一种尼曼-匹克C1样1蛋白抑制剂）联合使用可降低胆固醇合成和吸收，并降低循环LDL-胆固醇浓度。这种组合的显着降脂作用的分子机制尚未完全阐明在human.Methods和结果：一个中心，前瞻性，随机，平行三组研究72名健康男性（平均年龄32 - 19岁，平均体重指数25.7 +/- 3.2公斤/米（2））。每组24例受试者接受依折麦布（10 mg/天）、辛伐他汀（40 mg/天）或其联合治疗14天。在基线和研究结束时测量脂质水平、非胆固醇固醇与胆固醇浓度的比值（用作胆固醇合成和吸收的标志物）、细胞表面LDL受体（LDLR）蛋白以及单核血细胞中的LDLR和HMG-CoA还原酶基因表达。所有组的LDL-C均降低。辛伐他汀降低，依折麦布增加，二者联合对HMG-CoA还原酶活性无影响。辛伐他汀和依折麦布与辛伐他汀联合用药可增加HMG-CoA还原酶和LDLR基因表达，而依折麦布无影响。细胞表面LDLR蛋白表达在所有组中保持不变。依折麦布和辛伐他汀的组合增加了丝氨酸蛋白酶前蛋白转化酶枯草杆菌蛋白酶/kexin 9（PCSK 9）的表达，该酶显示出下调LDLR蛋白水平。依折麦布和辛伐他汀联合给药可消除依折麦布诱导的胆固醇合成增加，并上调LDLR基因但不上调蛋白表达，可能通过PCSK 9表达的平行上调介导的作用。(c)2007爱思唯尔爱尔兰有限公司保留所有权利。
Objective: The combination of simvastatin, an HMG-CoA reductase inhibitor, and ezetimibe, an inhibitor of Niemann-Pick C1-like 1 protein, decreases cholesterol synthesis and absorption and reduces circulating LDL-cholesterol concentrations. The molecular mechanisms underlying the pronounced lipid-lowering effects of this combination have not been fully elucidated in humans.Methods and results: One center, prospective, randomized, parallel three-group study in 72 healthy men (mean age 32 19 years, mean body mass index 25.7 +/- 3.2 kg/m(2)). Each group of twenty-four subjects received a 14-day treatment with either ezetimibe (10mg/day), simvastatin (40 mg/day) or their combination. Lipid levels, the ratio of non-cholesterol sterols to cholesterol concentrations (used as markers of cholesterol synthesis and absorption), cell surface LDL receptor (LDLR) protein as well as LDLR and HMG-CoA reductase gene expression in mononuclear blood cells were measured at baseline and at the end of the study. LDL-C decreased in all groups. Simvastatin decreased, ezetimibe increased and their combination had no effect on HMG-CoA reductase activity. Simvastatin and the combination of ezetimibe and simvastatin increased the HMG-CoA reductase and LDLR gene expression while ezetimibe had no effect. The cell surface LDLR protein expression remained unchanged in all groups. The combination of ezetimibe and simvastatin increased the expression of the serine protease proprotein convertase subtilisin/kexin 9 (PCSK9), an enzyme shown to down-regulate LDLR protein levels.Conclusions: The co-administration of ezetimibe and simvastatin abrogates the ezetin-tibe-induced increase in cholesterol synthesis and up-regulates the LDLR gene but not protein expression, an effect possibly mediated through a parallel upregulation of PCSK9 expression. (c) 2007 Elsevier Ireland Ltd. All rights reserved.