文章基本信息

标题：The molecular mechanisms underlying the reduction of LDL apoB-100 by ezetimibe plus simvastatin
本地全文：下载
作者：Telford, Dawn E. ; Sutherland, Brian G. ; Edwards, Jane Y. 等
期刊名称：JLR Papers In Press
印刷版ISSN：0022-2275
电子版ISSN：1539-7262
出版年度：2007
卷号：48
期号：3
页码：699-708
DOI：10.1194/jlr.M600439-JLR200
出版社：American Society for Biochemistry and Molecular Biology
摘要：The combination of ezetimibe, an inhibitor of Niemann-Pick C1-like1 protein (NPC1L1), and an HMG-CoA reductase inhibitor decreasescholesterol absorption and synthesis. In clinical trials, ezetimibeplus simvastatin produces greater LDL-cholesterol reductionsthan does monotherapy. The molecular mechanism for this enhancedefficacy has not been defined. Apolipoprotein B-100 (apoB-100)kinetics were determined in miniature pigs treated with ezetimibe(0.1 mg/kg/day), ezetimibe plus simvastatin (10 mg/kg/day),or placebo (n = 7/group). Ezetimibe decreased cholesterol absorption(–79%) and plasma phytosterols (–91%), which werenot affected further by simvastatin. Ezetimibe increased plasmalathosterol (+65%), which was prevented by addition of simvastatin.The combination decreased total cholesterol (–35%) andLDL-cholesterol (–47%). VLDL apoB pool size decreased26%, due to a 35% decrease in VLDL apoB production. LDL apoBpool size decreased 34% due to an 81% increase in the fractionalcatabolic rate, both of which were significantly greater thanmonotherapy. Combination treatment decreased hepatic microsomalcholesterol (–29%) and cholesteryl ester (–65%)and increased LDL receptor (LDLR) expression by 240%. The combinationincreased NPC1L1 expression in liver and intestine, consistentwith increased SREBP2 expression. Ezetimibe plus simvastatindecreases VLDL and LDL apoB-100 concentrations through reducedVLDL production and upregulation of LDLR-mediated LDL clearance. Supplementary key words cholesterol absorption • lipoproteins • apolipoprotein B kinetics • gene expression Abbreviations: apo B, apolipoprotein B; CE, cholesteryl ester; FC, free cholesterol; FCR, fractional catabolic rate; IG, intragastric gavage; LDLR, LDL receptor; NPC1L1, Niemann-Pick C1-like 1 protein; NS, not significant; qRT-PCR, quantitative real-time PCR; TC, total cholesterol; TG, triglyceride