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Journal of Lipid Research, Vol. 48, 699-708, March 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

The molecular mechanisms underlying the reduction of LDL apoB-100 by ezetimibe plus simvastatin

Dawn E. Telford^*, Brian G. Sutherland^*, Jane Y. Edwards^*, Joseph D. Andrews^*, P. Hugh R. Barrett and Murray W. Huff^1,*

^* Vascular Biology, Robarts Research Institute, The University of Western Ontario, Canada
School of Medicine and Pharmacology, University of Western Australia, Perth, Australia

The online version of this article (available at http://www.jlr.org) contains an additional table and three figures.

Published, JLR Papers in Press, November 27, 2006.

¹ To whom correspondence should be addressed. e-mail: mhuff{at}uwo.ca

The combination of ezetimibe, an inhibitor of Niemann-Pick C1-like 1 protein (NPC1L1), and an HMG-CoA reductase inhibitor decreases cholesterol absorption and synthesis. In clinical trials, ezetimibe plus simvastatin produces greater LDL-cholesterol reductions than does monotherapy. The molecular mechanism for this enhanced efficacy 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 were not affected further by simvastatin. Ezetimibe increased plasma lathosterol (+65%), which was prevented by addition of simvastatin. The combination decreased total cholesterol (–35%) and LDL-cholesterol (–47%). VLDL apoB pool size decreased 26%, due to a 35% decrease in VLDL apoB production. LDL apoB pool size decreased 34% due to an 81% increase in the fractional catabolic rate, both of which were significantly greater than monotherapy. Combination treatment decreased hepatic microsomal cholesterol (–29%) and cholesteryl ester (–65%) and increased LDL receptor (LDLR) expression by 240%. The combination increased NPC1L1 expression in liver and intestine, consistent with increased SREBP2 expression. Ezetimibe plus simvastatin decreases VLDL and LDL apoB-100 concentrations through reduced VLDL 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

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