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J. Lipid Res.
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A more recent version of this article appeared on March 1, 2007

Papers In Press, published online ahead of print November 27, 2006
J. Lipid Res., doi:10.1194/jlr.M600439-JLR200
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Submitted on October 3, 2006
Revised on November 21, 2006
Accepted on November 27, 2006

The molecular mechanisms underlying the reduction of LDL apoB100 by ezetimibe plus simvastatin

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

Robarts Research Institute, London, Ontario N6A 5K8

Corresponding Author: 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 monotherapy. The molecular mechanism for this enhanced efficacy has not been defined. Apolipoprotein (apo) B100 kinetics were determined in miniature pigs treated with ezetimibe (0.1 mg/kg/d), ezetimibe plus simvastatin (10 mg/kg/d) 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 (FCR), both of which were significantly greater than monotherapy. Combination treatment decreased hepatic microsomal cholesterol (-29%) and cholesteryl ester (-65%) and increased LDL receptor expression by 240%. The combination increased NPC1L1 expression in liver and intestine, consistent with increased SREBP2 expression. Ezetimibe plus simvastatin decreases VLDL and LDL apoB100 concentrations through reduced VLDL production and upregulation of LDL-receptor-mediated LDL clearance.


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