Abstract
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.
Highlights
The combination of ezetimibe, an inhibitor of Niemann-Pick C1-like 1 protein (NPC1L1), and an HMGCoA reductase inhibitor decreases cholesterol absorption and synthesis
Ezetimibe plus simvastatin decreased VLDL and LDL apoB-100 concentrations; ezetimibe inhibited cholesterol absorption, and simvastatin blocked the increase in cholesterol synthesis observed with ezetimibe alone
This study demonstrates for the first time in a large-animal model of lipoprotein metabolism the molecular mechanisms underlying the reductions in both VLDL and LDL apoB
Summary
The combination of ezetimibe, an inhibitor of Niemann-Pick C1-like 1 protein (NPC1L1), and an HMGCoA reductase inhibitor decreases cholesterol absorption and synthesis. Ezetimibe plus simvastatin produces greater LDL-cholesterol reductions than does monotherapy. Ezetimibe plus simvastatin decreases VLDL and LDL apoB100 concentrations through reduced VLDL production and upregulation of LDLR-mediated LDL clearance.—Telford, D. The molecular mechanisms underlying the reduction of LDL apoB-100 by ezetimibe plus simvastatin. HMG-CoA reductase inhibitors (statins) decrease cholesterol synthesis primarily in the liver [3], resulting in reduced hepatocyte cholesterol concentrations and, upregulation of the LDLR and enhanced clearance of LDL (as reviewed in Ref. 6). Recent research (14 –16) has revealed that ezetimibe inhibits the transport of cholesterol and phytosterols across the brush border membrane of the intestinal enterocyte by blocking the transport function of its molecular target, Niemann-Pick C 1-like 1 protein (NPC1L1), (as reviewed in Ref. 17). Reduced hepatic cholesterol has been reported in ezetimibetreated mice [14, 18] and dogs [12], and in mice, increases
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