The molecular mechanisms underlying the reduction of LDL apoB-100 by ezetimibe plus simvastatin.
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.
Telford
Dawn E
DE
Vascular Biology, Robarts Research Institute, The University of Western Ontario, Canada.
Sutherland
Brian G
BG
Edwards
Jane Y
JY
Andrews
Joseph D
JD
Barrett
P Hugh R
PH
Huff
Murray W
MW
D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D053299:Apolipoprotein B-100 / Q000097:blood*; D001384:Azetidines / Q000494:pharmacology*; D002784:Cholesterol / Q000378:metabolism; D000069438:Ezetimibe; D005260:Female; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D050356:Lipid Metabolism / Q000187:drug effects; D008055:Lipids / Q000097:blood; D008074:Lipoproteins / Q000097:blood; D008075:Lipoproteins, HDL / Q000097:blood; D008077:Lipoproteins, LDL / Q000097:blood; D008079:Lipoproteins, VLDL / Q000097:blood; D008954:Models, Biological; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019821:Simvastatin / Q000494:pharmacology*; D013552:Swine
D018528:ATP-Binding Cassette Transporters; D000924:Anticholesteremic Agents; D053299:Apolipoprotein B-100; D001384:Azetidines; D008055:Lipids; D008074:Lipoproteins; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D008079:Lipoproteins, VLDL; D012333:RNA, Messenger; D011973:Receptors, LDL; D002784:Cholesterol; D019821:Simvastatin; D000069438:Ezetimibe