The molecular mechanisms underlying the reduction of LDL apoB-100 by ezetimibe plus simvastatins⃞
| Autor: | Dawn E. Telford, Brian G. Sutherland, Jane Y. Edwards, Joseph D. Andrews, P. Hugh R. Barrett, Murray W. Huff |
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| Jazyk: | angličtina |
| Rok vydání: | 2007 |
| Předmět: | |
| Zdroj: | Journal of Lipid Research, Vol 48, Iss 3, Pp 699-708 (2007) |
| Druh dokumentu: | article |
| ISSN: | 0022-2275 74244833 |
| DOI: | 10.1194/jlr.M600439-JLR200 |
| Popis: | 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. |
| Databáze: | Directory of Open Access Journals |
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