期刊
JOURNAL OF LIPID RESEARCH
卷 56, 期 11, 页码 2085-2093出版社
ELSEVIER
DOI: 10.1194/jlr.M057794
关键词
cholesteryl ester transfer protein; cholesterol; metabolism; drug therapy; hypolipidemic drugs; low density lipoprotein; metabolism; lipids; lipoproteins; metabolism; proprotein convertase subtilisin; kexin type 9; very low density lipoprotein
资金
- Center for Translational Molecular Medicine [01C-104]
- Netherlands Heart Foundation [2009T038]
- Merck Sharp Dohme (MSD)
- Continuing Medical Education (CME)
- Astellas
- Astra-Zeneca
- Biotronik
- Boston Scientific
- Daiichi Sankyo
- Lilly
- Genzyme
- Medtronic
- Merck-Schering-Plough
- Pfizer
- Orbus Neich
- Novartis
- Roche
- Servier
- Sanofi Aventis
- Netherlands Heart Foundation
- Interuniversity Cardiology Institute of the Netherlands
- European Community
- Amgen
Recently, we showed in APOE*3-Leiden cholesteryl ester transfer protein (E3L.CETP) mice that anacetrapib attenuated atherosclerosis development by reducing (V)LDL cholesterol [(V)LDL-C] rather than by raising HDL cholesterol. Here, we investigated the mechanism by which anacetrapib reduces (V)LDL-C and whether this effect was dependent on the inhibition of CETP. E3L.CETP mice were fed a Western-type diet alone or supplemented with anacetrapib (30 mg/kg body weight per day). Microarray analyses of livers revealed downregulation of the cholesterol biosynthesis pathway (P < 0.001) and predicted downregulation of pathways controlled by sterol regulatory element-binding proteins 1 and 2 (z-scores -2.56 and -2.90, respectively; both P < 0.001). These data suggest increased supply of cholesterol to the liver. We found that hepatic proprotein convertase subtilisin/kexin type 9 (Pcsk9) expression was decreased (-28%, P < 0.01), accompanied by decreased plasma PCSK9 levels (-47%, P < 0.001) and increased hepatic LDL receptor (LDLr) content (+64%, P < 0.01). Consistent with this, anacetrapib increased the clearance and hepatic uptake (+25%, P < 0.001) of [C-14]cholesteryl oleate-labeled VLDL-mimicking particles. In E3L mice that do not express CETP, anacetrapib still decreased (V)LDL-C and plasma PCSK9 levels, indicating that these effects were independent of CETP inhibition. We conclude that anacetrapib reduces (V)LDL-C by two mechanisms: 1) inhibition of CETP activity, resulting in remodeled VLDL particles that are more susceptible to hepatic uptake; and 2) a CETP-independent reduction of plasma PCSK9 levels that has the potential to increase LDLr-mediated hepatic remnant clearance.
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