Anacetrapib reduces (V)LDL cholesterol by inhibition of CETP activity and reduction of plasma PCSK9 |
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Authors: | Sam J L van der Tuin Susan Kühnast Jimmy F P Berbée Lars Verschuren Elsbet J Pieterman Louis M Havekes José W A van der Hoorn Patrick C N Rensen J Wouter Jukema Hans M G Princen Ko Willems van Dijk Yanan Wang |
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Institution: | 8. Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands;4. Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands;2. Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands;11. TNO, Microbiology and Systems Biology, Zeist, The Netherlands |
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Abstract: | 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 14C]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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Keywords: | 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 |
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