Anacetrapib reduces (V)LDL-cholesterol by inhibition of CETP activity and reduction of plasma PCSK9
article
Recently, we showed in APOE*3-Leiden.CETP mice that anacetrapib attenuated atherosclerosis development by reducing (V)LDL-C rather than by raising HDL-C. Here, we investigated the mechanism by which anacetrapib reduces (V)LDL-C and whether this effect was dependent on the inhibition of CETP. APOE*3-Leiden.CETP mice were fed a Western type diet alone or supplemented with anacetrapib (30 mg/kg body weight/d). Microarray analyses of livers revealed down-regulation of the cholesterol biosynthesis pathway (P<0.001) and predicted down regulation of sterol regulatory element-binding protein-1 and -2 controlled pathways (z-score -2.56 and z-score -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 protein 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 APOE*3-Leiden 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. Anacetrapib reduces (V)LDL-C by two mechanisms: 1) inhibition of CETP activity, resulting in remodelled VLDL that are more susceptible to hepatic uptake and 2) a CETP-independent reduction of plasma PCSK9 levels that has the potential to increase LDL receptor mediated hepatic remnant clearance.
Topics
CETPCholesterolMetabolismDrug therapyHypolipidemic drugsLDLMetabolismLipidsLipoproteinsPCSK9AnacetrapibApolipoprotein BCholesterol ester transfer proteinLow density lipoprotein receptorProprotein convertase subtilisin kexin type 9RNASerine proteinaseSterol regulatory element binding protein 1Sterol regulatory element binding protein 2TriacylglycerolUnclassified drugVery low density lipoprotein cholesterolAnimal experimentAnimal tissueAtherosclerosisCholesterol synthesisControlled studyDown regulationDrug mechanismEnzyme blood levelFemaleLiverMicroarray analysisMouseNonhumanPolymerase chain reactionProtein expressionRNA isolationWestern diet
TNO Identifier
528177
Source
Journal of Lipid Research, 56(11), pp. 2085-2093.
Pages
2085-2093