Title
Anacetrapib reduces (V)LDL-cholesterol by inhibition of CETP activity and reduction of plasma PCSK9
Author
van der Tuin, S.J.
Kühnast, S.
Berbée, J.
Verschuren, L.
Pieterman, E.J.
Havekes, L.M.
van der Hoorn, J.W.
Rensen, P.C.
Jukema, J.W.
Princen, H.M.
Willems van Dijk, K.
Wang, Y.
Publication year
2015
Abstract
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.
Subject
Life
MHR - Metabolic Health Research MSB - Microbiology and Systems Biology
ELSS - Earth, Life and Social Sciences
Biomedical Innovation
Health
Healthy Living
CETP
Cholesterol
Metabolism
Drug therapy
Hypolipidemic drugs
LDL
Metabolism
Lipids
Lipoproteins
PCSK9
Anacetrapib
Apolipoprotein B
Cholesterol ester transfer protein
Low density lipoprotein receptor
Proprotein convertase subtilisin kexin type 9
RNA
Serine proteinase
Sterol regulatory element binding protein 1
Sterol regulatory element binding protein 2
Triacylglycerol
Unclassified drug
Very low density lipoprotein cholesterol
Animal experiment
Animal tissue
Atherosclerosis
Cholesterol synthesis
Controlled study
Down regulation
Drug mechanism
Enzyme blood level
Female
Liver
Microarray analysis
Mouse
Nonhuman
Polymerase chain reaction
Protein expression
RNA isolation
Western diet
To reference this document use:
http://resolver.tudelft.nl/uuid:8bc55533-9411-4f87-9b5e-cb65682f7b62
DOI
https://doi.org/10.1194/jlr.m057794
TNO identifier
528177
Source
Journal of Lipid Research, 56 (11), 2085-2093
Document type
article