Anacetrapib reduces (V)LDL cholesterol by inhibition of CETP activity and reduction of plasma PCSK9.
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 [(14)C]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.
Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.
Sam J L
SJ
van der Tuin
Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands The Netherlands Organization for Applied Scientific Research (TNO), Metabolic Health Research, Gaubius Laboratory, Leiden, The Netherlands.
Susan
S
Kühnast
Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.
Jimmy F P
JF
Berbée
TNO, Microbiology and Systems Biology, Zeist, The Netherlands.
Lars
L
Verschuren
The Netherlands Organization for Applied Scientific Research (TNO), Metabolic Health Research, Gaubius Laboratory, Leiden, The Netherlands.
Elsbet J
EJ
Pieterman
Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands The Netherlands Organization for Applied Scientific Research (TNO), Metabolic Health Research, Gaubius Laboratory, Leiden, The Netherlands.
Louis M
LM
Havekes
Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands The Netherlands Organization for Applied Scientific Research (TNO), Metabolic Health Research, Gaubius Laboratory, Leiden, The Netherlands.
José W A
JW
van der Hoorn
Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.
Patrick C N
PC
Rensen
Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.
J Wouter
JW
Jukema
The Netherlands Organization for Applied Scientific Research (TNO), Metabolic Health Research, Gaubius Laboratory, Leiden, The Netherlands.
Hans M G
HM
Princen
Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Ko
K
Willems van Dijk
Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Yanan
Y
Wang
D000818:Animals; D002318:Cardiovascular Diseases / Q000517:prevention & control; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D015243:Cholesterol, VLDL / Q000097:blood*; D015536:Down-Regulation; D004353:Drug Evaluation, Preclinical; D050171:Dyslipidemias / Q000097:blood* / Q000188:drug therapy / Q000201:enzymology; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D053263:Gene Regulatory Networks; D000960:Hypolipidemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D050356:Lipid Metabolism / Q000187:drug effects; D053858:Metabolic Networks and Pathways; D008822:Mice, Transgenic; D023303:Oxazolidinones / Q000494:pharmacology* / Q000627:therapeutic use; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000097:blood*; D012697:Serine Endopeptidases / Q000097:blood*
D053480:Cholesterol Ester Transfer Proteins; D015243:Cholesterol, VLDL; D000960:Hypolipidemic Agents; D023303:Oxazolidinones; C472126:Pcsk9 protein, mouse; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; C530884:anacetrapib
cholesterol/metabolism; cholesteryl ester transfer protein; drug therapy/hypolipidemic drugs; lipids; lipoproteins/metabolism; low density lipoprotein/metabolism; proprotein convertase subtilisin/kexin type 9; very low density lipoprotein