| Autor: |
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 |
| Jazyk: |
angličtina |
| Rok vydání: |
2015 |
| Předmět: |
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| Zdroj: |
Journal of Lipid Research, Vol 56, Iss 11, Pp 2085-2093 (2015) |
| Druh dokumentu: |
article |
| ISSN: |
0022-2275 |
| DOI: |
10.1194/jlr.M057794 |
| Popis: |
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. |
| Databáze: |
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