Anacetrapib reduces (V)LDL cholesterol by inhibition of CETP activity and reduction of plasma PCSK9

Abstract

High plasma levels of (V)LDL cholesterol [(V)LDL-C] and TGs, as well as low levels of HDL cholesterol (HDL-C), are important risk factors for cardiovascular diseases. The standard treatment for the reduction of cardiovascular disease risk is statin therapy aiming to reduce plasma (V) LDL-C. However, a substantial residual risk remains despite statin treatment. This has prompted the search for secondary treatment targets ( 1, 2 ). Prospective epidemiological studies indicate HDL-C as a potential target ( 3 ). The ratio of plasma (V)LDL-C to HDL-C is to a great extent affected by cholesteryl ester transfer protein (CETP). CETP facilitates the transfer of cholesteryl esters from HDL to (V)LDL in exchange for TG ( 4 ). In several mouse 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 [ 14 C]cholesteryl oleatelabeled 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 CETPindependent reduction of plasma PCSK9 levels that has the potential to increase LDLr-mediated hepatic remnant

Reduction in PCSK9 levels induced by anacetrapib: an off-target effect?

“…The ability of anacetrapib to reduce plasma levels of PCSK9 has now been confi rmed in a study of CETP-expressing APOE*3-Leiden mice published in this issue of the Journal of Lipid Research ( 25 ). In this study, the investigators found that administration of anacetrapib decreased hepatic expression and plasma levels of PCSK9 and increased hepatic LDL receptor levels not only in animals expressing CETP, but also in APOE*3-Leiden mice that do not express CETP.…”

Effect of atorvastatin, cholesterol ester transfer protein inhibition, and diabetes mellitus on circulating proprotein subtilisin kexin type 9 and lipoprotein(a) levels in patients at high cardiovascular risk

“…In contrast to our findings, other CETP inhibitors were shown to reduce PCSK9 expression in vitro, in mice and monkeys. [38][39][40][41] Additional research will be needed to determine whether changes in PCSK9 levels result from a modulation of the canonical sterol regulatory elementbinding protein 2 transcription factor pathway or from off-target effects of torcetrapib.…”

The Study of Longevity: Recent Updates and Further Direction. Part 2

“…Однако завершившиеся рандомизированные, клинические исследования указывают на ограниченную пользу применения этих препаратов в комбинации со стандартной терапией для улучшения исходов у пациентов с высоким сердечно-сосудистым риском, несмотря на ожидаемую модификацию липидного профиля [24], что лишний раз подчеркивает сложности изучения биологии старения. Недавно был установлен дополнительный (оff-target) эффект CEPT-ингибиторов в отношении proprotein convertase subtilisin/kexin 9 (PCSK9) [25,26] и продемонстрирована метаболическая ассоциация между уровнями CETP и PCSK9 [27], что в аспекте обсуждаемой проблемы усиливает интерес к бурно развивающейся и активно изучаемой группе липид-модифицирующих препаратов -ингибиторам PCSK9, с которой связывают большие надежды в области профилактики ССЗ и снижения резидуального риска.…”