Abstract 168: Effects of the CETP Inhibitor Anacetrapib on HDL3-to-HDL2 Transfer: Comparison of in Vitro and in Vivo Methodologies
Cholesteryl ester transfer protein (CETP) is a target for the treatment of dyslipidemia and coronary artery disease. In addition to the well-known effect of CETP to transfer CE from HDL to LDL and to VLDL, in vitro, CETP has been reported to transfer CE between small and large HDL particles (HDL2 and HDL3, respectively). We sought to understand how the CETP inhibitor anacetrapib (ANA) affects HDL3-to-HDL2 transfer under both in vitro and in vivo conditions. In vitro, ANA dose-dependently inhibited transfer of 3H-CE from total HDL to LDL (IC50 30nM), and from isolated HDL3 to HDL2 particles (IC50 200nM). In human CETP transgenic mice, animals treated with a single dose of ANA (100mg/kg) displayed 80% maximal reduction in plasma CETP activity and a 22% increase in total HDL cholesterol. In animals treated with either vehicle or ANA, 3H-CE-labeled HDL3 was injected intravenously and 3H-tracer was monitored in lipoprotein fractions following injection. Animals treated with ANA showed an increase in the amount 3H-tracer present in HDL2 compared to vehicle over time (20-70% increase across 6 hrs post 3H-CE-HDL3 injection, P<0.05 vs vehicle). The HDL2 CE pool was also increased with ANA treatment, and 3H-cholesterol flux into HDL2 was increased with ANA treatment when adjusted to the change in pool size (at 2 and 4 hrs post 3H-CE-HDL3 injection). No change in HDL2 3H-tracer was seen in C57BL6 mice (lacking CETP) treated with ANA. These results indicate that in contrast to in vitro findings, ANA increases flux of CE into HDL2 in vivo, a process which likely involves multiple pathways. Therefore, the in vitro phenomena of 1) HDL3-to-HDL2 transfer by CETP and 2) inhibition of this transfer by CETP inhibitors are not recapitulated in vivo. It is clear that in vivo approaches are necessary to understand the relevance of HDL3-to-HDL2 transfer in vivo, and to accurately study the effects of CETP inhibition on lipoprotein metabolism.
- © 2012 by American Heart Association, Inc.