Abstract 119: LCAT Activation in Combination with the CETP Inhibitor Anacetrapib Results in Enhanced Cholesterol Efflux and a Favorable Lipid Profile in Dyslipidemic Hamsters

Abstract

Lecithin cholesterol acyltransferase (LCAT) is a key enzyme involved in the metabolism of HDL. LCAT synthesizes cholesterol esters (CE) in plasma by catalyzing the transfer of the sn-2 fatty acid of phosphatidylcholine to cholesterol on HDL. The hydrophobic CE moves to the core of the HDL particle which results in HDL maturation and a progressive enlargement of the particle. Cholesteryl ester transfer protein (CETP) is a plasma protein that facilitates the transport of CE from HDL to ApoB-containing lipoproteins. CETP inhibition has been identified as a potential strategy for lowering LDL-c and raising HDL cholesterol levels for the treatment of CVD. The purpose of the current study was to test the hypothesis that CETP inhibition in the context of LCAT activation might yield an unfavorable lipoprotein profile (e.g. dysfunctional HDL). We measured plasma lipoprotein (via FPLC), particle size and ex vivo cholesterol efflux from dyslipidemic hamsters chronically treated with a small molecule LCAT activator (20 and 60 mpk/day) in the presence or absence of the CETP inhibitor anacetrapib (20mpk/day). As expected, anacetrapib significantly reduced LDL-c (-45%) and increased HDL-c (+63%) after chronic treatment. LCAT activation reduced TG (-35%) and increased HDL-c (+40-68%) but had no effect on LDL-c. Both treatments led to an apparent increase in HDL particle size as measured by FPLC. Additionally, LCAT activation showed a significant reduction in ABCA1-mediated efflux, presumably due to the resulting increase in HDL particle size. Animals that received both anacetrapib and the LCAT activator maintained the favorable lipid profile observed with single treatment. Moreover, HDL from hamsters treated with both LCATa and CETPi demonstrated a significant increase in ABCG1- and SRB1-mediated efflux whereas single treatment did not exhibit a measurable effect. We provide evidence that LCAT activation in the context of a CETP inhibitor, maintains a favorable lipid profile (lower LDL-c) and appear s to have a synergistic effect on cholesterol efflux.