Dalcetrapib
Simvastatin blunts the boost that dalcetrapib gives to cholesterol efflux from macrophages in vitro (Cardiovasc Drugs Ther 2015)
Original title: Statin-induced decrease in ATP-binding cassette transporter A1 expression via microRNA33 induction may counteract cholesterol efflux to high-density lipoprotein
In human THP-1 macrophages, 1 uM atorvastatin increased microRNA33 by 33% and decreased ABCA1 messenger RNA by 47%, both significant, linking statin treatment to reduced expression of the ABCA1 cholesterol transporter. In mouse J774A.1 macrophages, adding recombinant human CETP together with dalcetrapib augmented ABCA1-mediated cholesterol efflux from the cells. However, incremental concentrations of simvastatin decreased this efflux, and simvastatin at 1 uM or higher virtually eliminated both baseline HDL-ABCA1-mediated efflux and its augmentation by dalcetrapib. The findings suggest statin-induced microRNA33 upregulation may counteract the cholesterol efflux benefit of dalcetrapib and other HDL-raising agents.
Original abstract
Purpose: Cholesterol efflux from macrophages to HDL, measured in vitro, is augmented by treatment with agents which raise HDL cholesterol. In vitro, cholesterol depletion by statins is known to trigger a positive feedback on the cholesterol synthetic pathway via sterol regulatory element-binding protein (SREBP) transcription and changes in expression of SREBP regulated genes including microRNA33 (miR33) which is co-transcribed with SREBP and down-regulates ABCA1 and ABCG1 expression.
Methods: We investigated whether miR33 up-regulation, associated with SREBP increased transcription by statins, reduces macrophage ATP-binding cassette (ABC) transporter expression, thereby decreasing HDL-mediated cholesterol efflux at the tissue level.
Results: In human macrophage THP-1 cells cholesterol-loaded with acetylated LDL, incubation with 1 μM atorvastatin increased miR33 by 33 % (P < 0.05), and decreased ABCA1 messenger RNA (mRNA) and ABCG1 mRNA by 47 % (P < 0.05) and 27 % (NS), respectively. In J774A.1 mouse macrophage, labelled with 3H-cholesterol, ABCA1 mRNA and ABCA1-mediated cholesterol efflux were decreased by 1 μM statin: simvastatin > pitavastatin > atorvastatin > rosuvastatin > pravastatin. HDL incubated with rhCETP and dalcetrapib increased ABCA1-mediated cholesterol efflux. However, incremental simvastatin concentrations decreased cholesterol efflux to HDL treated with rhCETP and dalcetrapib. When HDL was incubated with rhCETP, addition of dalcetrapib augmented ABCA1-mediated cholesterol efflux from J774A.1 macrophages. However, simvastatin ≥1 μM virtually eliminated any HDL-ABCA1-mediated cholesterol efflux and any augmentation of that process by dalcetrapib.
Conclusions: In vitro, statins increase miR33 expression, and decrease ABCA1 expression and cholesterol efflux from peripheral tissues; this may counteract the potential benefit of agents that raise HDL and apolipoprotein A-I in statin-treated patients.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.