Inhibition of Cholesteryl Ester Transfer Protein by Torcetrapib Modestly Increases Macrophage Cholesterol Efflux to HDL

Abstract

Objective-This study examines the effects of pharmacological inhibition of cholesteryl ester transfer protein (CETP) on the ability of high-density lipoprotein particles (HDL) to promote net cholesterol efflux from human THP-1 macrophage foam cells. Methods and Results-Two groups of 8 healthy, moderately hyperlipidemic subjects received the CETP inhibitor torcetrapib at 60 or 120 mg daily for 8 weeks. Torcetrapib increased HDL cholesterol levels in both groups by 50% and 60%, respectively. Compared with baseline, torcetrapib 60 mg daily increased HDL-mediated net cholesterol efflux from foam cells primarily by increasing HDL concentrations, whereas 120 mg daily torcetrapib increased cholesterol efflux both by increasing HDL concentration and by causing increased efflux at matched HDL concentrations. There was an increased content of lecithin:cholesterol acyltransferase (LCAT) and apolipoprotein E (apoE) in HDL-2 only at the 120 mg dose. ABCG1 activity was responsible for 40% to 50% of net cholesterol efflux to both control and T-HDL. Conclusions-These data indicate that inhibition of CETP by torcetrapib causes a modest increase in the ability of HDL to promote net cholesterol efflux at the 60 mg dose, and a more dramatic increase at the 120 mg dose in association with enhanced particle functionality. The HDL-mediated removal of excess free cholesterol (FC) from macrophage foam cells is thought to play a major role in the protection against the development of atherosclerosis. 2 However, current therapies for raising HDL are limited. Despite the favorable effects of statins on coronary heart disease, these agents have only modest effects on HDL-C levels. 3,4 Fibrates and niacin can raise HDL-C, but the increases are rarely Ͼ30% and only some of the fibrate trials have shown prevention of coronary events in patients with low HDL, and niacin is often not well tolerated. 5,6 Novel targets to raise HDL-C have emerged from the recent understanding of HDL synthesis, maturation, and catabolism. In humans, cholesteryl ester (CE) generated by the lecithin:cholesterol acyltransferase (LCAT) enzyme in HDL is transferred to apoB-lipoproteins by the cholesteryl ester transfer protein (CETP). CETP promotes the removal of cholesteryl ester (CE) from antiatherogenic HDL to atherogenic apoB-containing particles in exchange for triglycerides (TGs). 7 The marked increase in HDL cholesterol associated with human deficiency of CETP has suggested CETP inhibition as a potential strategy to treat atherosclerotic disease. 8,9 However, there has been concern that HDL particles accumulating in CETP deficiency might be dysfunctional. 10 We recently reported that large CE-rich HDL particles from 4 subjects with complete CETP deficiency (CETP-D) showed increased ability to promote cholesterol efflux from macrophage foam cells. 11 Central to this observation was the key role of LCAT and apolipoprotein E (apoE) present at high levels in CETP-D HDL driving net cholesterol efflux. Cholesterol efflux from cells to HDL can occur by passive diffusion...

Advanced glycation end-products (AGEs) and functionality of reverse cholesterol transport in patients with type 2 diabetes and in mouse models

“…This is consistent with several reports that smaller particles are more active in cholesterol efflux [40,41], and our recent finding of a correlation between the ability of plasma to support cholesterol efflux and CETP concentration [12]. It is, however, inconsistent with findings that functionality of HDL particles formed as a result of inhibition of CETP was not impaired [42,43]. The only chemical modification of HDL known to increase its capacity to support cholesterol efflux is oxidative tyrosilation [44]; this was not tested in this study.…”

Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy

“…210 In agreement with these observations, in male subjects with high-risk HDL-cholesterol levels (<40 mg/dl), 6-week combination treatment with torcetrapib (60 mg/day) and atorvastatin (10 mg/day) enhanced the capacity of large HDL2 particles to mediate cholesterol efflux via SR-BI and the delivery of HDL cholesteryl esters to hepatoma cells when compared to atorvastatin monotherapy. 211 Similar findings were reported from a study in patients with mixed hyperlipidemia where HDL2-mediated cholesterol efflux and uptake of HDL cholesteryl esters by hepatocytes were shown to be augmented by a 6-week period of combined torcetrapib/atorvastatin (60/10 mg/day) therapy.…”

El ácido nicotínico aumenta el transporte celular de colesterol de las lipoproteínas de alta densidad en pacientes con hipoalfalipoproteinemia

“…Un estudio reciente indica que el incremento en la capacidad de eflujo de colesterol celular inducido por plasma humano post-tratamiento con AN se debe principalmente al cambio en la concentración de HDL, sin modificaciones en la función de las partículas de HDL per se 36 . Sin embargo, nuevos fármacos en desarrollo aumentarían la capacidad funcional intrínseca de las partículas de HDL en el proceso de eflujo celular de colesterol 32,37 . A pesar de estos efectos favorables sobre las lipoproteínas HDL, así como en los niveles de colesterol LDL y triglicéridos, los estudios de intervención más recientes no demostraron un beneficio clínico adicional del uso de AN asociado a estatinas 21,38 .…”

“…A partir de plasma total, las lipoproteínas no HDL se precipitaron con polietilenglicol (PEG) 32 . El sobrenadante fue utilizado para la medición del tamaño de las partículas de HDL mediante electroforesis no denaturante 33 .…”

“…Después de la precipitación con PEG 32 , el sobrenadante del plasma que contenía las partículas de HDL se concentró mediante ultrafiltración para luego utilizarlo en los ensayos de transporte celular de colesterol. El contenido de apolipoproteína A-I asociado a HDL se midió mediante ELISA (kit comercial obtenido de ABCAM, Cambridge, MA, EUA).…”