RESUMO
The large HDL particles generated by administration of cholesteryl ester transfer protein inhibitors (CETPi) remain poorly characterized, despite their potential importance in the routing of cholesterol to the liver for excretion, which is the last step of the reverse cholesterol transport. Thus, the effects of the CETPi dalcetrapib and anacetrapib on HDL particle composition were studied in rabbits and humans. The association of rabbit HDL to the LDL receptor (LDLr) in vitro was also evaluated. New Zealand White rabbits receiving atorvastatin were treated with dalcetrapib or anacetrapib. A subset of patients from the dal-PLAQUE-2 study treated with dalcetrapib or placebo were also studied. In rabbits, dalcetrapib and anacetrapib increased HDL-C by more than 58% (P < 0.01) and in turn raised large apo E-containing HDL by 66% (P < 0.001) and 59% (P < 0.01), respectively. Additionally, HDL from CETPi-treated rabbits competed with human LDL for binding to the LDLr on HepG2 cells more than control HDL (P < 0.01). In humans, dalcetrapib increased concentrations of large HDL particles (+69%, P < 0.001) and apo B-depleted plasma apo E (+24%, P < 0.001), leading to the formation of apo E-containing HDL (+47%, P < 0.001) devoid of apo A-I. Overall, in rabbits and humans, CETPi increased large apo E-containing HDL particle concentration, which can interact with hepatic LDLr. The catabolism of these particles may depend on an adequate level of LDLr to contribute to reverse cholesterol transport.
Assuntos
Anticolesterolemiantes , Humanos , Coelhos , Animais , Anticolesterolemiantes/farmacologia , Anticolesterolemiantes/uso terapêutico , Colesterol/metabolismo , Apolipoproteínas E/metabolismo , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , HDL-ColesterolRESUMO
Background Macrophage cholesterol efflux to high-density lipoproteins ( HDLs ) is the first step of reverse cholesterol transport. The cholesterol efflux capacity ( CEC ) of HDL particles is a protective risk factor for coronary artery disease independent of HDL cholesterol levels. Using a genome-wide association study approach, we aimed to identify pathways that regulate CEC in humans. Methods and Results We measured CEC in 5293 French Canadians. We tested the genetic association between 4 CEC measures and genotypes at >9 million common autosomal DNA sequence variants. These analyses yielded 10 genome-wide significant signals ( P<6.25×10-9) representing 7 loci. Five of these loci harbor genes with important roles in lipid biology ( CETP , LIPC , LPL , APOA 1/C3/A4/A5, and APOE /C1/C2/C4). Except for the APOE /C1/C2/C4 variant ( rs141622900, P nonadjusted=1.0×10-11; P adjusted=8.8×10-9), the association signals disappear when correcting for HDL cholesterol and triglyceride levels. The additional 2 significant signals were near the PPP 1 CB / PLB 1 and RBFOX 3/ ENPP 7 genes. In secondary analyses, we considered candidate functional variants for 58 genes implicated in HDL biology, as well as 239 variants associated with blood lipid levels and/or coronary artery disease risk by genome-wide association study . These analyses identified 27 significant CEC associations, implicating 5 additional loci ( GCKR , LIPG , PLTP , PPARA , and TRIB 1). Conclusions Our genome-wide association study identified common genetic variation at the APOE /C1/C2/C4 locus as a major determinant of CEC that acts largely independently of HDL cholesterol. We predict that HDL -based therapies aiming at increasing CEC will be modulated by changes in the expression of apolipoproteins in this gene cluster.