The ability of plasma to stimulate fibroblast cholesterol efflux is associated with the -629C-->A cholesteryl ester transfer protein promoter polymorphism: role of lecithin: cholesterol acyltransferase activity.
A recent population-based study showed that cholesteryl ester transfer protein (CETP) gene variations, which relate to lower plasma CETP, may predict increased cardiovascular risk, in spite of higher HDL cholesterol. Among other functions, CETP activity contributes to cellular cholesterol efflux, an early step in the anti-atherogenic reverse cholesterol transport (RCT) process. We hypothesized that cellular cholesterol efflux stimulating capacity of plasma could be associated with CETP gene variation. In this study, we tested the extent to which the ability of plasma to promote cholesterol efflux from cultured human fibroblasts is associated with CETP gene variation. In 223 men, the -629C-->A CETP promoter polymorphism, plasma lipids, CETP mass, cholesteryl ester transfer (CET), lecithin:cholesterol acyltransferase (LCAT) activity and the ability of plasma to promote cholesterol efflux from human skin fibroblasts, obtained from a single normolipidemic donor, were determined. In -629CC homozygotes (n=52), cholesterol efflux, plasma CETP mass, CET and LCAT activity were higher, whereas HDL cholesterol was lower compared to -629 AA homozygotes (n=62) and -629CA+AA carriers (n=171) (P<0.05 to P<0.001). Univariate correlation analysis showed that cellular cholesterol efflux was related to CETP genotype (P=0.04), plasma CET (P<0.05), LCAT activity (P<0.001) and apo A-I (P<0.05). Multiple linear regression analysis confirmed the independent association of cellular cholesterol efflux to plasma with CETP genotype. In conclusion, an association of cellular cholesterol efflux with the -629C-->A CETP polymorphism, possibly also involving LCAT activity, could provide a mechanism explaining why CETP gene variation, which relates to lower plasma CETP, does not confer diminished cardiovascular risk.
Borggreve
S E
SE
Department of Endocrinology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.
de Vries
R
R
Dallinga-Thie
G M
GM
Wolffenbuttel
B H R
BH
Groen
A K
AK
van Tol
A
A
Dullaart
R P F
RP
D000225:Adenine / Q000378:metabolism; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D053480:Cholesterol Ester Transfer Proteins / Q000235:genetics / Q000378:metabolism*; D003596:Cytosine / Q000378:metabolism; D005347:Fibroblasts / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D008297:Male; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000378:metabolism*; D010949:Plasma; D011110:Polymorphism, Genetic / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*
D053480:Cholesterol Ester Transfer Proteins; D003596:Cytosine; D002784:Cholesterol; D007862:Phosphatidylcholine-Sterol O-Acyltransferase; D000225:Adenine