Restoration of high-density lipoprotein levels by cholesteryl ester transfer protein expression in scavenger receptor class B type I (SR-BI) knockout mice does not normalize pathologies associated with SR-BI deficiency.
OBJECTIVE
Disruption of scavenger receptor class B type I (SR-BI) in mice impairs high-density lipoprotein (HDL)-cholesterol (HDL-C) delivery to the liver and induces susceptibility to atherosclerosis. In this study, it was investigated whether introduction of cholesteryl ester transfer protein (CETP) can normalize HDL-C transport to the liver and reduce atherosclerosis in SR-BI knockout (KO) mice.


RESULTS
Expression of human CETP in SR-BI(KO) mice resulted in decreased plasma HDL-C levels, both on chow diet (1.8-fold, P<0.001) and on challenge with Western-type diet (1.6-fold, P<0.01). Furthermore, the presence of CETP partially normalized the abnormally large HDL particles observed in SR-BI(KO) mice. Unexpectedly, expression of CETP in SR-BI(KO) mice did not reduce atherosclerotic lesion development, probably because of consequences of SR-BI deficiency, including the persistence of higher VLDL-cholesterol (VLDL-C) levels, unchanged elevated free cholesterol/total cholesterol ratio, and the increased oxidative status of the animals. In addition, CETP expression did not normalize other characteristics of SR-BI deficiency, including female infertility, reticulocytosis, thrombocytopenia, and impaired platelet aggregation.


CONCLUSIONS
CETP restores HDL-C levels in SR-BI(KO) mice, but it does not change the susceptibility to atherosclerosis and other typical characteristics that are associated with SR-BI disruption. This may indicate that the pathophysiology of SR-BI deficiency is not a direct consequence of changes in the HDL pool.
Hildebrand
Reeni B
RB
Leiden/Amsterdam Center for Drug Research, Division of Biopharmaceutics, Leiden, the Netherlands.
Lammers
Bart
B
Meurs
Illiana
I
Korporaal
Suzanne J A
SJ
De Haan
Willeke
W
Zhao
Ying
Y
Kruijt
J Kar
JK
Praticò
Domenico
D
Schimmel
Alinda W M
AW
Holleboom
Adriaan G
AG
Hoekstra
Menno
M
Kuivenhoven
Jan Albert
JA
Van Berkel
Theo J C
TJ
Rensen
Patrick C N
PC
Van Eck
Miranda
M
D000818:Animals; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D053480:Cholesterol Ester Transfer Proteins / Q000235:genetics / Q000378:metabolism*; D008076:Cholesterol, HDL / Q000097:blood*; D008078:Cholesterol, LDL / Q000097:blood; D015243:Cholesterol, VLDL / Q000097:blood; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007247:Infertility, Female / Q000235:genetics / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018384:Oxidative Stress; D010316:Particle Size; D010974:Platelet Aggregation / Q000235:genetics; D010976:Platelet Count; D045262:Reticulocytosis / Q000235:genetics; D051122:Scavenger Receptors, Class B / Q000172:deficiency* / Q000235:genetics
C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D015243:Cholesterol, VLDL; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B