TY - JOUR
T1 - 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
AU - Hildebrand, R. B.
AU - Lammers, B.
AU - Meurs, I.
AU - Korporaal, S. J. A.
AU - De Haan, W.
AU - Zhao, Y.
AU - Kruijt, J. K.
AU - Praticò, D.
AU - Schimmel, A. W. M.
AU - Holleboom, A. G.
AU - Hoekstra, M.
AU - Kuivenhoven, J. A.
AU - van Berkel, T. J. C.
AU - Rensen, P. C. N.
AU - van Eck, M.
PY - 2010
Y1 - 2010
N2 - 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. Methods and Results-Expression of human CETP in SR-BIKO 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-BIKO mice. Unexpectedly, expression of CETP in SR-BIKO 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. Conclusion-CETP restores HDL-C levels in SR-BIKO 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. (Arterioscler Thromb Vasc Biol. 2010; 30: 1439-1445.)
AB - 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. Methods and Results-Expression of human CETP in SR-BIKO 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-BIKO mice. Unexpectedly, expression of CETP in SR-BIKO 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. Conclusion-CETP restores HDL-C levels in SR-BIKO 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. (Arterioscler Thromb Vasc Biol. 2010; 30: 1439-1445.)
U2 - https://doi.org/10.1161/ATVBAHA.110.205153
DO - https://doi.org/10.1161/ATVBAHA.110.205153
M3 - Article
C2 - 20431066
SN - 1079-5642
VL - 30
SP - 1439-U419
JO - Arteriosclerosis, Thrombosis, and Vascular Biology
JF - Arteriosclerosis, Thrombosis, and Vascular Biology
IS - 7
ER -