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. Methods and 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 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^ko deficiency, including female infertility, reticulocytosis, thrombocytopenia, and impaired platelet aggregation. Conclusion-: 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.