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.

Abstract

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(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.

• Authors: Reeni B Hildebrand, Bart Lammers, Illiana Meurs, Suzanne J A Korporaal, Willeke De Haan, Ying Zhao, J Kar Kruijt, Domenico Praticò, Alinda W M Schimmel, Adriaan G Holleboom, Menno Hoekstra, Jan Albert Kuivenhoven, Theo J C Van Berkel, Patrick C N Rensen, Miranda Van Eck
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 30 Issue 7 Pg. 1439-45 (Jul 2010) ISSN: 1524-4636 [Electronic] United States
• PMID: 20431066 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CETP protein, human
• Cholesterol Ester Transfer Proteins
• Cholesterol, HDL
• Cholesterol, LDL
• Cholesterol, VLDL
• Scarb1 protein, mouse
• Scavenger Receptors, Class B

Topics

• Animals
• Atherosclerosis (genetics, metabolism, pathology)
• Cholesterol Ester Transfer Proteins (genetics, metabolism)
• Cholesterol, HDL (blood)
• Cholesterol, LDL (blood)
• Cholesterol, VLDL (blood)
• Disease Models, Animal
• Female
• Humans
• Infertility, Female (genetics, metabolism)
• Kinetics
• Liver (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Transgenic
• Oxidative Stress
• Particle Size
• Platelet Aggregation (genetics)
• Platelet Count
• Reticulocytosis (genetics)
• Scavenger Receptors, Class B (deficiency, genetics)