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

Arterioscler Thromb Vasc Biol. 2010 Jul;30(7):1439-45. doi: 10.1161/ATVBAHA.110.205153. Epub 2010 Apr 29.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Atherosclerosis / genetics
  • Atherosclerosis / metabolism*
  • Atherosclerosis / pathology
  • Cholesterol Ester Transfer Proteins / genetics
  • Cholesterol Ester Transfer Proteins / metabolism*
  • Cholesterol, HDL / blood*
  • Cholesterol, LDL / blood
  • Cholesterol, VLDL / blood
  • Disease Models, Animal
  • Female
  • Humans
  • Infertility, Female / genetics
  • Infertility, Female / 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*
  • Scavenger Receptors, Class B / genetics

Substances

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