Cholesteryl ester transfer protein expression partially attenuates the adverse effects of SR-BI receptor deficiency on cholesterol metabolism and atherosclerosis.

Scavenger receptor SR-BI significantly contributes to HDL cholesterol metabolism and atherogenesis in mice. However, the role of SR-BI may not be as pronounced in humans due to cholesteryl ester transfer protein (CETP) activity. To address the impact of CETP expression on the adverse effects associated with SR-BI deficiency, we cross-bred our SR-BI conditional knock-out mouse model with CETP transgenic mice. CETP almost completely restored the abnormal HDL-C distribution in SR-BI-deficient mice. However, it did not normalize the elevated plasma free to total cholesterol ratio characteristic of hepatic SR-BI deficiency. Red blood cell and platelet count abnormalities observed in mice liver deficient for SR-BI were partially restored by CETP, but the elevated erythrocyte cholesterol to phospholipid ratio remained unchanged. Complete deletion of SR-BI was associated with diminished adrenal cholesterol stores, whereas hepatic SR-BI deficiency resulted in a significant increase in adrenal gland cholesterol content. In both mouse models, CETP had no impact on adrenal cholesterol metabolism. In diet-induced atherosclerosis studies, hepatic SR-BI deficiency accelerated aortic lipid lesion formation in both CETP-expressing (4-fold) and non-CETP-expressing (8-fold) mice when compared with controls. Impaired macrophage to feces reverse cholesterol transport in mice deficient for SR-BI in liver, which was not corrected by CETP, most likely contributed by such an increase in atherosclerosis susceptibility. Finally, comparison of the atherosclerosis burden in SR-BI liver-deficient and fully deficient mice demonstrated that SR-BI exerted an atheroprotective activity in extra-hepatic tissues whether CETP was present or not. These findings support the contention that the SR-BI pathway contributes in unique ways to cholesterol metabolism and atherosclerosis susceptibility even in the presence of CETP.
AuthorsMajda El Bouhassani, Sophie Gilibert, Martine Moreau, Flora Saint-Charles, Morgan Tréguier, Francesco Poti, M John Chapman, Wilfried Le Goff, Philippe Lesnik, Thierry Huby
JournalThe Journal of biological chemistry (J Biol Chem) Vol. 286 Issue 19 Pg. 17227-38 (May 13 2011) ISSN: 1083-351X [Electronic] United States
PMID21454568 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antigens, CD36
  • Cholesterol Ester Transfer Proteins
  • Cholesterol, HDL
  • Cholesterol
  • Animals
  • Antigens, CD36 (metabolism)
  • Atherosclerosis (metabolism)
  • Cholesterol (metabolism)
  • Cholesterol Ester Transfer Proteins (biosynthesis)
  • Cholesterol, HDL (metabolism)
  • Erythrocytes (cytology)
  • Female
  • Gene Expression Regulation
  • Humans
  • Liver (metabolism)
  • Macrophages (metabolism)
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic

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