title: Cholesteryl ester transfer protein expression partially attenuates the adverse effects of SR-BI receptor deficiency on cholesterol metabolism and atherosclerosis.
abstract: 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.
authors: INSERM UMR-S 939, Hôpital de la Pitié, F-75013, Paris, France.
authors: Majda
authors: M
authors: El Bouhassani
authors: Sophie
authors: S
authors: Gilibert
authors: Martine
authors: M
authors: Moreau
authors: Flora
authors: F
authors: Saint-Charles
authors: Morgan
authors: M
authors: Tréguier
authors: Francesco
authors: F
authors: Poti
authors: M John
authors: MJ
authors: Chapman
authors: Wilfried
authors: W
authors: Le Goff
authors: Philippe
authors: P
authors: Lesnik
authors: Thierry
authors: T
authors: Huby
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism*; D018955:CD36 Antigens / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism*; D053480:Cholesterol Ester Transfer Proteins / Q000096:biosynthesis*; D008076:Cholesterol, HDL / Q000378:metabolism; D004912:Erythrocytes / Q000166:cytology; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008099:Liver / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic
chemical_list: D018955:CD36 Antigens; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D002784:Cholesterol