Knockdown expression and hepatic deficiency reveal an atheroprotective role for SR-BI in liver and peripheral tissues
Thierry Huby, … , M. John Chapman, Philippe Lesnik
Thierry Huby, … , M. John Chapman, Philippe Lesnik
Published October 2, 2006
Citation Information: J Clin Invest. 2006;116(10):2767-2776. https://doi.org/10.1172/JCI26893.
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Research Article Cardiology

Knockdown expression and hepatic deficiency reveal an atheroprotective role for SR-BI in liver and peripheral tissues

Abstract

Scavenger receptor SR-BI has been implicated in HDL-dependent atheroprotective mechanisms. We report the generation of an SR-BI conditional knockout mouse model in which SR-BI gene targeting by loxP site insertion produced a hypomorphic allele (hypomSR-BI). Attenuated SR-BI expression in hypomSR-BI mice resulted in 2-fold elevation in plasma total cholesterol (TC) levels. Cre-mediated SR-BI gene inactivation of the hypomorphic SR-BI allele in hepatocytes (hypomSR-BI–KOliver) was associated with high plasma TC concentrations, increased plasma free cholesterol/TC (FC/TC) ratio, and a lipoprotein-cholesterol profile typical of SR-BI–/– mice. Plasma TC levels were increased 2-fold in hypomSR-BI and control mice fed an atherogenic diet, whereas hypomSR-BI–KOliver and SR-BI–/– mice developed severe hypercholesterolemia due to accumulation of FC-rich, VLDL-sized particles. Atherosclerosis in hypomSR-BI mice was enhanced (2.5-fold) compared with that in controls, but to a much lower degree than in hypomSR-BI–KOliver (32-fold) and SR-BI–/– (48-fold) mice. The latter models did not differ in either plasma lipid levels or in the capacity of VLDL-sized lipoproteins to induce macrophage cholesterol loading. However, reduced atherosclerosis in hypomSR-BI–KOliver mice was associated with decreased lesional macrophage content as compared with that in SR-BI–/– mice. These data imply that, in addition to its major atheroprotective role in liver, SR-BI may exert an antiatherogenic role in extrahepatic tissues.

Authors

Thierry Huby, Chantal Doucet, Christiane Dachet, Betty Ouzilleau, Yukihiko Ueda, Veena Afzal, Edward Rubin, M. John Chapman, Philippe Lesnik

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Figure 5

Quantification of atherosclerosis and inflammation in mice fed the atherogenic HFC diet.

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Quantification of atherosclerosis and inflammation in mice fed the ather...
(A) Degree of atherosclerosis in the aortic root area. Lipid deposits were visualized by oil red O staining of aortic root sections. Each symbol represents the mean lesion area in a single mouse. The horizontal bar indicates the mean value for the group. Statistically significant differences between groups are indicated. (B) Quantification of lipid lesions in the aortic arch and thoracic aorta of hypomSR-BI–KOliver and SR-BI–/– mice. Each symbol represents the percentage of the aorta stained for lipid with Sudan IV in a single mouse. The horizontal bar indicates the mean value for each group. Statistically significant differences between the 2 groups are indicated. No lipid staining could be detected in controls and in hypomSR-BI mice. (C) Increased monocyte/macrophage accumulation in atherosclerotic lesions of SR-BI–/– mice as compared with hypomSR-BI–KOliver mice. Aortic atherosclerotic lesions were immunostained for monocyte/macrophage CD68 antigen (upper panels; nuclei are visualized in blue with DAPI staining) and subsequently processed for lipid staining with oil red O (lower panels). (D) The surface ratio of CD68+ staining to oil red O–positive staining was calculated for both groups. Values represent the mean ± SD of 6 size-matched lesions analyzed per group. (E) IL-6 plasma levels in HFC diet–fed mice. #P < 0.03 compared with controls; *P < 0.05 compared with hypomSR-BI mice; †P < 0.05 compared with hypomSR-BI–KOliver mice. NS, not statistically different compared with values for controls.